This Note argues that WTO member nations should use bilateral and regional trade agreements to solve key issues facing the Doha Round negotiations in order to lower trade barriers and foster a climate of free trade necessary to resurrect the stalled Doha Round. Several problems including the WTO's lack of authority to enforce DSU decisions, protectionist trade measures, and the single undertaking have threatened the long term stability of the WTO's multilateral trading system. However, if bilateral and regional trade agreements were used to solve key issues, much like they were used by the United States in the 1970s, WTO member nations would have a legitimate opportunity to end the Doha Round stalemate once and for all.


BACKGROUND: Acute low back pain (LBP) is a common condition that is encountered by many physicians with varied treatments instituted in its management. Ultrasound physiotherapy is a common modality used in its management, although its effectiveness and its role in management of acute LBP is not well known.
 METHODS: A randomised controlled trial was conducted to compare the effect of the addition of ultrasound therapy to a defined analgesia protocol in patients presenting with acute LBP at the Aga Khan University Hospital, Nairobi. The main outcomes were reduction in disability and pain which were evaluated using the mean change in Oswestry Disability Index (ODI) and Visual Analogue Scale (VAS) score for pain, respectively. Patients were followed up for a minimum of four weeks with assessment using the ODI and VAS at weekly clinic visits.
RESULTS:Seventy-four patients were included in the study. Thirty-six patients were allocated to the analgesia with additional ultrasound group and 38 to the analgesia alone group. The Minimal Clinically Important Difference (MCID) of 10% points at four weeks after initiation of treatment was achieved in the ultrasound group but not in the analgesia only group. This difference was not statistically significant though, 10.35% vs 8.44%; p=0.36. There was no difference in the mean change in the ODI score between the two groups at any of the four follow-up visits after initiation of treatment. Mean difference in change of ODI (95% confidence interval) was -3.2(-7.0 to 0.6) after the first week, 2.96(-1.3 to 7.2) after the second and 1.90(-2.3 to 6.1) after the third week, p=0.36, 0.17 and 0.096 respectively. There was also no difference detected in the mean change of VAS score between the two groups at the first and fourth visit. Mean difference in VAS between the first and fourth weeks was 0.2 with a 95% confidence of -0.85 to 1.2 (p=0.72).
 CONCLUSION: The addition of ultrasound therapy to the treatment of acute LBP improved patient outcomes as assessed by an MCID of a disability index, but which was not statistically significant. No outcome difference was noted in the two groups using the VAS pain score.


In images of complex scenes, objects are often occluding each other which makes perception tasks such as object detection and tracking, or robotic control tasks such as planning, challenging. To facilitate downstream tasks, it is thus important to reason about the full extent of objects, i.e., seeing behind occlusion, typically referred to as amodal instance completion. In this paper, we propose a variational generative framework for amodal completion, referred to as Amodal-VAE, which does not require any amodal labels at training time, as it is able to utilize widely available object instance masks. We showcase our approach on the downstream task of scene editing where the user is presented with interactive tools to complete and erase objects in photographs. Experiments on complex street scenes demonstrate state-of-the-art performance in amodal mask completion, and showcase high quality scene editing results. Interestingly, a user study shows that humans prefer object completions inferred by our model to the human-labeled ones.


The narrow steeply dipping strata bound sediment hosted copper deposit, Nussir, located in Kvalsund community, Finmark, Norway, have been subject to an assessment of underground mining. Resources classified as Indicated, within a 0,9%Cu cut-off limit have been identified as suitable for sublevel open stoping mining method, accessed by 590m long tunnel from fjord, a 2000m haulage tunnel in footwall progressing westward along strike and two individual ramps separated by 1280m along strike. Stopes are dimensioned 40m long and 3m wide on average with 62m and 102m height, with two and three sublevel drifts respectively. The stoping layout's stability rely on 5m rib pillars, 8m sill pillars and yielding pillars in stope centre, calculated from geotechnical data and empirical design methods. The retreating mining method implies narrow ore mining practices, utilizing small mechanized equipment, developing drifts along strike in two directions from ramp. Stopes are planned produced by up-and-downward drilling of 20m holes carefully planned within the narrow mineralisation, blasted carefully to avoid dilution from stope walls. Dilution causing head grade drop and obtaining of available treatment capacity, must be expected and dealt with. Cable bolting of the on average 60⁰ dipping hangwall from drifts, is necessary to avoid caving. Dillution, estimated as dependent on mineralisation thickness, have been added to the stope resources obtained by wireframe evaluation of block model in DataMine. A planned production schedule of development tunnels and stoping, producing 3Mt in 6 years time, is the basis for a financial model with 245million NOK in capital expenditures and 177NOK/tonne in mining costs. The planned mining operation gives a Net Present value of 32million NOK. Project value is considered highly sensitive to changes in copper price, mining costs and copper grade.


Fish embryos are excellent models for studies aimed at the understanding of toxic mechanisms and the indication of possible acute and chronic effects. For the past 3 years, an Arabian killifish fish embryo test (FET) has been developed in our laboratory as a routine ecotoxicological test for risk assessment of potential contaminants in the Arabian Gulf around Qatar. To further explore the applicability of the killifish embryos as a model for the Arabian Gulf conditions, we tested the toxicity of heavy metals such as zinc and copper using Arabian seawater conditions. A breeding stock of sexually mature killifish, variable in age, was used for egg production. Eggs from several females were pooled and placed in salt water for fertilization. Embryos were examined under a dissecting microscope and viable embryos that were less than 6 h were selected. Eggs were distributed in replicates by stratified random assortment into 24 well plates. Observation was performed in 48-hour increments (± 2 hours). Endpoints included: coagulated eggs, absence of heartbeat, tail deformity and delayed hatching. Literature review was compiled for fish species that have been recommended for ELS toxicity testing. The data collected was then used for comparison to the current findings and the sensitivity was then extrapolated for the killifish embryos. Past findings indicate that toxicity is reduced in high salinity waters. This was confirmed in this study where at salinity 40 psu there were no apparent effects on embryos for any concentration tested and all embryos hatched at expected duration. When salinity was reduced from 40 to 20 psu, metal toxicity increased significantly (P > 0.05). Examination of the existing literature on acute Zn and Cu toxicity to fish and larvae showed similar results to the findings in this study using killifish embryos. The findings further support the use of killifish embryos as indicator organisms for environmental risk assessments of Qatari waters. Benefits include; sensitivity to wide range of substances and conditions, animal alternative, ease of fish breeding, clarity of the embryos, reduced sample size, reduced waste generation and shorter study duration. By expanding this test to evaluate its sensitivity towards other potential contaminants in the Arabian Gulf, we will further enhance the potential of killifish embryos to be adopted as a model species in marine ecotoxicology and risk assessment in this region.


SARS-CoV-2 is continually evolving, with more contagious mutations spreading rapidly. Using in vitro evolution to affinity maturate the receptor-binding domain (RBD) of the spike protein towards ACE2 resulted in the more contagious mutations, S477N, E484K, and N501Y, to be among the first selected, explaining the convergent evolution of the "European" (20E-EU1), "British" (501.V1),"South African" (501.V2), and ''Brazilian" variants (501.V3). Plotting the binding affinity to ACE2 of all RBD mutations against their incidence in the population shows a strong correlation between the two. Further in vitro evolution enhancing binding by 600-fold provides guidelines towards potentially new evolving mutations with even higher infectivity. For example, Q498R epistatic to N501Y. Nevertheless, the high-affinity RBD is also an efficient drug, inhibiting SARS-CoV-2 infection. The 2.9Å Cryo-EM structure of the high-affinity complex, including all rapidly spreading mutations, provides a structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.


This paper utilizes a large cross-section of data sets such as the ILOSTAT, NSSO Quinquennial Employment and Unemployment Survey, Labour Bureau Annual Employment and Unemployment Survey, National Family Health Survey and CMIE Consumer Pyramid Household Survey to comment on the falling female labour force participation rates in India. It is found that not only has there been a fall in the female labour force participation rates, but the size of the total female labour force has also shrunk in recent years. Besides presenting a series of demand and supply side factors that might possibly explain this trend, it aims to look at it particularly in conjunction with education and provide a commentary on the same. It is proposed that prevailing social norms and patriarchy hinders the participation of women in the economy despite high levels of education. Bivariate and multivariate analyses is conducted on state level cross-sectional data and it is found that patriarchy is indicative of the large proportion of women out of the labour force at high levels of education. It is concluded that education in the current form alone might not be sufficient to spur growth in female labour force participation rates in India. Government schemes must target the fundamental cultural and social forces that shape patriarchy. These coupled with policies that simultaneously address some of the other demand and supply side constraints will go a long way in bolstering the participation of women in the economy.


The results of the present article extend the results of [Pa]. The main result of the article is Theorem 1.1 below. The proof is based on a moving lemma from [LM], a recent improvement due to O. Gabber of de Jong's alteration theorem, and the main theorem of [PR]. A purity theorem for quadratic spaces is proved as well in the same generality as Theorem 1.1, provided that R is local. It generalizes the main purity result from [OP] and it is used to prove the main result in [ChP].


A novel series of solution-processable aromatic polyimide membranes with trimethyl-substituted triphenylamine units for gas separation were prepared from a newly synthesized dianhydride, N,N-bis(3,4-dicarboxyphenyl)-2,4,6-trimethylaniline dianhydride (2), and various diamines via one-step high-temperature solution polymerization. The corresponding polyimides derived from structurally related dianhydrides with different pendant groups such as phenyl, naphthyl, and pyrenyl moieties were also prepared for comparison. All the polyimides were readily soluble in many polar solvents and showed useful levels of thermal stability associated with high glass-transition temperatures (Tg, 324–455 °C) and high char yields (higher than 58% at 800 °C in nitrogen). The noncoplanar triphenylamine-containing polyimides IV with pendant trimethyl-phenyl moieties exhibited an effective improvement of gas permeability with a minor decrease in permselectivity.


The predator-prey interactions in the offshore food web of Lake Superior have been well documented, but the sensory systems mediating these interactions remain unknown. The deepwater sculpin, (Myoxocephalus thompsoni), siscowet (Salvelinus namaycush siscowet), and kiyi (Coregonus kiyi) inhabit low light level environments. To investigate the potential role of vision in predator-prey interactions, electroretinography was used to determine visual sensitivity for each species. Spectral sensitivity curves revealed peak sensitivity at 525 nm for each species which closely corresponds to the prevalent downwelling light spectrum at depth. To determine if sufficient light was available to mediate predator-prey interactions, visual sensitivity was correlated with the intensity of downwelling light in Lake Superior to construct visual depth profiles for each species. Sufficient daytime irradiance exists for visual interactions to approximately 325 m for siscowet and kiyi and 355 m for the deepwater sculpin during summer months. Under full moon conditions, sufficient irradiance exists to elicit ERG response to light available at approximately 30 m for the siscowet and kiyi and 45 m for the deepwater sculpin. Visual interactions are therefore possible at the depths and times when these organisms overlap in the water column indicating that vision may play a far greater role at depth in deep freshwater lakes than had been previously documented.


Much of clinical data is free text, which is challenging to use together with machine learning, visualization tools, and clinical decision rules. In this paper, we compare supervised and unsupervised dimensionality reduction techniques, including the recently proposed sLDA and MedLDA algorithms, on clinical texts. We evaluate each dimension-ality reduction method by using them as features for two important prediction problems that arise in emergency departments: predicting whether a patient has an infection, which can progress to sepsis, and predicting the likelihood of a patient being admitted to the Intensive Care Unit (used for risk stratification). We find that, on this data, existing supervised dimensionality reduction techniques perform better than unsupervised techniques only for very low dimensional representations .


Glaucoma is a disease causing damage to the optic nerve head due to a too high eye pressure. This damage will lead to visual field loss, and finally to blindness. The current surgery treatment improves the drainage of the eye fluid by introducing a draining device. The problem is that one cannot predict in advance the value of the eye pressure after surgery and it cannot be adjusted to the optimum eye pressure of the patient, after surgery. A continuous adjustment of the eye pressure would simplify and improve the present treatment. The goal of this research is to develop a micromachined actuator that could be combined with existing glaucoma implants. This microactuator, that acts as an active valve would allow the eye pressure to be adjusted continuously around a desired value. The actuator can be used to adjust the eye fluid pressure, for patients suffering from glaucoma, by changing the fluid resistance of an implanted flow channel due to deflection of an integrated membrane. To obtain a low energy consumption and to have the possibility of discontinuous supply of power, it was opted for electrochemical actuation, which is based on the electrolysis of an aqueous electrolyte solution. The reversible electrochemical reactions, which are driven by an external current source, lead to gas evolution or gas reduction (depending on the direction of the current). In a closed system the corresponding gas pressure rise or drop is used to change the deflection of a flexible membrane, which in turn can close or open a liquid channel. If such an electrolytic cell is operated under open-circuit conditions, the pressure and thus the deflection state of the diaphragm will, ideally, be maintained. This means that no energy is required to maintain the state of the valve. It has been proven that relatively large pressures (up to tens of bar) and large deflections can be reached in this electrochemical actuator with a low energy consumption. The complete microactuator system should have a maximum size of 5x5x2 mm3 and will be powered by wireless energy supply. The energy is transmitted by using a pair of coils which are inductively coupled; one coil is implanted and the other one is outside the body.


Liberia is a small country on the west coast of Africa, lying within the monsoon tropical forest belt and recording some of the highest annual precipitation rates of any place on earth. Early agriculturalists adapted rain-fed rice to the forest clearings and the alternating wet and dry seasons, with women providing the majority of the labor in food production. Regional trade routes have historically linked this area with savannah polities to the north and west, exchanging products such as gold, salt, hides, and dye woods across multiple environmental and climatic zones. Europeans who arrived by ship beginning in the 1460s redirected some of this trade toward the coast, making access to the sea strategically important and creating a new source of employment for male laborers as longshoremen and mariners. In the early 19th century, the coast became a site of settlement for free people of color from the United States, and Liberia declared its independence as a republic in 1847.
 As in other West African countries, documentary sources on women's lives are minimal, yet Liberia stands out for the impressive number of women who have achieved international distinction in the 20th and 21st centuries. This small country of fewer than five million people has produced the first woman president of an African national university, the first African woman to chair the United Nations General Assembly, and the first woman elected president of an African country. Liberian women in the past and the present have used their position as breadwinners, as mothers, as community leaders, and as ritual specialists to shape events and assert authority over others. In the early 21st century, they have become known especially for their success in peacemaking, resulting in two Nobel Peace Prize winners in 2011. Comparing the careers of some prominent Liberian women over the decades shows that willingness to reach across lines of ethnicity and language and the ability to coordinate resources from both rural and urban areas have been key factors in explaining this success.


Abstract Advances in the application of stable isotopes have allowed the quantitative evaluation of previously cryptic ecological processes. In particular, researchers have utilized the predictable spatial patterning in natural abundance of isotopes to better understand animal dispersal and migration. However, quantifying dispersal via natural abundance alone has proven to be of limited utility for species exhibiting short- or mid-distance dispersal events, including most mammalian species. In previous experimental work, we demonstrated that consumption of 1 dose of isotopically enriched baits elicited a distinct "mark" in hair of captive martens (Martes spp.). Herein, we report findings from a field test of our isotopic enrichment approach to mark free-ranging animals and quantify dispersal of martens across forest stands at sites in southeastern Alaska and northern British Columbia. In the field, we supplemented bait used in single-capture hair traps with the amino acid glycine artificially enriched in 2H, 13C, or 15N. By applying unique combinations of artificially enriched isotopic markers within discrete forest stands, the isotopic signature of collected hair reflected the forest patch where the individual originated. From our isotopic marks, we were able to infer dispersal events between forested stands and, thus, estimate rates and approximate dispersal distances. Our findings demonstrate that isotopic enrichment can be a cost-effective method to mark the hair of midsized mammals for the quantification of dispersal.


From the moment they are constructed, rubble-mound breakwaters are due to be damaged someway. Accepting damage is one of the basic principles of mound breakwaters design. Damage can take place either gradually in time or catastrophically after a major storm. Gradual deterioration of the armour layers or foundation may be unnoticed without the aid of a monitoring program and may ultimately result in the failure of the armour layer, in slope instability or in unacceptable large settlements. By comparison of measurements of the state of the structure at a number of points in time, a monitoring program allows these changes to be identified at an early stage, thus enabling the appropriate maintenance action to be carried out. Several structural and environmental monitoring techniques are used in Zeebrugge. Three structural monitoring techniques are presented in more detail. The emerged armour units of the Zeebrugge breakwaters are monitored using aerial remote sensing. An observation flight is made once a year. Each time, the position of over 15,000 armour units is very accurately retrieved by stereometric digitization. The coordinates are stored in a computer database. Several types of data visualization have been developed for a fast and efficient evaluation of the survey results. For the underwater inspections of the breakwater two acoustic techniques are used. On the one hand, digital side-scan sonar recordings are used to produce highresolution and contrasting images of the breakwaters'underwater armour layer. Such images allowed the detection of structure modifications in the breakwaters'toe protection. On the other hand, high-frequent multibeam echosoundings, allow to exactly quantify the actual underwater armour unit movements in time. 1) Ministry of Flemish Community, Coastal Division, Vrijhavenstraat 3, B-8400 Ostend, Belgium. 2) Civil Engineering Dept., University of Ghent, HAECON NV, Technologiepark9, B-9052 Ghent, Belgium.


An important domain for autonomic systems is the area of ubiquitous computing: users are increasingly surrounded by technology that is heterogeneous, pervasive, and variable. In this paper we describe our work in developing self-adapting computing infrastructure that automates the configuration and reconfiguration of such environments. Focusing on the engineering issues of self-adaptation in the presence of heterogeneous platforms, legacy applications, mobile users, and resource variable environments, we describe a new approach based on the following key ideas: 1) explicit representation of user tasks allows us to determine what service qualities are required of a given configuration; 2) decoupling task and preference specification from the lower level mechanisms that carry out those preferences provides a clean engineering separation of concerns between what is needed and how it is carried out; and 3) efficient algorithms allow us to calculate in real time near-optimal resource allocations and reallocations for a given task


Purpose - – Expatriate workforces are growing as a result of globalisation and the considerable cost associated with expatriation is a strong incentive to identify which employees are most likely to adjust to the host nation. One area relevant to cross-cultural adjustment is interpersonal needs. The theory of fundamental interpersonal relations orientation as measured by the fundamental interpersonal relations orientation-behaviour (FIRO-B) may offer insights as to the relationship between interpersonal needs and cross-cultural adjustment. The paper aims to discuss these issues. Design/methodology/approach - – In total, 180 paper and pencil measures of the FIRO-B and expatriate adjustment scales (general, work, and interaction) were distributed via informed international associates and convenience and snowball sampling. In total, 112 expatriates from the UK (44 percent), South Africa (22 percent), India (20 percent), and other nations (14 percent) returned completed questionnaires. Findings - – Expatriates with higher levels of wanted affection were higher on all subscales of cross-cultural adjustment. Those who wanted and expressed the need for inclusion were significantly higher in interaction adjustment while those who expressed and wanted control were less adjusted to work. Research limitations/implications - – The cross-sectional design limits the extent to which these findings can be interpreted as causal and the small sample size may limit the generalisability of the findings and common method via self-report may also inflate inter-relationship. However, the underlying theoretical premise would strongly support the hypothesised directional relationships in the normal population. A number of factors beyond the scope of this study may play a fundamental role including cultural similarity. Practical implications - – Whilst not predictive, and acknowledging that environmental factors may vary, these results give an indication that interpersonal needs are related to successful adjustment in expatriates. As such these findings could be used to help inform the recruitment and training of expatriates in areas of interpersonal interaction taking into consideration intrapersonal needs. Originality/value - – No study to date has explored the inter-relationship between the interpersonal needs and expatriate adjustment. This is the first paper to do so and identify that there is a significant association between expatriate's motives for interaction and their level of cross-cultural adjustment.


Background Emtricitabine/rilpivirine/tenofovir (FTC/RPV/TDF) was initially approved for the treatment of human immunodeficiency virus type 1 in treatment-naïve adult patients with a viral load ≤ 100,000 copies/mL. Purpose To evaluate the effectiveness and safety of off-label use of FTC/RPV/TDF after this drug was included in our hospital's formulary. Material and methods This retrospective observational study included all patients for whom FTC/RPV/TDFwasdispensed from our university hospital's pharmacy department from October 2013 to March 2014. We collected the following information from medical records: age, sex, drug history, prior antiretroviral treatment, reasons for treatment change, viral load, CD4 count and atherogenic index at the start and end of the study period, adherence, side effects and reasons for discontinuing treatment. Results We included 19 consecutive patients (14 men and 5 women; mean age, 44.7 years). All patients were treatment-experienced; 78% had previously been treated with efavirenz/emtricitabine/tenofovir. The most frequent reasons for changing antiretroviral treatment were hyperlipidaemia (38.8%) and interaction with methadone (22%). The viral load was <50 copies/mL in 10 patients. The mean CD4 count was 634.6/mm3 at baseline and 596.4/mm3 at study end (normal range: 450–1400/mm3). The mean atherogenic index, recorded in 16 patients, was 4.5 (normal range: 0–5) at both the beginning and end of the study. No side effects were documented. Two patients discontinued treatment for reasons unrelated to the antiretroviral (pregnancy and death). We detected no non-adherence to the treatment. Conclusion In our centre, changing treatment to FTC/RPV/TDF is mostly due to side effects and interactions in the previous treatment. Although our preliminary data preclude definitive conclusions, FTC/RPV/TDF seems safe and effective. References and/or Acknowledgements Molina JM, et al. Lancet 2011;378:238–46 Nelson M, et al. Multicentre Open-Label Study of Switching from Atripla to Eviplera for Possible Efavirenz Associated CNS Toxicity. 2013 Enferm Infecc Microbiol Clin 2013;31:604–13 No conflict of interest.


Various marine and estuarine species utilize chemical cues during settlement. We inves- tigated responses by megalopae and first juvenile (J1) blue crabs to common Chesapeake Bay sub- strates in mesocosm and field experiments. Mesocosm trials examined responses of megalopae or J1 crabs to sand, marsh mud, live oysters Crassostrea virginica, sun-bleached oyster shell, eel grass Zos- tera marina and artificial seagrass in replicate 160 l tanks. Either 10 megalopae or J1 crabs isolated in each of 6 substrates were allowed total access after acclimation to test the null hypothesis of equal distribution among substrates after 13 h. Thirty-five percent of megalopae were recovered from Z. marina, with the remaining substrates containing fewer than half that many. In contrast, 30 % of J1 crabs (with only 17% recovered from Z. marina) were found in live C. virginica. A field experiment quantified responses of ingressing megalopae to Z. marina, marsh mud, and C. virginica. Overnight settlement was significantly higher in Z. marina (x = 3.3 ind.; 60% of total) when compared to mud (x = 0.9; 16 %) or C. virginica (x = 1.3; 24 %). Likewise, J1 crabs were significantly more numerous in Z. marina (x = 3.7 ind.; 55% of total) than in C. virginica (x = 1.8; 27 %) and mud (x = 1.2; 18 %). J1 crab distribution in field plots likely reflected habitat selection by megalopae; laboratory results were equivocal and probably due to artifacts associated with density-dependent agonism. The initial non-random distribution of blue crabs in Chesapeake Bay may be deterministic and due to habitat- selection behavior by megalopae. Selection for seagrass assures the greatest likelihood of maximal survival and accelerated growth. Similar relationships may also exist in estuarine-dependent species with comparable habitat requirements and life-history characteristics.


Addictive disorders are a public health crisis that affects our society by draining our workforce, health care, judicial, education, and law enforcement, resources. Adolescents are particularly susceptible to social influence for better and for worse and addiction. Through social media, today's youth experience a whole new way of communicating. Not enough is known about adolescent perceptions of addiction, and messages of addiction they are exposed to on social media. Social Learning Theory and the Learning Theory of Addiction provided the framework for understanding how adolescents are at risk for developing unhealthy practices that create numerous psychological, social and physical problems in adulthood. Concurrent, mixedmethods, were used to explore adolescent perceptions of addiction and Instagram hashtags related to addiction. A content analysis of Instagram hashtags related to addiction and interview data from 11 adolescents aged 16-18 from a Students Against Destructive Decisions (SADD) club in New Jersey was collected and analyzed. The sample for phase one of this study was comprised of 819,155 Instagram posts, hashtagged #addiction, #recovery, #alcohol, and #drugs, collected on 5 dates over a month. Phase 2, adolescent interviews, included open-ended and Addiction Belief Survey (ABS) questions. The study's findings led to the conclusion that the adolescents interviewed have uncertain, and at times prejudicial, understandings of addiction. They see social media as potentially helpful in the fight against addiction and feel protected from negative messages of addiction by a strong circle of friends and family. Addiction related posts on Instagram, though littered with unhealthy messages, reflect the belief that addiction is recoverable and avoidable through social support. Adolescent perceptions of addiction align with those expressed on Instagram in both healthy and unhealthy ways. Beliefs of addiction expressed by adolescents and on Instagram reflect recent findings in the scientific literature on the nature of


As the population of the world becomes increasingly urban there is a need to examine the fertility and family planning needs of urban populations particularly among the urban poor. While it is often assumed that urban residents are better off than their rural counterparts the reality in many settings is that the urban poor are equally disadvantaged because of over-crowding high demand for limited resources increased cost of services in urban settings and lack of access to clean water and sanitation. The definition and measurement of poverty in a population has become increasingly important as reduction of poverty is identified as the first Millennium Development Goal. This study applies new approaches proposed by the MEASURE Evaluation project to classify wealth using nationally-representative surveys such as the Demographic and Health Surveys (DHS). These approaches are particularly important in cases where identifying and targeting of services to the urban poor are of interest. Applying these new approaches to DHS data from Bangladesh and Pakistan this paper demonstrates that the standard DHS wealth measures under-estimate the percent of the urban population that is poor and demonstrates that using the re-classified wealth indices women in the lowest quintiles remain worse off on fertility and family planning indicators. Even in Bangladesh where family planning services are easily available distinctions are still found between the urban poor and non-poor in terms of family planning method use and sources of methods. Larger differences are found in Pakistan where programmatic efforts have been less widespread. Without reclassification of standard DHS wealth measures programs risk misrepresenting the urban poor and may miss some of the women and households most in need of family planning services. Ensuring access to family planning among all women men and households but particularly among the urban poor who lack access to some of the urban advantages available to their better-off counterparts will lead to improved health outcomes for women and children especially in concentrated urban areas.


Redway certifies that in accordance with General Order No. 22, he sent valise containing his company books and records to Martinsburg West Virginia for storage. Redway believes that it was captured by the enemy on July 3, 1864, so Redway was unable to make out his returns.


Aim : Risk charts and risk score, based on the global absolute risk, are key tools for CVD risk assessment. When applied to the population from which they derive, they provide the best estimate of CVD risk. That is why the CUORE Project has among its objectives the assessment of the Italian population's cardiovascular risk, identifying the model for the prediction of coronary and cerebrovascular events in 10 years. Methods : Data fromdifferent cohorts enrolled in the North, Centre and South of Italy between the 1980s and the 1990s were used. From the 7,056 men and 12,574 women aged 35-69 years, free of cardiovascular disease at base-line and followed up for a mean time of 10 years for total and cause-specific mortality and non fatal cerebrovascular and coronary events, 894 major cardiovascular events (596 coronary and 298 cerebrovascular) were identified and validated. To assess 10-year cardiovascular risk, the risk score and risk chart were developed for men and women separately, considering the first major coronary or cerebrovascular event as the endpoint. Results : The risk score is applied tomen andwomen aged 35-69 years and includes age, systolic blood pressure, total cholesterol, HDL-cholesterol, smoking habit, diabetes and hypertension treatment using continuous values when possible. The risk chart is applied to persons aged 40-69 years and includes the same risk factors as risk score, except for HDL-cholesterol and hypertension treatment, and uses categorical values for all variables. Conclusions : The risk score and risk chart are easy-to-use tools which enable general practitioners and specialists to achieve an objective evaluation of the absolute global cardiovascular risk of middle-aged persons in primary prevention.


Borneo Etam educational institution manages and integrates the IQ, EQ, and SQ abilities on the basis of religious values and internalizes them into the whole elements of human resources. The religion-based on ESQ (ESQ Model) in educational management significantly advantages to the educational organization progress. This study describes the implementation of ESQ process model to the educational management in Borneo Etam educational
institution through qualitative approach. The data were collected documentarily, by having interview and observation methods, and were analyzed by using descriptive thinking method. The data were validated by using triangulation, peer discussion and etc


The article investigates the intellectual capital disclosure of Italian banks over the years 2016–2017, applying the specific lens of healthy and distressed banks. To this end, we used content analysis and encoding techniques. The main results point out that intellectual capital (IC) disclosure is generally poor and that the intensity of disclosure varies slightly between healthy and distressed banks. Regarding the quality of disclosure, healthy banks present a higher, albeit modest, tendency to disclose non-qualitative and forward-looking information, maybe due to the fact that they are more focused on the strategies and the relationships with stakeholders as opposed to a more short-term approach of the distressed banks. To complement our study on healthy and distressed banks, we repeated the analysis focusing on bank size and independent directors. In this case, results do not show relevant differences in terms of IC disclosure. Hence, our findings suggest the need to consider banks' IC disclosure as a strategic asset for increasing, among others, transparency and reputation.


This article investigates the use and effect of optimizing strategies in the online game World of Warcraft. Specifically, it looks at the phenomenon known as "theorycrafting," wherein expert players reverse engineer the game and use its underlying algorithms to calculate maximized play strategies. Play from a theorycrafting perspective is about the correct input and output of numbers, challenging the narrative of play as something free and frivolous. Seeking to understand how play and knowledge relate to each other, the article discusses how theorycrafting's seemingly abstract, objective, and neutral information about the game is also embedded with values, ideas, and norms. Based on a 1-year ethnographic study, the article uses Jasanoff's idiom of coproduction to discuss how abstract calculations are rendered meaningful and valuable by players, and the consequences of this in stabilizing particular ways of playing World of Warcraft.


Economic models in much of the public economics literature have been slow to reflect the significant changes towards double-income households throughout the developed world. This graduate-level text develops a more sophisticated approach to household economics, one that allows for multiple-income earners and shared decision-making. This approach is used to present a fundamentally new view of consumption. It is then applied to an analysis of tax systems, combining theoretical analysis of optimal taxation and tax reform with a careful empirical study of the characteristics of income tax systems in four different countries: Australia, Germany, the UK and the USA. The book is particularly concerned with analysing, both theoretically and empirically, the impact of taxation on female labour supply, and identifying its effects on work incentives and fairness of income distribution. All this adds up to a fascinating new approach to the economics of households for researchers in both the public and private sectors.


Higher education institutions generate a significant amount of wastes in their laboratories. Toxic reagents can react to other chemicals and form unknown products which are dangerous to both human and environment. Despite the severity of the situation, these wastes are not always discarded properly due to either lack of awareness by students and employees or lack of follow-up inspection. As education institutions, the universities should be the best example of how to manage their wastes and therefore show concern about the environment. This work is aimed at applying the Soft Systems Methodology (SSM) for management of hazardous wastes in a laboratory at the Federal University of Uberlândia, including their storage and disposal, in order to improve the awareness by those involved in scientific laboratory research about this issue


Competition between visually presented stimuli is associated with reduced neural firing, longer reaction time and reduced BOLD response. It is not known whether the effects of competition extend to working memory (WM), nor whether competition represents a common limiting-factor, compromising both WM performance in the absence of distraction, as well as effective distractor exclusion. Here we measured WM precision for an item placed with small or large spatial separation from another item to be remembered, or from a distractor. In both cases, WM precision was significantly reduced for small relative to large spatial separation. This indicates that the effects of competition extend to WM precision, and identifies competition as a potential common mechanism affecting WM regardless of whether the two items being encoded are both to be remembered, or whether one is a distractor. Such a mechanism is a potential basis for the association identified between distractor exclusion and WM in the absence of distraction.


This thesis provides a critical examination, from the perspective of three hapū (subtribes) of the Ngāti Awa iwi (tribe) from Te Moananui-a-Toi (the Bay of Plenty), in Te Ika a Maui (the North Island) in Aotearoa (New Zealand), of how changes to important aspects of ahu whenua trusts under Te Ture Whenua Māori Bill 2016 might have impeded hapū in achieving their land utilisation objectives. This form of trust, established under Te Ture Whenua Māori Act 1993, is the principal vehicle for Māori land management involving hundreds of thousands of hectares valued in billions of dollars on behalf of hundreds of thousands of owners, their whānau (family) and hapū. These trusts are sometimes of more significance to tribal communities than are post settlement governance entities; so expansive are their economic, social, cultural and political footprints. The radical proposals for change, contained in the now defunct Te Ture Whenua Māori Bill 2016 are examined, as they concerned core elements of the functioning of ahu whenua trusts, given what might have been their potential impacts on the management of Māori land. Those functions include the establishment, review and termination of such trusts and their operation in the normal course of business. The role of trustees and beneficial owners, their rights and obligations and their relationships with each other, are also considered. The overarching aim of this research is to assess key aspects of the proposed changes against the status quo and identify potential risks in the context of how they might operate in practice, should such proposals be revived, wholly or in part, by a future government. More importantly, proposals to amend the current legislation as an alternative approach are also explored with an emphasis on devolving a significant part of the existing transactional jurisdiction of the Māori Land Court from judicial to administrative oversight. In this way, it is intended that an original contribution to the study of Māori land can be made.


A new, unique, IOR concept has been investigated for application in light oil reservoirs that have been previously water flooded, but which can be applied at any stage of oil prodn. The method operates via GSGI (gravity stabilized gas injection), but does not require the injection of displacement gas from the surface. Instead, gas is generated in situ, using a downhole (underground) gasification unit. The economics of the process, in terms of the energy required to produce a barrel of incremental oil appears to be very attractive. In addn. to addnl. oil, the process also produces hydrogen, and other inert gases. These gases can be stored in the reservoir for future use. The primary scope for applying the method appears to be in watered flooded reservoirs, or other depleted light oil reservoirs, in which the pressure has been reduced to less than 150 bar, if co-evapn. of oil and water is employed. However, if water (steam) is injected sep., then there is no restriction on reservoir pressure, within the limits of economic operation. The paper reports the first, preliminary set of results for downhole gasification. A small exptl. gasifier was developed to simulate the steam reforming of 'light naphtha' fractions, cut from light crude oils. Although designed for operation up to 800 DegC and 140 bar pressure, the continuous flow system was restricted in these trials to around 75 bar pressure. The commissioning and preliminary trials used methane gas as feedstock, in order to test if it was possible to convert methane to hydrogen and other gases at significantly higher pressures than those normally used in surface reforming plant. Methane is also a very significant component of most reservoir oils and therefore has an important influence on how much displacement gas can be produced. The initial expts. achieved a hydrogen concn. in the reformer-gasifier exit gas of nearly 60%. Further trials were also made using a reservoir gas. [on SciFinder (R)]


The number of dairy farms in Austria has decreased during the last decade. Comparisons with other European countries reveal that dairy farms in Austria are quite small. Thus there is a serious concern about the competitiveness and efficiency of the dairy sector in the future. The objective of this study is to measure efficiency scores of Austrian dairy farms and to examine the relationship between efficiency and farm size. Data envelopment analysis (DEA) was applied to a sample of 222 highly specialised dairy farms. The results show an average technical efficiency of 79 % and a scale efficiency of 94 %. This suggests that natural conditions and management practices had a stronger impact on technical efficiency than farm size. An analysis of returns to scale revealed that 18 % of the sample farms were operating at constant returns to scale, 9 % above and 73 % below efficient scale.


"The Mediterranean Diet" is a commonly used term in the U.S. denoting healthful eating and a healthy lifestyle. It appears to be inspired by the traditional diets of two Mediterranean countries based on post-World War II studies conducted in Naples, Italy and Crete. Popularization of the Mediterranean diet is associated with increased demand for red wine and olive oil in the United States. As noted in the American Heart Association (AHA) website, there is no one "Mediterranean" diet. The Mediterranean diet, as typically presented, appears to be inspired by traditional diets in Southern Italy, Greece, and Spain. The AHA outlines the common characteristics of the Mediterranean dietary pattern. At least two non-profit organizations promote their version of a Mediterranean diet pyramid, and hundreds of books present their version of the Mediterranean diet. There appears to be an outstanding opportunity for a well-funded and motivated organization to effectively market a Mediterranean diet plan, based on accepted marketing models. Research on market segments, product definition and product positioning will be required. Questions to be considered relate to the effectiveness of diet pyramids, diet benefits sought by various consumer segments, and the medical and health benefits of individual food products as documented by medical and nutrition research. Examples of the health and nutrition research and promotion programs for four California commodity groups provide information on an alternative approach to presenting information on diet and health.


Fault kinematics in Cardigan Bay during the Cretaceous/Tertiary are problematic. In spite of abundant evidence of basin inversion across the region, there are few recognized examples of typical inversion-type structural geometry. Sub-surface structural mapping of the southern part of the Cardigan Bay basin reveals evidence of sinistral oblique-reactivation of an Early Palaeozoic fault during the Tertiary. A new kinematic scheme depicts Cardigan Bay as one part of a structurally compartmentalized Irish Sea–Cardigan Bay–Celtic Sea basin system. In this model, pre-existing NE-trending faults in Cardigan Bay exhibit sinistral displacement within a larger, NW-trending dextral shear couple. The geometry and magnitude of Tertiary inversion within this basin system was largely dependent on the relative orientation of the Early Tertiary palaeostress to the basement lineaments within each sub-compartment. Some of the implications of strike-slip fault reactivation for hydocarbon exploration and production are discussed.


In this paper, carbon blacks (CB) and charcoal powders (CP) were used as conductive fillers for fabricating conductive polymer composites. Those carbon fillers were dispersed into high density polyethylene (HDPE) by a melt compounding method using a twin screw extruder. The resulting composite with pellet shape was used to produce specimens for the evaluation of their electrical properties. The electrical properties of the polymer composite were evaluated by the four-point probe array method following JIS K 7194. The HDPE/CB/CP composites showed low volume resistivity when the filler contents were 9 wt% of CB and 20 wt% of CP, which indicated sufficient dispersion of CB and CP within HDPE to form a conductive network. In order to observe the dispersion state of fillers in the HDPE/CB/CP composites, 3-D computed tomography (CT) was used. In addition, the tensile properties of the HDPE/CB/CP composites were also measured to verify the reinforcement effect by carbon fillers. Furthermore, HDPE/CB/CP composite pipes were fabricated and their electrical properties were investigated by the four-point probe array method.


Diverse assemblages of thecamoebians are reported here from the Early Permian Manjir Formation of the northwest Himalaya in India. These thecamoebian tests were found in palynological preparations and are assigned an Early Permian age based on co-occurrence of age-diagnostic palynomorphs. Several of them show very close morphological affinity with extant thecamoebian genera, such as Amphitrema, Arcella, Centropyxis, Cyclopyxis, Cucurbitella, Difflugia and Trinema. This fauna lived in shallow-marine environments during the Early Permian deglacial phase of the widespread Late Carboniferous–Early Permian glaciation of Gondwana. The extant forms used for morphological comparison with the fossil forms were recorded from lakes and ponds in various parts of India. This study supports the current hypothesis of minimal evolution in thecamoebian lineages through geological time, and this group of protists has survived through long geological time and several mass extinction events without any significant morphological change. Stratigraphical and palaeontological evidence indicates that this fauna lived in the shallow-marine environments along the northwestern margin of Indian Gondwana during the deglacial phase of Late Carboniferous–Early Permian glaciation.


Editors' introduction Sinclair, like Coulthard, Darnton and Edge & Wharton in this volume, concerns himself with the uses andusability of text. Where Coulthard concerns himself with a text user's need to detect and investigate plagiarismin existing sets of text, and Darnton and Edge & Wharton with learners, however, Sinclair is interested inidentifying, interpreting and thence in questioning patterns in dialogue between people and computers. Sinclair's argument concerns feedback between the human and the computer, Human-MachineInteraction (HMI). Before the advent of complex switching systems (of which a computer is an example), a simpleelectric light switch provided immediate feedback to the user by an easily noticeable change in the environment. Thevery position, up or down, of a light switch generally indicates in a given culture the presence or absence ofpower, so there was often no need for a label on the switch itself. HMI of the very simplest kind possible. Similarly andearlier still, the use of spurs or a twitch of the reins usually gave feedback in the form of a change of direction or pace.No need for an hourglass display on the horse's neck, a Horse-Human Interaction which is not formalised.With the development of switching systems where the current state could not be easily inferred at a glance, e.g. arailway control system, more complex and varied systems of interaction between the system and its different classes ofusers (train drivers, current passengers, prospective passengers, controllers, etc.) became necessary; in the case of theInformation Age, this problem has become greater still. This increasing complexity of switching systems is like a Rubik cube toy, that plastic cube with rotatingcoloured segments where a very few changes of state bring about confusion for the human interactant. The humanuser cannot make sense of the current state of the system and the Rubik cube does not store a "historylist" of its own states, either. Nor does the human know how to alter its states systematically to reach acomprehensible state (such as the starting position). The system is too complex to grasp but provides no feedbackother than its current state. But in the case of computers it gets worse: the interaction is not one-way; the computerprogram and user need mutual knowledge. Each participant — and there may be more than two —needs to (but often does not) know not only what the "current state of play" is, but also whatrepresentation the other participants probably have of the current state of play. As Sinclair points out, natural conversation has evolved through millennia to deal with this problem; in adiscussion, there are discourse methods which are effortlessly used to control and order the state of play, so that evenidle gossip manages to avoid stating the obvious, proceeding systematically, as it were by a managed series of tips andhints. In the seventies Sinclair was working concurrently on adapting computers to tackling language data as well asnumbers, and devising linguistic means of analysing human discourse. The strength of this paper is that, building onthe notions of Discourse Analysis which he was largely instrumental in creating, he takes a step back from the paradoxthat computerised systems are highly complex but interact with users in over-simple ways. He considers a set of aspectsof the flow of communication both in natural discourse and in the discourse between the user and the computersystem; he shows how a radical shift will need to be made before there can be any hope of easy communicationbetween humans and virtual systems. Such is the pace of technological change and consumer avidity, contrasting with the processes of productionof academic text, that Sinclair's paper, though first committed to paper only a very few years ago, now looksdated in some of the time-scales mentioned and some of its references, e.g. to the Superhighway, a term which had apositive semantic prosody in the middle 1990s but which seems to have languished since. However, the problemswhich he addresses have not changed materially. Indeed Microsoft's Office Assistant and"Intellisense" have arguably made them worse. The software we have come to interact with is nowmore powerful, but it still seems to operate with its own mysterious agenda, we users are still all too often mere"clickers", as Sinclair puts it, and are like to remain so until software engineering learns from thelinguistic descriptions which Sinclair and others are attempting to provide. The problem is increasinglyurgent.


This paper details the response of a triple GEM detector with a 55 μmetre pitch pixelated ASIC for readout. The detector is operated as a micro TPC with 9.5 cm3 sensitive volume and characterized with a mixed beam of 120 GeV protons and positive pions. A process for reconstruction of incident particle tracks from individual ionization clusters is described and scans of the gain and drift fields are performed. The angular resolution of the measured tracks is characterized. Also, the readout was operated in a mixed mode where some pixels measure drift time and others charge. This was used to measure the energy deposition in the detector and the charge cloud size as a function of interaction depth. The future uses of the device, including in microdosimetry are discussed.


An effective immune system is essential for constant surveillance of potential threats to the organism, its' primary role being to provide resistance to infection. Thus, the immune system must be able to discriminate between pathogenic and self or harmless foreign antigens in order to not only achieve a productive immune response but also to avert unwarranted hyperreactivity and the potential development of autoimmunity. A delicate balance between these two fundamental requirements of the immune system must therefore exist.
T cells take central roles in the orchestration of the immune response. They are responsible for adaptive cell-mediated immunity and as such they can eliminate infected cells, produce cytokines that help in the resolution of the infection, stimulate other cells of the immune system to participate in the immune response and turn into long-lived memory cells. It is not surprising then that a wealth of mechanisms exist in order to ensure that T cells mediate immunity against pathogenic antigens but not to self or harmless ones. Indeed, various checkpoints in T cell development exist in the thymus to enable, on the one hand a large pool of diverse and functional T cells capable of recognising virtually all antigens while, on the other hand, eliminating self-reactive T cells. As some self-reactive T cells manage to leave the thymus, additional mechanisms have evolved to continually protect against auto-reactive and allergic inflammatory responses in the periphery. These mechanisms of peripheral tolerance include cell-mediated suppression of T cell responses, T cell apoptosis and T cell anergy. Anergy is a long-lived, cell-intrinsic mechanism that is characterised by cell cycle progression arrest and reduced IL-2 production. While T cell priming requires recognition of the cognate antigen in the context of MHC and co-stimulation via the interaction of its CD28 receptor with CD80/86 on an APC, recognition of the cognate antigen in the context of MHC without co-stimulation, such as when antigen is presented by immature APCs in the absence of inflammation, leads to anergy. These anergic T cells will also be hyporresponsive to re-challenge, even under immunogenic conditions.
The acquisition of the anergic phenotype is an active process, with negative regulators of T cell signalling being induced. Among these are some E3 ubiquitin-protein ligases which recognize target proteins for ubiquitination and catalyse the transfer of ubiquitin to them, directing them to the proteasome or to the endosomes. While a protein targeted to the proteasome is degraded by it, proteins in the endosomes can either be recycled for further signalling or directed to the lysosomes, where they are also degraded; in any case, ubiquitination leads to downregulation of the activity of signalling elements, whether permanently (degradation) or temporarily (recycling). Therefore a stable difference in the gene expression profile between anergic and primed T cells could be achieved through ubiquitin modification translating into an increase in turnover of signalling mediators involved in the T cell response, thereby establishing a persistent unresponsive state. In fact, some key signalling mediators involved in T cell activation, such as PLC and PKC, have been shown to be downregulated by the ubiquitin pathway in the context of anergy induction. Conversely, the E3 ubiquitin-protein ligases Cbl-b, Itch and Grail have been shown to be upregulated during anergy. These and other E3-ubiquitin-protein ligases have also been shown to ubiquitinate and downregulate TCR signalling elements.
However, many of the studies leading to these findings have relied upon biochemical assessment of signalling in T cell lines or clones, at the population level following pharmacological stimulation in vitro. The data generated in this way is sometimes conflicting with that of studies which focused on the knockout of a single gene, followed by analysis of the phenotype. Moreover, as in vitro pharmacological stimulation data represents the responses of all cell types in the sample population at any one time, it does not necessarily reflect the responses of individual antigen-specific T cells within their environmental niche within lymphoid tissue. Information relating to differential kinetics or subcellular localisation of signals generated by functionally distinct subgroups within a population could help assess the full picture regarding the role of E3 ubiquitin-protein ligases during the induction and maintenance phases of T cell anergy.
The main objectives of this thesis were therefore to determine the expression of Cbl-b, Itch and Grail in individual antigen-specific CD4+ T cells in both the induction and maintenance phases of anergy, in vitro and in vivo, and to investigate their functional signalling role(s) in the maintenance of the tolerance phenotype. In order to accomplish these objectives, induction of priming or tolerance in ovalbumin (OVA323-339 peptide)-specific T cells from DO11.10 TCR transgenic mice in vitro or, following adoptive transfer of near physiologically relevant numbers of such cells into recipients, in vivo, was carried out. Functional outcome, measured in terms of cell cycle progression, proliferation, cytokine readout assays, antibody production and T cell migration was correlated with E3 ubiquitin-protein ligases expression and the ubiquitination status of the TCR signalling machinery. Cbl-b, Itch and Grail protein expression in LN tissue, antigen-specific CD4+ T cells and subcellular compartments was assessed. Moreover, quantitative analysis at the single cell level was carried out by tracking the antigen-specific CD4+ T cells in vitro and in vivo by using Laser Scanning Cytometry. This relatively new technology combines the quantitative capabilities of flow cytometric analysis of cells with the ability to analyse them within a tissue in situ within their microenvironmental niche, thus more within physiological parameters.
This study shows Cbl-b expression to be upregulated in CD4+ T cells undergoing induction of both anergy and priming, when compared to naive cells. This is a departure from the view that states Cbl-b is a differential factor promoting anergy. In the maintenance phase, Cbl-b levels also appear upregulated in both anergic and primed antigen-specific T cells. Interestingly, Cbl-b concentrates in the periphery of anergic cells immediately after re-stimulation and this concentration of Cbl-b in the periphery of the cells was also observed for primed T cells after re-stimulation but at later time points. These data may therefore implicate Cbl-b in the modulation of T cell activation in the context of CD28 co-stimulation, rather than acting solely as a selective agent in the promotion of anergy.
Itch was similarly found to be upregulated in anergising and priming CD4+ T cells, when compared to naive cells. In fact, cells undergoing priming were found to express more Itch than those undergoing anergy. Likewise, in the maintenance phase, re-stimulation of primed cells resulted in higher Itch expression than re-stimulation of anergic antigen-specific T cells. Itch appears therefore to not play an exclusive role in anergy but instead acting in the general context of TCR signalling. Moreover, Grail expression was found to be upregulated in priming CD4+ T cells while there is also evidence it was transiently expressed at high levels during the anergy induction phase. Intriguingly, in the maintenance phase, Grail is associated with the migration of antigen-specific T cells into the follicles.
In summary, the data presented here indicate that upregulation of Cbl-b, Itch and Grail is not exclusive to T cells undergoing or maintaining anergy, as priming and primed T cells also exhibit expression and upregulation of these signals. While these data therefore show that these molecules cannot be used as markers for T cell anergy, and while the search for a bona fide T cell anergy marker continues, it also opens up new possibilities for their role(s) in modulation of T cell activation. By advancing knowledge of the key signalling events that take place during antigen recognition, more targeted approaches for enhancing or inhibiting immunity or tolerance can be devised.


This paper aims to present a theoretical and practical analysis of new pedagogical approaches (Self-Directed Learning, Gamification and Augmented Reality) in working with users with special educational needs. These new pedagogical approaches are proposed in the NEWTON European project. NEWTON project, as a part of European Union's Horizon 2020 Research and Innovation programme, is currently developing new pedagogical environments in order to improve the way STEM subjects are taught throughout European schools. NEWTON project include 14 European academic and industry partners. NEWTON emphasizes, among other things, the adaptation of modern methods and technologies to the needs of students with special educational needs, including children with hearing impairments. Using new approaches in education like Augmented Reality or Gamification has been a trending issue in the recent years. However, there is a limited body of research on these approaches for students with special educational needs. In order to analyze the modern pedagogical approaches proposed by NEWTON from the perspective of the activity with the children with hearing impairment, we followed, the following steps: o Description of the main features of the development of children with hearing impairment, because from these result the special requirements in the school activity. o Collecting and analyzing the opinions of teachers working with this category of children regarding the benefits and limitations of modern pedagogical approaches proposed in comparison to classical ones. This included 32 teachers who have experience of working with children with hearing impairment. There were meetings with teachers presenting modern pedagogical approaches and answers to questions. Later, each teacher was asked to fill out a questionnaire with open questions on the benefits and limitations of these methods for learning with children with hearing disabilities.


Recasting of economic alloys can change several properties. The number of recasting was found to have negligible effect on surface texture and on the amount of corrosion products released. The methods and equipments utilized in the casting of an alloy are important on the quality of casting. Carbon incorporated in a noble or economic alloy during casting is known to affect the mechanical values of the metal. In the present study we aimed to investigate the change in structure and metal hardness due to recasting. Materials and method: The effect of recasting, up to four times of a non precious "Finalloy" commercial dental alloy on their Rocwell C hardness behavior and their microstructures was inspected. Using "Kerr casting waxes" patterns were prepared similar to the samples from "Finalloy". The investments were pre-heated to phase at temperatures between 900°C and 1000°C. The alloy was melted by an acetylene-oxygen flame in a silicate crucible and four groups were compared: New alloy and alloys casted two, three, and four times (n = 7). After casting, Brinell harnesses were recorded. Values of Rocwell C strength, for each specimen group were analyzed by one-way analysis of variance, followed by the Student- Newman-Keuls multiple range test. A metal microscope was used to evaluate the surface morphology of the samples before hardness tests. 1st Casting :30.65 ± 0.3 kgf, 2nd Casting: 31.33 ± 0.4 kgf, 3rd Casting:34.80 ± 0.3 kgf, 4th Casting: 35.5 ± 28 kgf represents the Rocwell hardness of the castings. The results showed that hardness, increased with repeated castings. The experimental data indicates that increasing the number of successive recasting of "Finalloy" enhances the Rocwell C hardness, thus, after remelting and recasting, the biological properties decreases. Microscope study: Increase of the carbon content on the gren bounders of a cobalt-chromium alloy causes a considerable change in its microstructure. The hardness and yield point for 0.05 %, 0.1 % and 0.2 % tensile strength and elongation were determined for these test-pieces. The results showed that hardness, yield points and tensile strength increased with increased carbon content, whereas the elongation lessened. We determined that carbon concentrated at gren bounders. The clinical importance of the study is that recasting affected the properties of the metal, for best biological results with dental alloys always new metals must be used.


Economic sanctions are a frequent instrument of foreign policy. In a diplomatic conflict, they aim to elicit a change in the policies of foreign governments by damaging their economy. However, sanctions are not costless for the sending economy, where domestic firms involved in business with the target countries might incur collateral damages. This paper evaluates these costs in terms of export losses of the diplomatic crisis that started in 2014 between the Russian Federation and 37 countries, (including the United States, the EU, and Japan) over the Ukrainian conflict. We first gauge the global impact of the sanctions' regime using a structural gravity framework and quantify the trade losses in a general equilibrium counterfactual analysis. We estimate this loss at US$60.2 billion from 2014 until mid-2015. Interestingly, we find that the bulk of the impact stems from products that are not directly targeted by Russian retaliations (taking the form of an embargo on imports of agricultural products). This result suggests that most of the losses are not attributable to the Russian retaliation but to Western sanctions. We then investigate the underlying mechanism at the firm level using French customs data. Results indicate that neither consumer boycotts nor perceived country risk can account for the decline in exports of products that are not targeted by the Russian embargo. Instead, the disruption of the provision of trade finance services is found to have played an important role.


For the biomanufacturing of protein biologics, establishing stable cell lines with high transgene transcription is critical for high productivity. Modern genome engineering tools can direct transgene insertion to a specified genomic locus and can potentially become a valuable tool for cell line generation. In this study, the authors survey transgene integration sites and their transcriptional activity to identify characteristics of desirable regions. A lentivirus containing destabilized Green Fluorescent Protein (dGFP) is used to infect Chinese hamster ovary cells at a low multiplicity of infection, and cells with high or low GFP fluorescence are isolated. RNA sequencing and Assay for Transposase Accessible Chromatin using sequencing data shows integration sites with high GFP expression are in larger regions of high transcriptional activity and accessibility, but not necessarily within highly transcribed genes. This method is used to obtain high Immunoglobulin G (IgG) expressing cell lines with a single copy of the transgene integrated into transcriptionally active and accessible genomic regions. Dual recombinase-mediated cassette exchange is then employed to swap the IgG transgene for erythropoietin or tumor necrosis factor receptor-Fc. This work thus highlights a strategy to identify desirable sites for transgene integration and to streamline the development of new product producing cell lines.


Mice immunized with more SRBC than are required to produce optimal delayed-type hypersensitivity reactions, developed good antibody responses and poor delayed foot pad reactions. Cyclophosphamide treatment in low doses (20 mg/kg) before immunization, augmented the delayed-type hypersensitivity without affecting antibody responses. Cyclophosphamide did not augment delayed responses to optimal doses of SRBC (0.01%), but did augment the delayed hypersensitivity response of mice immunized with a suboptimal antigen dose (0.001%); which produced no detectable antibody response with or without cyclophosphamide pretreatment. These results suggest that antibody feedback is not the sole regulator of delayed reactions; the possibility that suppressor T cells may also be involved is discussed.


The diversity and community structure of the β-proteobacterial ammonia oxidising bacteria (AOB) in a range of different lab-scale industrial wastewater treatment reactors were compared. Three of the reactors treat waste from mixed domestic and industrial sources whereas the other reactor treats waste solely of industrial origin. PCR with AOB selective primers was combined with denaturing gradient gel electrophoresis to allow comparative analysis of the dominant AOB populations and the phylogenetic affiliation of the dominant AOB was determined by cloning and sequencing or direct sequencing of bands excised from DGGE gels. Different AOB were found within and between different reactors. All AOB sequences identified were grouped within the genus Nitrosomonas. Within the lab-scale reactors there appeared to be selection for a low diversity of AOB and predominance of a single AOB population. Furthermore, the industrial input in both effluents apparently selected for salt tolerant AOB, most closely related to Nitrosococcus mobilis and Nitrosomonas halophila.


Two sorghum genotypes (Pioneer 8244® and H2183210351) with different degree of adaptation to tropical areas were planted in march in Marin, N.L. Mexico (tropical environment). The objective was to relate dark respiration with the lack of genetic adaptation. The dark respiration measurements were made 85 days after planting, during the grain fill period. The plants in one meter long of the central row were used for the measurements. A plexiglass chamber of 1 m long, 0.8 m width and 1 m tall was seated on top of a wood base to cover all plants in the meter of the row. The wood base was to avoid CO2 influx from the soil. The CO2 measurements inside the camber were made with an infrared gas analyzer LI-COR 6200 (LI-COR, CO. USA) at 9:00 hr PM and 05:00 hr AM. The temperature difference between 9:00 PM and 5 AM was 2.3o C. Pioneer was more sensitive in respiration to temperature changes than H2183210351 (3.8 µMolCO2Kg-1s-1 and 0.7 µMolCO2Kg-1s-1, respectively). The respiration rate in Pioneer 8244 was 200 % higher than H2183210351 (13.7 µMolCO2Kg-1s-1 and 4.15 µMolCO2Kg-1s-1, respectively). The differences in respiration rates are probably due to the lack of adaptation of Pioneer 8244, that it is recommended for temperate environments, compared with the hybrid H2183210351, which parents are more tropical adapted.


Model-agnostic meta-reinforcement learning requires estimating the Hessian matrix of value functions. This is challenging from an implementation perspective, as repeatedly differentiating policy gradient estimates may lead to biased Hessian estimates. In this work, we provide a unifying framework for estimating higherorder derivatives of value functions, based on off-policy evaluation. Our framework interprets a number of prior approaches as special cases and elucidates the bias and variance trade-off of Hessian estimates. This framework also opens the door to a new family of estimates, which can be easily implemented with auto-differentiation libraries, and lead to performance gains in practice.


The sceptical challenge known as the problem of the criterion is one of the major issues in the history of epistemology. This volume provides its first comprehensive study, in a span of time that goes from Sextus Empiricus to Quine.


Farmers' and improved potato ( Solanum tuberosum L.) cultivars growing in Eritrea are main sources of food and income to many growers. The current study was proposed to characterize 17 farmers' and 4 imported cultivars of potato using 33 morphological descriptors. Planting was done in two geographically distinct locations, HAC and Asmara, Eritrea. The experiment was laid out in a randomized complete block design with three replications having 18 plants per plot. Plants grown at HAC emerged early (24.52 days) and reach maturity (94.84 days) while at Asmara it took 43.77 and 123.59 days, respectively. However, yield was higher in Asmara (0.49 kg/plant) compared to HAC (0.37 kg/plant). An accession having many and longer stems was associated with more tuber production, but inversely related to yield. Similarly, accessions with higher stem thickness and tuber size were associated with high yields. The PCA analysis indicated that the first four components explained about 85% of the total variability among the studied materials. The PCA clustered the materials in to four main groups (GI, GII, GIII, GIV) mainly explained by flowering patterns and yield related descriptors. The work has provided useful information on morphological characteristics of the farmer's potato to avoid duplication of resources and identify promising materials for future breeding program.


Clinical islet transplantation has progressed considerably over the past 12 years, and >750 patients with type 1 diabetes have received islet transplants internationally over this time. Many countries are beginning to accept the transition from research to accepted and funded clinical care, especially for patients with brittle control that cannot be stabilized by more conventional means. Major challenges remain, including the need for more than one donor, and the requirement for potent, chronic immunosuppression. Combining immunological tolerance both to allo- and autoantigens, and a limitless expandable source of stem cell- or xenograft-derived insulin-secreting cells represent remaining hurdles in moving this effective treatment to a potential cure for all those with type 1 or 2 diabetes.


Mass spectrometry (MS) is a widely used technique in many different fields such as proteomics, drug discovery and genomics. It measures the m/z ratio of the different components of a sample producing a mass spectrum, which has to be calibrated with internal or external calibration standards. In this project we studied if flower-like gold nanoparticles (AuNFs), red gold nanoparticles (red AuNPs) and red phosphorus (red P) could be used as internal calibration standards for matrix assisted laser desorption/ionization (MALDI) time-of-flight (TOF) MS analyses of intact eukaryotic (HEK 293) cells.
These elements form distinct monoisotopic clusters by laser desorption/ionization (LDI) which makes them ideal for being used as external calibration standards. When studying their capability as internal calibration standards for MALDI TOF MS technique we realized that sinapinic acid (SA) interacted with gold nanoparticles (AuNPs) impeding gold clusters to appear on the spectrum. Still AuNPs could not be used as internal calibration standards when we removed the matrix using surface-assisted laser desorption/ionization (SALDI) TOF MS technique as no organic compounds of HEK 293 cells at a high m/z range could be seen on the spectrum. Thus, we let crystallize the matrix with the cells before adding the AuNFs. By doing so, we minimized the interaction between sinapinic acid and gold and at the same time enhanced the ionization of high molecular compounds of HEK 293 cells. We partially succeeded by following this methodology as HEK 293 organic compounds could be seen at a high m/z range but gold clusters could only be seen at a low m/z range (800 m/z). The same methodology was used for red P and obtained better results. Phosphorus clusters could be seen up to 2600 m/z together with HEK 293 organic compounds at a high m/z range.
Cytotoxicity of these three elements was also studied in HEK 293 cells. Gold nanoparticles have numerous applications in the medicine field, thus studying its toxicity is of great importance. Red phosphorus is not as widely used but still its toxicity was also studied. Cell viability and proliferation was not affected by AuNPs whereas it was negatively altered by red phosphorus in dose dependent manner.
A further analysis was done by comparing the mass spectra of treated cells (with AuNPs and red P) and non-treated cells. We determined that AuNPs geometry is an important issue to be considered. Regarding red P, no differences were observed when comparing the mass spectra


This session will explore how East Carolina University's Joyner Library developed an interface to their digitized special collections to facilitate user browsing. The library's digital collections contain thousands of items digitized from hundreds of collections – in some cases only one or two items are digitized from a collection. This hodge-podge approach is a result of the library's image management practices which attempt to store materials digitized on a daily basis (for patron requests, preservation concerns, publication or exhibits, etc.) into the publicly available digital repository. As the repository was being developed, the staff of Joyner Library decided that the traditional approach to presenting digitized special collections materials as a sort of online "exhibit" where materials are selected to illustrate a theme or to systematically convert an entire collection to the digital format would not work. Instead, the staff experimented with different ways to enhance user browsing through materials. They looked to the world of commercial websites, next generation catalog interfaces, and social networking sites to develop a suite of navigation tools that enhance serendipitous discovery using their own home-grown solutions that are built on top of an SQL database and an XML database. The final collection interface includes: broad thematic "collections", "tag cloud"-style navigation, and a faceted-browsing refinement tool, all developed from cataloguer-created subject headings; hyperlinked terms in item records to facilitate broadening searches; links back and forth between collection finding aids and other digital resources at the library; user commenting and tagging of resources to begin to integrate emerging folksonomies. The session will describe the technologies and techniques used to develop these tools, examine some of the benefits and drawbacks to this approach, and discuss user feedback collected through usability testing, website statistics, and reference interaction.


It seems intuitive that as firms continue to try and keep in touch with the customers they serve, research should play an increasingly important role in determining the needs and wants of the consumer. Accordingly, as goods and services are tailored to meet these needs, so too does the accompanying advertising. Additionally, there is constant pressure on advertising agencies to produce advertising that consistently meets the objectives of their clients. Marketing departments, in turn, have to justify and be accountable to top management for advertising budgets. Consequently, agencies increasingly have to provide measures of effectiveness (Flandin et al 1992). In order to optimize the process(es) that will meet client objectives, agencies have to ensure that they understand how the consumer thinks and feels. One such approach to understanding the consumer's view is account planning. The main objective of this paper will be to provide a thorough review of the account planning phenomenon in advertising and in so doing, highlight the use of advertising research from a developmental perspective. This paper will describe the account planning process and how it differs from traditional agency practices. The justification for such a paper is the fact that billions of dollars are spent annually on advertising, in the hopes that the advertiser's objectives will consistently be met. If it could be demonstrated that increased attention to the consumer, in the development stages of advertising leads to more effective advertising than when consumer input is limited to the evaluation of advertising, after the fact, this would be of significant interest to advertisers as well as advertising agencies.


In order to examine the foraging behavior of whale sharks at Ningaloo Reef in Western Australia, stable isotope analysis of the dermis was used to estimate 13C and 15N values. These were compared to isotope values obtained from likely species of local prey. Ontogenetic and sex-related variations in the isotopic composition of dermis were also examined. The 13C values of zooplankton and nektonic taxa at Ningaloo ranged from -18.9‰ to -16.5‰ reflecting the different carbon sources entering the food web (from a pelagic to a more inshore and benthic productivity). The isotopic composition suggests that whale sharks had greater reliance on pelagic primary and secondary productivity over a period of ~3 years. Whale shark isospace matched some of the potential prey at Ningaloo Reef including krill, zooplankton and polychaetes. Consistency on 13C values indicated regional foraging ranges across the Ningaloo Reef area and the western Australian coast. More variability in 15N values showed, however, the different patterns of foraging among whale sharks. There was evidence of enrichment in 15N occurring with increasing size in male and female whale sharks, a pattern that could have been due to changes in growth rate and trophic level with age and/or an ontogenetic shift in feeding grounds. Our study brings new insights into the diet and feeding habits of an important whale shark population over large temporal and spatial scales in the eastern Indian Ocean. Such temporal and spatial information is essential for a better conservation management of this highly migratory and elusive species.


Sound-field amplification systems (SFA) have proven effective in overcoming classroom listening difficulties associated with noise, distance and reverberation. However, whether improving the classroom listening environment is sufficient to enhance young children's learning in areas critical to early reading acquisition, such as awareness of the sound structure of spoken words (phonological awareness: PA), is unclear. This study aimed to examine the effectiveness of an enhanced listening environment combined with PA intervention which aimed to specifically increase children's PA compared to an enhanced listening environment alone. Participants were 38 children aged 5-6 years from two classes at a low-decile primary school. All children were hearing screened at baseline, preand post-intervention. PA, letter-sound knowledge, real and non-word decoding were measured three times over 10 weeks (Term 1) prior to SFA installation in both classrooms, as well as preand post-intervention. In Term 2, children in class 1 were randomly assigned to receive SFA and an eight-week class-based teacher-administered PA programme. Class 2 received SFA only. A significant learning effect for all children occurred during the first phase of the monitoring period. Yet, a plateau was reached for most children between assessment times two and three prior to intervention. Following intervention, class 1 demonstrated a significant difference compared to class 2 in one PA assessment. Other measures failed to show any differences between classes. Visual data analyses revealed particular (non-significant) improvements for poor readers in class 1. These children outperformed poor readers in class 2 on all measures. Teacher questionnaires indicated that children's listening skills improved with SFA. The significant difference observed in one measure of PA between classes demonstrated that the combination of enhanced classroom acoustic environment and PA intervention actively improved PA development. The results of this study have implications for: (a) facilitating attention to sound structure, (b) optimal intervention for early PA development, (c) early reading acquisition in New Zealand classrooms, and, (d) the use of typical models of professional teacher development.


The post-translational modification of proteins with N-acetylglucosamine (O-GlcNAc) is involved in the regulation of a wide variety of cellular processes and associated with a number of chronic diseases. Despite its emerging biological significance, the systematic identification of O-GlcNAc proteins is still challenging. In the present study, we demonstrate a significantly improved O-GlcNAc protein enrichment procedure, which exploits metabolic labeling of cells by azide-modified GlcNAc and copper-mediated Click chemistry for purification of modified proteins on an alkyne-resin. On-resin proteolysis using trypsin followed by LC−MS/MS afforded the identification of around 1500 O-GlcNAc proteins from a single cell line. Subsequent elution of covalently resin bound O-GlcNAc peptides using selective β-elimination enabled the identification of 185 O-GlcNAc modification sites on 80 proteins. To demonstrate the practical utility of the developed approach, we studied the global effects of the O-GlcNAcase inhibitor GlcNAcstatin G on the level of O-GlcNAc modification of cellular proteins. About 200 proteins including several key players involved in the hexosamine signaling pathway showed significantly increased O-GlcNAcylation levels in response to the drug, which further strengthens the link of O-GlcNAc protein modification to cellular nutrient sensing and response.


Several international electronic primary financial exchanges have begun to announce they will explore the adoption of blockchain technology in their trade processing and reporting for execution and clearing. Therefore, in this work we will begin by providing an overview of the new exchange regulations appearing in different jurisdictions around the world, including EMIR, Dodd Frank, MiFID I/II, MiFIR, REMIT, Reg NMS and T2S. We will discuss some of their key features, specifically in regard to transparency reporting and trade/transaction reporting requirements.The current status of regulatory requirements for reporting and the massive data sets such regulation will generate as well as the significant challenges faced by firms and market participants in meeting such requirements in an automated manner, is a key to the discussion in this paper. We explain different blockchain solutions based on blockchain architectures being currently developed in the market place to handle key aspects of transparency and pre and post trade reporting requirements that will be universal in applicability in both UK, Europe and U.S. regulations.In the process of this commentary we will discuss the different emerging architectures and features that are being developed in a range of different blockchain technologies. This will include details on different forms of blockchain technology including : permissionless blockchains, where anyone can participate in the veri cation process, i.e. no prior authorisation is required and a user can contribute his/her computational power, usually in return for a monetary reward. Permissioned blockchains, where verification nodes are preselected by a central authority or consortium. Public blockchains, where anyone can read and submit transactions to the blockchain and Private blockchains, where this permission is restricted to users within an organisation or group of organisations. We detail which market participants and which blockchain architectures are emerging as possible solutions for addressing pre and post trade reporting requirements in modern electronic exchanges.


In Helsinki, the current number of immigrants is quickly rising. Ethnic retail has emerged as a new, but visible, part of the city landscape. Compared to other European countries, becoming an entrepreneur is typically not very popular in Finland. Therefore, in this paper, we seek to comprehend this phenomenon and more specifically discover: what motivates immigrants to become entrepreneurs; what is the impact of their background and culture on the phenomenon; and finally, is the help provided by the city useful for them? Based on interviews and observations, we conclude that immigrant entrepreneurship facilitates in fluid ways the maintenance of cultural practices, while simultaneously enhancing meaningful encounters between immigrants and mainstream society. In our sample, we identify three types of entrepreneurs: growth-oriented, investors and status builders, as well as freedom and stability seekers. Although the groups are neither mutually exclusive nor collectively exhaustive, they display differences in certain aspects, which include their ways of entering into entrepreneurship, how their business is run, who their main clientele is, as well as in the future prospects for their businesses. We further infer that immigrant entrepreneurs, via their practices, also participate in making immigrant needs visible to politicians and policy-makers, thus also adding a layer to the local context within which they operate. However, we surmise that more effort is needed in addressing the freedom and stability seeker entrepreneurs if the aim of the city is to anchor immigrant retail in the city.


PURPOSE
RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype.

PATIENTS AND METHODS
Patients with chemotherapy-refractory KRAS G13D mutation-positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m(2) loading dose and then 250 mg/m(2) once per week with or without irinotecan 180 mg/m(2) once every 2 weeks. The primary end point was 6-month progression-free survival; secondary end points were response rate, overall survival, quality of life, and toxicity.

RESULTS
Fifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar; toxicities were higher with combination therapy.

CONCLUSION
In patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.


We present HealthGear, a real-time wearable system for monitoring, visualizing and analyzing physiological signals. HealthGear consists of a set of non-invasive physiological sensors wirelessly connected via Bluetooth to a cell phone which stores, transmits and analyzes the physiological data, and presents it to the user in an intelligible way. In this paper, we focus on an implementation of HealthGear using a blood oximeter to monitor the user's blood oxygen level and pulse while sleeping. We also describe two different algorithms for automatically detecting sleep apnea events, and illustrate the performance of the overall system in a sleep study with 20 volunteers.


In previous structure-activity relationship (SAR) studies, we identified (3 R)-7-hydroxy- N-((1 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 1) as the first potent and selective kappa opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [ (35) S]GTPgammaS binding assay. The results from the studies better define the pharmacophore for this class of kappa opioid receptor antagonist and has identified new potent and selective kappa antagonist. (3 R)-7-Hydroxy- N-[(1 S,2 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide ( 3) with a K e value of 0.03 nM at the kappa receptor and 100- and 793-fold selectivity relative to the mu and delta receptors was the most potent and selective kappa opioid receptor antagonist identified.


Strong magnetic couplings are generally observed intramolecularly in organic diradicals or in systems in which they are promoted by crystal engineering strategies involving, for example, transition metal ligation. We herein present a strong intermolecularly coupling verdazyl radical in the solid state without the use of such design strategies. The crystal structure of an acetylene-substituted verdazyl radical shows a unique antiparallel face-to-face orientation of the neighboring verdazyl molecules along with verdazyl-acetylene interactions giving rise to an alternating antiferromagnetic Heisenberg chain. Single crystal structural data at 80, 100, 173, and 223 K show that one of the π-stacking distances depends on temperature, while heat capacity data indicate the absence of a phase transition. Based on this structural input, broken symmetry DFT calculations predict a change from an alternating linear Heisenberg chain with two comparable coupling constants J1 and J2 at higher temperatures towards dominant pair interactions at lower temperatures. The predicted antiferromagnetic coupling is confirmed experimentally by magnetic susceptibility, solid-state EPR and NMR spectroscopic results.