New mechanism identified for resistance to targeted lung cancer drugs Unrelated protein activated to bypass blocked growth signal, new treatment approach suggested An international research team, led by investigators from the Massachusetts General Hospital (MGH) Cancer Center and Dana-Farber Cancer Institute, has found a new way that some lung tumors become resistant to treatment with targeted therapy drugs like Iressa and Tarceva. Their report, which appeared online in the journal Science, describes a totally new resistance mechanism that may apply to many types of cancer. It also suggests a treatment strategy for patients with these resistant tumors. "We found that, for about 20 percent of patients with tumors that become resistant to Tarceva or Iressa, resistance is caused by the genetic activation of an oncogene that is not the normal target of the drug, which is something that has never been seen before," says Jeffrey Engelman, MD, PhD, scientific director of the MGH Center for Thoracic Cancers, the paper's lead author. "Importantly, we also identified a potential new way to treat these resistant tumors with combination therapy directed against both protein targets," adds Pasi A. Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology at Dana-Farber, the study's senior author. Drugs like Iressa (gefitinib) and Tarceva (erlotinib) are used to treat advanced non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths in the U.S. They act by blocking the epidermal growth factor receptor (EGFR), a molecule on the surface of cancer cells. In 2004, research teams from MGH and Dana-Farber found that only tumors in which the EGFR gene has been mutated in a way that magnifies the cells' response to the growth factor, a process that fuels tumor growth, were sensitive to treatment with these drugs. Although tumors that respond to EGFR inhibitors do so rapidly and dramatically, eventually the tumors become resistant and resume growing. About half the time, a secondary mutation that interferes with the drugs' binding to the receptor develops within the EGFR gene. A new group of so-called irreversible EGFR inhibitors that permanently bind to the protein are currently being tested in clinical trials. But what leads to other cases of resistance has been unknown, and the current study was designed to discover additional mechanisms. To do so, the investigators modeled in a laboratory setting what happens in lung cancer patients; they used a line of NSCLC cells with the sensitizing EGFR mutation and created a cell line resistant to treatment with Iressa. In a number of experiments comparing the resistant line with still-sensitive cells, they focused on the cell signalling pathway controlled by EGFR. In earlier research, Engelman and colleagues had found that the growth signal that starts with EGFR works through a related protein called ERBB3. The current study showed that, in some of the resistant cells, ERBB3 is activated by amplification of a different oncogene called MET, in essence bypassing the blockage of EGFR. Analysis of samples from patients whose tumors became resistant after initially responding to Iressa revealed that MET was amplified in resistant samples from 4 of 18 patients. Although treating resistant cell lines with either Iressa or a MET inhibitor did not stop tumor growth, treatment with both agents did induce cell death. "This method of reactivating the EGFR signalling pathway with MET may be a common resistance mechanism in other therapies that target receptors of the ERBB family, which are used against breast cancer, colon cancer, head and neck cancer, and the brain tumor glioblastoma multiforme," says Jänne, who is an assistant professor of Medicine at Harvard Medical School (HMS). "Our results suggest that, when patients' tumors become resistant, repeat biopsies to identify which resistance mechanism is involved will be critical and could help us develop effective therapies for those resistant tumors," adds co-author Lewis Cantley, PhD, of the Beth Israel Deaconess Medical Center. To that end, the investigators are working on a research protocol for combined treatment with FDA-approved EGFR inhibitors and with MET inhibitors, which are in preapproval trials against other types of cancer. They also plan to analyze a larger number of resistant samples to get a clearer idea of the frequency of this resistance mechanism. Additional co-authors of the Science report are Kreshnik Zejnullahu, Joon Oh Park, MD, PhD, Xiaojun Zhao, PhD, Alison Holmes, Andrew Rogers and Bruce Johnson, MD, of Dana-Farber; Tetsuya Mitsudomi, MD, and Takayuki Kosaka, MD, Aichi Cancer Center Hospital, Nagoya, Japan; Youngchul Song and Christopher-Michael Gale; Courtney Hyland, Neal Lindeman, MD, and Charles Lee, PhD, Brigham and Women's Hospital; James Christensen, PhD, Pfizer Global Research and Development; Federico Cappuzzo, MD, Instituto Clinico Humanitas, Rozzano, Italy; and Tony Mok, MD, Chinese University of Hong Kong. The study was supported by grants from the National Institutes of Health, including the National Cancer Institute; the American Cancer Society, the American Association for Cancer Research; the International Association for the Study of Lung Cancer; and the Italian Association for Cancer Research. Massachusetts General Hospital (www.massgeneral.org), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.


With the discovery of insulin came a deeper understanding of therapeutic options for one of the most devastating chronic diseases of the modern era, diabetes mellitus. The use of insulin in the treatment of diabetes, especially in those with severe insulin deficiency (type 1 diabetes), with multiple injections or continuous subcutaneous infusion, has been largely successful, but the risk for short term and long term complications remains substantial. Insulin treatment decisions are based on the patient's knowledge of meal size, exercise plans and the intermittent knowledge of blood glucose values. As such, these are open loop methods that require human input. The idea of closed loop control of diabetes treatment is quite different: automated control of a device that delivers insulin (and possibly glucagon or other medications) and is based on continuous or very frequent glucose measurements. Closed loop insulin control for type 1 diabetes is not new but is far from optimized. The goal of such a system is to avoid short-term complications (hypoglycemia) and long-term complications (diseases of the eyes, kidneys, nerves and cardiovascular system) by mimicking the normal insulin secretion pattern of the pancreatic beta cell. A control system for automated diabetes treatment consists of three major components, (1) a glucose sensing device that serves as the afferent limb of the system; (2) an automated control unit that uses algorithms which acquires sensor input and generates treatment outputs; and (3) a drug delivery device (primarily for delivery of insulin), which serves as the system's efferent limb. There are several major issues that highlight the difficulty of interacting with the complex unknowns of the biological world. For example, development of accurate continuous glucose monitors is crucial; the state of the art in 2009 is that such devices sometimes experience drift and are intended only to supplement information received from standard intermittent blood glucose data. In addition, it is important to acknowledge that an "automated" closed loop pancreas cannot approach the complexity of the normal human endocrine pancreas, which takes continuous data from substrates, hormones, paracrine compounds and autonomic neural inputs, and in response, secretes four hormones. Another major issue is the substantial absorption/action delay of insulin given by the subcutaneous route. Because of this delay, some researchers have recently given a portion of the meal-related insulin in an open loop manner before the meal and found this hybrid approach to be superior to closed loop control. Proportional-Integral-Derivative (PID) systems adapted from the industrial sector utilize control algorithms that alter output based on proportional (difference between actual and target levels), derivative (rate of change) and integral (time-related summative) errors in glucose. These algorithms have proven to be very promising in limited clinical trials. Related algorithms include a "fading memory" system that combines the proportional-derivative components of a classic PID system with time-relating decay of input signals that allow greater emphasis on more recent glucose values, a characteristic noted in mammalian beta-cells. Model Predictive Control (MPC) systems are highly adaptive methods that utilize mathematical models based on observations of biological behavior patterns using system identification and are now undergoing testing in humans. The application of further mathematical models, such as fuzzy control and artificial neural networks, are also promising, but are largely clinically untested. In summary, the prospects for closed loop control of glycemia in persons with diabetes have improved considerably. Major limitations include the delayed absorption/action of subcutaneous insulin and the imperfect stability of currently-available continuous glucose sensors. The potential for improved glycemic control in persons with diabetes brings with it the potential for reduction in the frequency of acute and chronic complications of diabetes.


ABSTRACT. The desire to overcome fragmented management of the natural ecosystems on which human beings depend has contributed to a growing interest in landscape approaches and to deeper questions about landscape governance systems. We assessed the emergent governance system that corresponds to the Mt. Marsabit landscape ecosystem in northern Kenya, applying a framework that includes 17 different indicators. We found that in this governance system, the most important spaces where coordination and joint planning took place were district level coordination committees, within which representation of communities and voices from the grassroots was poor. Institutional and organizational linkages were such that those parts of the governance system for which legitimacy and accountability were strongest were the parts for which ability to generate resources was weakest, while the parts of the governance system that had the best access to resources was where accountability was weakest or the most indirect. In this paper we use the Mt. Marsabit case study to explore the role that organizational and institutional linkages play in the strengths and weaknesses of landscape governance systems, and consider the implications for governance design at landscape level. Institutional linkages play a critical role in determining how landscape governance systems function across scales and levels, and their degree of fit. Appropriate linkages can help to create connections among key dimensions of effective governance within the system, dimensions such as use of knowledge, capacity to generate resources, fit, learning, legitimacy, accountability, and responsiveness, strengthening the system as a whole. Of the various linkages that characterize a governance system, it is those that give community-level actors a meaningful voice at higher levels and in spaces where key decisions are being made that are most critical for enabling effective landscape governance.


This explorative study captured the perceptions of faculty members new to technology enhanced learning and the longitudinal observations of the e-learning manager during dedicated professional development in order to compile a socially transformative emergent learning technology integration framework for open and distance learning at the School of Continuing Teacher Education at North-West University, South Africa. A pragmatic approach guided the bounded case study. The study followed a fully mixed sequential equal status design of mixing sequential qualitative and quantitative findings. Data collection strategies concern a custom-made questionnaire, interviews with faculty members, and longitudinal observations by the e-learning manager. The first phase uncovered 34 qualitative codes. After quantitating of the data, a t -test indicated significant differences for 17 variables between faculty perceptions and observations of the e-learning manager. Ward's method of Euclidean distances grouped the variables into five clusters according to the researchers' paradigm of looking in and looking out from the development context. The clusters formed the basis of a model for faculty development towards socially transformative learning technology integration for open distance learning. The five aspects of the model comprise (i) the environment in which faculty members should gain support from the institution; (ii) the environment in which faculty have to address the realities of adopting TEL; (iii) human factors relating to the adoption of TEL; (iv) concerns and reservations about the use of TEL; and (v) continuing professional development needs, expectations, and motivators. The sustainable integration of ICT into higher education institutions remains a major challenge for the adoption of TEL.


BACKGROUND
Despite evidence on the benefits of participating in cardiac-rehabilitation (CR) following coronary artery bypass graft (CABG) surgery and the inclusion of CR in the basic "Health Basket", referral and uptake of CR in Israel remain low.

OBJECTIVES
To assess the CR participation rate and CR-related outcomes 1-year following CABG-surgery among patients born in the former Soviet Union and veteran-Israelis.

METHODOLOGY
An interventional trial was conducted in which 489 and 472 CABG patients from 5 cardiothoracic wards across Israel were interviewed in hospital before surgery, and at home a year later for the control arm and the intervention arm respectively. The intervention included dissemination of information on CR to medical staff and patients.

FINDINGS
USSR-born patients constituted 22.5% of the sample. They were one year older than veteran-Israelis (median-age: 68 and 67 years, respectively, p = 0.2), had a larger proportion of women (31.5% vs. 22.4% respectively, p = 0.006), and a larger proportion of widows (20.0% vs. 13.6%, respectively, p = 0.02). Following the intervention, the CR participation rate of veteran-Israeli males increased from 24.6% to 40.4% (p < 0.001), and that of USSR-born males increased from 3.7% to 13.4% (p = 0.037). No USSR-born female participated in CR, while participation rates of veteran-Israeli females increased from 14.6% to 26.9%, p = 0.056. CR participants reported better health-related quality of life and higher levels of cardio-respiratory fitness (p < 0.001) at follow-up, compared to patients who did not participate in CR.

CONCLUSION
The intervention was effective in increasing the participation in CR programs among all but USSR-born females. Further research is needed to assess the needs of this subgroup and develop effective interventions.


Reinforcement learning for robotic applications faces the challenge of constraint satisfaction, which currently impedes its application to safety critical systems. Recent approaches successfully introduce safety based on reachability analysis, determining a safe region of the state space where the system can operate. However, overly constraining the freedom of the system can negatively affect performance, while attempting to learn less conservative safety constraints might fail to preserve safety if the learned constraints are inaccurate. We propose a novel method that uses a principled approach to learn the system's unknown dynamics based on a Gaussian process model and iteratively approximates the maximal safe set. A modified control strategy based on real-time model validation preserves safety under weaker conditions than current approaches. Our framework further incorporates safety into the reinforcement learning performance metric, allowing a better integration of safety and learning. We demonstrate our algorithm on simulations of a cart-pole system and on an experimental quadrotor application and show how our proposed scheme succeeds in preserving safety where current approaches fail to avoid an unsafe condition.


We examined the circumstances of death and injury among victims of the tornado that struck Wichita Falls, Texas, on 10 April 1979. We also assessed the protective measures taken by a representative sample of community residents who suffered no major injury in order to estimate the relative risk of injury to people directly in the tornado's path. Twenty-six (60 percent) of the 43 traumatic deaths and 30 (51 percent) of the 59 serious injuries occurred in people who, despite ample warning, went to their cars to drive out of the storm's path. These people had a risk of serious or fatal injury of 23 per 1000. People who remained indoors and in stationary homes were at relatively low risk (3 per 1000) if they took simple precautions; people in mobile homes were at greatest risk (85 per 1000). Current safety recommendations and housing codes for single family homes and mobile homes need to be amended to decrease the impact of future tornadoes on human health.


We show how to apply the Mellin-Laplace transform to process time-resolved reflectance measurements for diffuse optical tomography. We illustrate this method on simulated signals incorporating the main sources of experimental noise and suggest how to fine-tune the method in order to detect the deepest absorbing inclusions and optimize their localization in depth, depending on the dynamic range of the measurement. To finish, we apply this method to measurements acquired with a setup including a femtosecond laser, photomultipliers and a time-correlated single photon counting board. Simulations and experiments are illustrated for a probe featuring the interfiber distance of 1.5 cm and show the potential of time-resolved techniques for imaging absorption contrast in depth with this geometry.


Abstract. An assessment of global particulate nitrate and ammonium aerosol based on simulations from nine models participating in the Aerosol Comparisons between Observations and Models (AeroCom) phase III study is presented. A budget analysis was conducted to understand the typical magnitude, distribution, and diversity of the aerosols and their precursors among the models. To gain confidence regarding model performance, the model results were evaluated with various observations globally, including ground station measurements over North America, Europe, and east Asia for tracer concentrations and dry and wet depositions, as well as with aircraft measurements in the Northern Hemisphere mid-to-high latitudes for tracer vertical distributions. Given the unique chemical and physical features of the nitrate occurrence, we further investigated the similarity and differentiation among the models by examining (1) the pH-dependent NH3 wet deposition; (2) the nitrate formation via heterogeneous chemistry on the surface of dust and sea salt particles or thermodynamic equilibrium calculation including dust and sea salt ions; and (3) the nitrate coarse-mode fraction (i.e., coarse/total). It is found that HNO3, which is simulated explicitly based on full O3-HOx-NOx-aerosol chemistry by all models, differs by up to a factor of 9 among the models in its global tropospheric burden. This partially contributes to a large difference in NO3−, whose atmospheric burden differs by up to a factor of 13. The atmospheric burdens of NH3 and NH4+ differ by 17 and 4, respectively. Analyses at the process level show that the large diversity in atmospheric burdens of NO3−, NH3, and NH4+ is also related to deposition processes. Wet deposition seems to be the dominant process in determining the diversity in NH3 and NH4+ lifetimes. It is critical to correctly account for contributions of heterogeneous chemical production of nitrate on dust and sea salt, because this process overwhelmingly controls atmospheric nitrate production (typically > 80 %) and determines the coarse- and fine-mode distribution of nitrate aerosol.


Objectives To evaluate potential sex differences and other factors associated with complications within 4 months after a hip fracture. Methods A total of 1,915 patients ≥65 years (480 men) with hip fracture were consecutively included in a prospective multicenter cohort study. A review of medical records and patient interviews according to a study protocol based on the Standardized Audit of Hip Fractures in Europe (SAHFE, RIKSHÖFT) was performed. Sex differences in comorbidity according to the American Society of Anesthesiologists score and complications 4 months after a hip fracture were registered. Multivariate logistic regression analysis was performed to identify factors related to complications. Results Male sex was associated with worse general health according to the American Society of Anesthesiologists classification (P=0.005) and with more comorbidities (P<0.001). Male sex emerged as a risk factor for developing pneumonia (P<0.001), and additionally, 18% of the men suffered from cardiac complications compared with 13% of the females (P=0.018). Female sex was predisposed for urinary tract infections, 30% vs 23% in males (P=0.001). Mortality was higher in the male vs female group, both within 30 days (15% vs 10%, P=0.001) and at 4 months (24% vs 14%, P=0.001). Conditions associated with pneumonia were male sex, pulmonary disease, and cognitive impairment. Cardiac complications were associated with delayed surgery and cardiovascular and pulmonary disease. Conclusion Before surgery, men with hip fracture already have a poorer health status and higher comorbidity rate than women, thus resulting in a twofold increased risk of pneumonia. Cognitive dysfunction and pulmonary disease contributed to pneumonia in men. Delayed surgery seems to increase the risk for cardiac complications. It is important to consider the sex perspective early on together with cardiopulmonary comorbidity and cognitive dysfunction to be able to counteract serious complications that may lead to death.


Xeroderma pigmentosum variant (XPV) patients with mutations in the DNA polymerase eta (pol eta) gene are hypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer. Consistent with the ability of Pol eta to efficiently bypass UV light-induced cyclobutane pyrimidine dimers, XPV cells lacking Pol eta have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light-induced killing and mutagenesis. To better understand these and other Pol eta functions, we generated Pol eta-deficient mice. Mice homozygous for a null mutation in pol eta are viable, fertile, and do not show any obvious spontaneous defects during the first year of life. However, fibroblasts derived from these mutant mice are sensitive to killing by exposure to UV light, and all Pol eta-deficient mice develop skin tumors after UV irradiation, in contrast to the wild-type littermate controls that did not develop such tumors. These results and biochemical studies of translesion synthesis by mouse Pol eta indicate that Pol eta-dependent bypass of cyclobutane pyrimidine dimers suppresses UV light-induced skin cancer in mice. Moreover, 37.5% of pol eta heterozygous mice also developed skin cancer during 5 months after a 5-month exposure to UV light, suggesting that humans who are heterozygous for mutations in pol eta may also have an increased risk of skin cancer.


As we celebrate the fiftieth anniversary of Title VII's prohibition against sex-based compensation discrimination in the workplace, the gender wage gap remains robust and progress toward gender pay equity has stalled. This article reveals the role that causal narratives play in undermining the law's potential for reducing the gender pay gap. The most recent causal narrative is illustrated by the "women don't ask" and "lean in" storylines, which reveal our society's entrenched view that women themselves are responsible for their own pay inequality. This causal narrative has also embedded itself in subtle but pernicious ways in antidiscrimination doctrine, which helps shield employers from legal liability for gender pay disparities. The disability civil rights movement faced a similar challenge, however, and their response provides a potential path forward on gender pay issues. The causal narrative that erected barriers for disability rights was engrained in the medical model of disability, which also identified internal deficits as the source of individuals' own limitations. The disability rights movement responded with a reconceptualized "social model," which explains disability instead as the result of the environment in which an individual's characteristics interact. The social model of disability is an alternative causal narrative: one that shifts focus onto the role played by employer practices and organizational norms in producing inequality. This article explores how a social model approach to women's compensation could help shift the causal focus away from the manner in which women negotiate, and onto the institutional practices that produce unequal results. In doing so, the social model may help resuscitate Title VII's disparate impact theory to allow challenges to employment practices that base compensation on employees' individual demands, thereby moving us toward more effective structural solutions to the gender pay divide.


Gastrointestinal carcinoid tumors are uncommon neuroendocrine tumours that may be associated with synchronous or metachronous primary tumours of other histological type, most frequently colorectal adenocarcinomas. Primary ovarian mucinous adenocarcinomas have been reported to coincide with few other ovarian tumours and minority of these tumours may occur in association with Lynch syndrome. However association of duodenal carcinoid with ovarian mucinous adenocarcinoma is distinctly unusual and, to our knowledge, has not been previously described. We report a case of occult metastasising duodenal atypical carcinoid that was incidentally detected during surgical intervention performed for left ovarian mucinous cystadenocarcinoma in a middle aged female. The carcinoid tumour was Stage IIIB with regional nodal metastasis and the ovarian tumour was Stage IA with low grade histology.


Rhizopus oryzae is a filamentous fungus, belonging to the order Mucorales. It can ferment a wide range of carbohydrates hydrolyzed from lignocellulosic materials and even cellobiose to produce ethanol. However, R. oryzae also produces lactic acid as a major metabolite, which reduces the yield of ethanol. In this study, we show that significant reduction of lactic acid production could be achieved by short (25nt) synthetic siRNAs targeting the ldhA gene. The average yield of lactic acid production by R. oryzae during the batch fermentation process, where glucose had been used as a sole carbon source, diminished from 0.07gm/gm in wild type to 0.01gm/gm in silenced samples. In contrast, the average yield of ethanol production increased from 0.39gm/gm in wild type to 0.45gm/gm in silenced samples. These results show 85.7% (gm/gm) reduction in lactic acid production as compared with the wild type R. oryzae, while an increase of 15.4% (gm/gm) in ethanol yield.


Purpose

The purpose of this paper is to explore English and Finnish paramedic perceptions of the healthcare blame culture, its relationship to complaints, the use of defensive practice and if this impacts on paramedic practice and clinical care.

Design/methodology/approach

Participants were recruited from English and Finnish ambulance services that have similar organisational and professional scopes of practice. The aim was to gain insight into the similarities and differences between the countries regarding the existence of a blame culture in paramedic practice. Semi-structured focus groups and interviews involving 20 English and Finnish paramedics were undertaken. Qualitative perceptions concerning the reality of a blame culture in paramedic practice and its impact on professional roles were sought.

Findings

Three major themes that were identified in the thematic analysis included: blame culture and its influences; the impact of complaints against paramedics; and the use of defensive practice within their roles. These data themes were similar for both groups of participants. The majority of participants thought the healthcare blame culture to be widespread and believed that this was likely to directly influence paramedics' working practices.

Originality/value

Whilst the impact of blame culture and complaints on the medical profession has previously been examined, this study makes an important contribution by exploring the factors that impact on paramedics' lives and their practice, within two European countries. The inappropriate use of social media by some members of the public in both countries was a disturbing issue for many participants and was identified as an area for further research.


In this work, a decision support system (DSS) coupled with wastewater treatment plant (WWTP) simulator tool that uses a hierarchical set of key performance indicators (KPIs) to provide an assessment of the performance of WWTP systems is presented. An assessment of different Scenarios in a real WWTP case study, each consisting of a different set of sludge line technologies and derived combinations, was successfully conducted with the developed DSS–WWTP simulator, based on Scenario simulation and hierarchical KPI analysis. The test carried out on the selected WWTP showed that although thermal valorisation and thermal hydrolysis showed similar (the best) economic viability, the latter showed additional benefits, including synergies related to improving the thermal balance of the overall WWTP even when considering other technologies. On the other hand, biogas-upgrading technologies allowed reduction of emissions, but with higher costs and thermal demands. The usage of this tool may allow the development of proposals for technological priorities as a pathway to the transition to circular economy based on the management criteria of the correspondent sanitation system.


Under the U.S. Constitution as amended by the Sixteenth Amendment, any federal tax that is a "direct tax" (which is not an "income tax") must be apportioned among the states in accordance with the respective populations of the various states. The purpose of this Article to solve the riddle of what is a "direct tax" that is subject to the apportionment requirement. Since the apportionment requirement can only apply inequitably across the nation, the correct labeling of any federal tax (other than an income tax) as a "direct tax" amounts to the proverbial "kiss of death," as no such tax will be enacted. Recent commentary has staked out positions on this issue that I consider to be incorrect. Bruce Ackerman argues that that the Thirteenth Amendment (abolishing slavery) effectively repealed the apportionment-of-direct-tax clauses. Calvin Johnson argues that "direct tax" means only a tax capable (without effort) of being fairly apportioned among the states in accordance with population, namely, a capitation tax or a tax on the states (a requisition). At the other end of the spectrum, Erik Jensen argues that "direct tax" means any personal tax other than an income tax. I argue, on the basis of constitutional text, the formation of the constitution, post-ratification history, function, historical evolution, and judicial doctrine that "direct tax" encompasses only (1) capitation (head) taxes, (2) requisitions, and (3) taxes on real estate. The apportionment requirement made "political" sense in the Framing period by linking the representation of states with the taxation of states, and also appeared to serve some narrow instrumental concerns. However, the theory is skewed, mainly because states are not really taxed as states, and states (as states) are only tenuously represented in Congress. Also, although apportionment dealt with some instrumental concerns, it aggravated others. I conclude that (apart from requisitions and head taxes), apportionment makes sense only with respect to real estate taxes, which is the nearest tax to a state tax. I also conclude that a real estate tax cannot be bootstrapped into validity as an "income tax." Nevertheless, federal taxes on personal property and imputed income from real estate are constitutional, if endowment taxes are not.


Introduction A Marie Curie review1 highlighted that the Jewish population, alongside Black and Minority Ethnic (BME) groups, are under-represented in utilising palliative care.2 Explanations may include concerns around gaining trust and being culturally understood. Preferred Place of Death (PPoD) has been used as a key performance indicator (KPI) for measuring effective palliative care. Aim To establish a palliative care outreach clinic in a faith-based setting and subsequently evaluate patient experience and measure the KPI of PPoD. Methods In 2011 a cancer charity supporting the Jewish community, in collaboration with Marie Curie and The Royal Free London NHS Foundation Trust, developed a palliative care clinic, serving an area with a large Jewish population. The clinic runs weekly. A palliative care consultant sees and discusses all patients at the Marie Curie multidisciplinary team meeting. Data was collected via anonymous semi-structured patient experience survey in 2013 and 2016 and all patients are offered Advance Care Planning, including PPoD. Actual place of death has been recorded for all deceased patients. Results 39 patients completed the survey. 100% rated the service 'excellent' or 'good' In 2016, 17 patients in the service died. 13 achieved their PPoD (76%). Conclusion Achieving a 76% PPoD contrasts with the London average of 38.1% deaths in usual place of residence.3 This demonstrates the success of a faith based service catering for a traditionally 'hard to reach' population and represents a unique model within the United Kingdom. This model could be extended to other faith based communities to broaden access to palliative care. References 1. https://www.mariecurie.org.uk/globalassets/media/documents/policy/policy-publications/june-2013/palliative-and-end-of-life-care-for-black-asian-and-minority-ethnic-groups-in-the-uk.pdf 2. Dorff E. End of Life; Jewish Perspectives. The Lancet 2005;366:862–5 3. https://www.endoflifecare.org.uk/data_sources/place_of_death


People seeking therapy for mental health issues often also have medical problems such as diabetes, AIDS, asthma, or heart conditions. As a therapist, should you ignore the medical conditions that your clients may have, and simply stick to what you're trained in, healing the mind and not focusing on medical or bodily issues? Or, should you inquire about any medical issues during intake and give them full attention? As a non-medically trained practitioner, how much should you really be expected to know about these issues? These answers and more can be found in this book. Geared specifically to nonmedically trained mental health professionals, it gives practitioners a better understanding of exactly how physical health issues play out in the context of mental health issues, equipping clinicians with the information necessary to more effectively create and manage a comprehensive psychotherapeutic treatment regimen.


Abstract Background Infectious diseases, especially those caused by multidrug-resistant bacteria, are becoming a serious problem worldwide because of the lack of effective therapeutic agents. Moreover, most antifungal drugs exhibit low efficacy and high toxicity because of the similarity between fungal and human cells. These issues warrant the search for potential new agents. Objectives To synthesize potent 2-(2-iodophenylimino)-5-arylidenethiazolidin-4-one derivatives, improve the synthetic process, elucidate their structures, and determine their antimicrobial activity. Methods 2-Iodoaniline was used as an initial reactant in a 3-step process for the synthesis of 2-(2-iodophenylimino)-5-arylidenethiazolidin-4-one derivatives, including an acylation reaction, a cyclization reaction, and aldol condensation reactions. The structures of the obtained derivatives were investigated and elucidated using spectral methods. Antimicrobial activity toward 5 bacterial strains and 2 fungal strains was determined using Kirby–Bauer and agar dilution methods. Results We successfully synthesized 12 novel compounds and elucidated their structures. The derivatives had no antifungal activities. By contrast, they showed remarkable antibacterial activities. Some of them with minimum inhibitory concentrations (MICs) ≤8 μg/mL in both Staphylococcus aureus and methicillin-resistant S. aureus. Conclusions A simple and flexible way to synthesize new compounds with a thiazolidin-4-one ring was determined. Some of these new compounds have outstanding effects with low MICs for bacteria. Their further investigation as therapeutic agents is warranted.


Model-based evolutionary algorithms (MBEAs) are praised for their broad applicability to black-box optimization problems. In practical applications however, they are mostly used to repeatedly optimize different instances of a single problem class, a setting in which specialized algorithms generally perform better. In this paper, we introduce the concept of a new type of MBEA that can automatically specialize its behavior to a given problem class using tabula rasa self-learning. For this, reinforcement learning (RL) is a naturally fitting paradigm. A proof-of-principle framework, called SL-ENDA, based on estimation of normal distribution algorithms in combination with reinforcement learning is defined. SL-ENDA uses an RL-agent to decide upon the next population mean while approaching the rest of the algorithm as the environment. A comparison of SL-ENDA to AMaLGaM and CMA-ES on unimodal noiseless functions shows mostly comparable performance and scalability to the broadly used and carefully manually crafted algorithms. This result, in combination with the inherent potential of self-learning model-based evolutionary algorithms with regard to specialization, opens the door to a new research direction with great potential impact on the field of model-based evolutionary algorithms.


"Any further advances in scholarship on the late medieval Balkans will have to begin with this book."---George Majeska, University of Maryland"The Late Medieval Balkans" is the first comprehensive examination of the events of the late medieval Balkan history---events that were as important as they were fascinating.The period that John Fine examines was an era of significant demographic, political, and religious change in the region. During this time, native populations were supplemented or replaced by the Bulgars and various Slavic tribes, who were to become the Bulgarians, Serbs, and Croats---ethnic identities whose historical conflicts have persisted to this day."The Late Medieval Balkans" is an important source for those who wish to expand their knowledge of this turbulent period and who wish to broaden their understanding of the region.John V. A. Fine, Jr., is Professor of History, University of Michigan.


This study was conducted to guide the prioritisation of efforts to manage Cryptosporidum contamination of drinking water supplies in Trinidad, W.I. The main objective was to investigate the relative importance of three main types of sources of Cryptosporidium oocysts: urban, agriculture and wildlife. Weekly surface water samples were collected from 19 sites distributed among three watersheds, and examined for the presence of oocysts. A stratified random sampling design was used with each watershed representing one of the three main sources of oocysts listed above. Results showed a significant association between watershed and the occurrence of positive samples (chi(2)=16.523, d.f. =2, p = 0.000), indicating that land use influenced the presence of oocysts. Urban and forested lands were the two most important sources of oocysts. There was no apparent association between agriculture and the presence of oocysts, and there was no significant difference between the percentage of positive samples at sites below agricultural facilities and sites not associated with agriculture within a single watershed (chi(2)=2.45, d.f. =1, p = 0.117). We conclude that urban and wildlife are the main types of sources of Cryptosporidium contamination of surface water, whereas the contribution of agriculture is minor.


This book is a contemporary overview of selected topics in fiber optics. It focuses on the latest research results on light wave manipulation using nonlinear optical fibers, with the aim of capturing some of the most innovative developments on this topic. The book's scope covers both fundamentals and applications from both theoretical and experimental perspectives, with topics including linear and nonlinear effects, pulse propagation phenomena and pulse shaping, solitons and rogue waves, novel optical fibers, supercontinuum generation, polarization management, optical signal processing, fiber lasers, optical wave turbulence, light propagation in disordered fiber media, and slow and fast light. With contributions from leading-edge scientists in the field of nonlinear photonics and fiber optics, they offer an overview of the latest advances in their own research area. The listing of recent research papers at the end of each chapter is useful for researchers using the book as a reference. As the book addresses fundamental and practical photonics problems, it will also be of interest to, and benefit, broader academic communities, including areas such as nonlinear science, applied mathematics and physics, and optical engineering. It offers the reader a wide and critical overview of the state-of-the-art within this practical – as well as fundamentally important and interesting – area of modern science, providing a useful reference which will encourage further research and advances in the field.


Recent years have seen the increasing use of graphics processing units (GPUs) for nongraphics related applications. Applications that have harnessed the computational power of GPUs span across numerical algorithms, computational geometry, database processing, image processing, astrophysics and bioinformatics. There are many compelling reasons behind exploiting GPUs for such general-purpose computing tasks. First, modern GPUs are extremely powerful. For example, highend GPUs such as the NVidia GeForce GTX 480 and ATI Radeon 5870 have 1.35 TFlops and 2.72 TFlops of peak single precision performance, whereas a high-end general-purpose processor such as the Intel Core i7-960 has a peak performance of 102 Gflops. Additionally, the memory bandwidth of these GPUs are more than 5x greater than what is available to a CPU, which allows them to excel even in low compute intensity but high bandwidth usage scenarios. Second, GPUs are now commodity items as their costs have dramatically reduced over the last few years. In spite of a wide variety of computationally expensive system-level design tasks (in the context of embedded systems design) that are regularly solved by software tools running on desktops and laptops equipped with high-end GPUs, the use of GPUs for accelerating such problems is still not a conventional practice within the design automation community. As a result, of late, there has been a lot of research interest in demonstrating the applicability of GPUs in accelerating design automation tasks. Some of tasks that have been accelerated using modern GPUs include schedulability/timing analysis, hardware/software partitioning, fault simulation, and verification of digital designs. In this tutorial we will describe techniques for programming GPUs for general purpose computing (i.e., nongraphics applications) and cover a number of case studies from the electronic design automation area. We will demonstrate how GPUs can lead to significant improvement in running times and hence the usability of the design tools that exploit them. In particular, we will start by introducing the graphics processor architecture and programming models for GPUs (OpenCL and CUDA). OpenCL is an open standard for programming GPUs (and also other modern processors) and is a cross-platform alternative to CUDA. It has been created by a consortium that includes AMD, Apple, IBM, Intel, and Nvidia. We will then discuss various examples of system-level design tasks and identify their computational kernels. Finally, we will present different case studies to illustrate how system-level design algorithms have to be suitably modified in order to map them onto GPUs.


As reuse of municipal water resource recovery facility (WRRF) effluent becomes vital to augment diminishing fresh drinking water resources, concern exists that conventional barriers may prove deficient and the upcycling of contaminants of emerging concern (CECs) could prove harmful to human health and aquatic species if more effective and robust treatment barriers are not in place. There are no federal Safe Drinking Water Act (SDWA) regulations in place specifically for direct potable reuse (DPR) of WRRF effluent. Out of necessity, some states are developing their own DPR reuse regulations. Currently, reverse osmosis (RO) is the default full advanced treatment (FAT) barrier for CEC control. However, the potential exists for tight thin-film composite (TFC) nanofiltration (NF) membranes to provide acceptable CEC rejection efficacies for less capital, operations and maintenance (O&M), energy, and waste generated. Recognizing the inherent complexity of CEC rejection by membranes, this research program was designed to elucidate the vital predictive variables influencing the rejection of 96 CECs found in municipal WRRF effluents. Each of the CECs was cataloged by their intended use and quantitative structure activity relationship (QSAR) properties, and measured in secondary effluent samples from WRRFs in Texas and Oklahoma. These secondary effluent samples were then processed in bench-scale, stirred, dead-end pressure cells with water treatment industry-specified TFC NF and RO membranes. A multi-level, multi-variable model was developed to predict the probable rejection coefficients of CECs with the studied NF membrane. The model was developed from variables selected for their association with known membrane rejection mechanisms, CEC-specific QSAR properties, and characteristics of the actual solute matrix. R statistics software version 3.1.3 was utilized for property collinearity analysis, outlier analysis, and regression modeling. The Pearson correlation method was utilized for selection of the most vital predictor variables for modeling. The resulting Quantitative Molecular Properties Model (QMPM) predicted the NF rejection CECs based on size, ionic charge, and hydrophobicity. Furthermore, the QMPM was verified against a CEC rejection dataset published by an independent study for a similar commercially available TFC NF membrane.


Both as discourse and as practice, e-learning in Higher Education (HE) is shaped by many factors, the most critical of which are the political motivations driving its adoption. In this dissertation I attest that e-learning policies relevant to HE issued by government departments and non-departmental public bodies in the United Kingdom (UK) between 2003 and 2013 were predominantly underpinned by neoliberal ideology. The enquiry is grounded in the Critical research paradigm's intention to expose, critique, and ultimately overcome sources of oppression. Thirteen policy texts were analysed via two critical lenses. First, via thematic analysis (Braun and Clarke 2006) of the corpus I identified recurring themes. These were then clustered around a trilogy of master narratives: Marketisation, Instrumentality, and Modernisation. Through an ideology critique of these master narratives, I uncovered and unpacked the motivations underpinning claims made in relation to e-learning. My second mode of analysis was a detailed Critical Discourse Analysis (CDA) of each document. CDA sees the wider context as essential to making sense of a text (Bloor and Bloor 2007; Van Dijk 2008). My critique, therefore, considered each document within its historical and socio-economic context, and examined the extent to which the three master narratives were evident both over time, and across England, Scotland, and Wales. How policy is communicated and presented is as important as what is said (Barnett 2000). Indeed, ideologies can be both enacted and obscured by language (Jones and Stilwell Peccei 2004; Henriksen 2011). My analysis, therefore, also examined the role of visual presentation, lexical choices, and rhetorical techniques in communicating the policies. Taken together, the two prongs of my analysis demonstrate that − although there are variances in different contexts and at different times − overall, the policies considered were motivated by neoliberal imperatives aimed at placing HE within the realm of the market and enhancing the UK's economic competitiveness. The policies also persistently reflect a deterministic and uncritical perspective towards technology. Furthermore, many of the claims made are exaggerated, unsubstantiated, contradictory, and even duplicitous, or are justified via reference to contested discourses. While neoliberal ideology is privileged and promoted across the corpus, alternative value systems are not. I argue that this problematic framing of e-learning is intensifying the negative impacts of neoliberalism on HE's role as a public good, as well as exacerbating social inequalities. Furthermore, it is channelling e-learning into a restricted form that limits any possible pedagogical or egalitarian opportunities that the judicious application of digital technologies in HE teaching and learning might support. I reflect on the implications of this for HE and for society, and for the professional practice of Learning Technologists. Finally, I present an alternative vision for e-learning in HE.


This paper examines the factors and process underlying agrarian distress in Kerala by undertaking the case studies of three villages situated in Wayanad and Idukki districts namely, Cherumad, Kappikkunnu and Upputhara. The impact of distress on household livelihoods and indebtedness and how they cope up with the situation are examined with entire village and intra village analysis of data. The process of agrarian distress which resulted in suicides were analysed through a few in-depth studies. Decline in crops yield, coupled with sharp fall in their prices, created severe distress in all sections of agricultural population. Many household cope with these distresses by reducing household expenditure, diversifying their household incomes and searching for jobs in other places. Meanwhile, government interventions in terms of PDS, health care provision, education and supply of drinking water gave some relief to the affected persons. However, these measures could not completely prevent the occurrence of suicides among the members of agrarian households. The paper shows that the villages in which household income are more diversified and social networks much stronger, the distress conditions did not result in suicides. Mitigation of agrarian distress requires not only for debt relief but also implementation of long term strategies containing policies to promote price stability, ecological sustainability of agriculture, strengthening of formal rural credit and support networks, and income and employment generation programmes.


Objective: To compare the efficacy of sublingual misoprostol tablet and intracervical dinoprostone gel for induction of labor and also to assess the maternal and fetal outcome after induction. Methodology: A prospective observational study was conducted over a period of 6 months. Of 200 cases, 100 received sublingual misoprostol tablet (Group 1) and remaining received intracervical dinoprostone gel (Group 2). The time required from induction to delivery interval (IDI), and maternal and fetal outcome were assessed by the mode of delivery, Apgar score, and need for neonatal intensive care unit (NICU) admission. Data were analyzed using descriptive statistics, Student's t-test, and Chi-square test. Results: Induction to delivery time was 14.1 h in Group 1, whereas 13.9 h in Group 2. Stage II of labor was 2.3 h and 3.1 h in Group 1 and 2 (P < 0.05) respectively. Normal vaginal delivery occurred in 66 cases in Group 1 and 56 cases in Group 2. Apgar score (≥7) at 1 min was observed in 91 and 93 cases of Group 1and Group 2, respectively. Augmentation of labor by artificial rupture of the membrane was needed in 17 cases in Group 1 and 39 cases in Group 2 (P < 0.05). The need of NICU admission was 20 in Group 1 and 19 in Group 2 (P < 0.05). Conclusion: The misoprostol group showed shorter IDI, more number of vaginal deliveries, and reduced need of cesarean section, compared to dinoprostone group. There was a significant difference in the post induction Bishop's score, Stage II process of labor and reduction in the requirement of augmentation (ARM) between the two groups. Misoprostol was found to be more efficacious when compared to dinoprostone.


This creative thesis seeks to understand how the intersectional experiences and history of minority female authors of speculative fiction have impacted the content, style, and response to the works they produce before incorporating the understanding of that background into a speculative fiction short story. Representing diverse voices through the paradigm of intersectionality, which posits that social identity is a function of multiple, interwoven factors such as race and gender and the relationship of those aspects of social identity with wider social power structures, is a way of acknowledging the role of minority female authors in the speculative fiction genre. The first portion of this thesis describes the historical representation of minority female authors in speculative fiction and its relationship to the emergence of four waves of feminist thought in mainstream American society and how the social forces that facilitated those outbreaks of feminism also infiltrated the genre of speculative fiction from the 1970s to the present day. The background component of this thesis also includes a review of the backgrounds themes of three current authors of speculative fiction, Nalo Hopkinson, N.K. Jemisin, and Benjanun Sriduangkaew, extracting some general themes and examples of intersectionality within their bodies of work. The conclusion of the first section discusses the nature of the creative work which comprises the second component of the thesis.


Decision guidance models are a means for design space exploration and documentation. In this paper, we present decision guidance models for microservice monitoring. The selection of a monitoring system is an essential part of each microservice architecture due to the high level of dynamic structure and behavior of such a system. We present decision guidance models for generation of monitoring data, data management, processing monitoring data, and for disseminating and presenting monitoring information to stakeholders. The presented models have been derived from literature, our previous work on monitoring for distributed systems and microservice-based systems, and by analyzing existing monitoring systems. The developed models have been used for discussing monitoring requirements for a microservice-based system with a company in the process automation domain. They are part of a larger effort for developing decision guidance models for microservice architecture in general.


Inferences about brain function, using functional neuroimaging data, require models of how the data were caused. A variety of models are used in practice that range from conceptual models of functional anatomy to nonlinear mathematical models of hemodynamic responses (e.g. as measured by functional magnetic resonance imaging, fMRI) and neuronal responses. In this review, we discuss the most important models used to analyse functional imaging data and demonstrate how they are interrelated. Initially, we briefly review the anatomical foundations of current theories of brain function on which all mathematical models rest. We then introduce some basic statistical models (e.g. the general linear model) used for making classical (i.e. frequentist) and Bayesian inferences about where neuronal responses are expressed. The more challenging question, how these responses are caused, is addressed by models that incorporate biophysical constraints (e.g. forward models from the neural to the hemodynamic level) and/or consider causal interactions between several regions, i.e. models of effective connectivity. Some of the most refined models to date are neuronal mass models of electroencephalographic (EEG) responses. These models enable mechanistic inferences about how evoked responses are caused, at the level of neuronal subpopulations and the coupling among them.


This article examines the differences between exporter and nonexporter small and medium enterprises (SMEs) in Turkey to understand the impact of government programs on their export decisions. The empirical data are from a survey of 300 Turkish SMEs (150 exporters and 150 nonexporters) in Turkey. As our question is why some SMEs are exporting while others of a similar size are not, although the government export promotion programs are same for all SMEs, the dependent variable should be dichotomous, and the applicable analytical model should come from the binary-choice genre of models, namely. Results suggest that government export-promoting programs, size of the firms, and manufacturing status of the firms contribute positively to export performance in SMEs, but barriers such as educational level of managers, lack of financial resources, lack of language knowledge, too many government regulations, and high taxes negatively affect the export performance of Turkish SMEs.


The Hebrides of Scotland - around 500 diverse islands - form the north-western Atlantic fringe of Europe. This book surveys the cultural landscape of this dramatically beautiful, complex and conflicted area, with emphasis on what may be interpreted through aerial photography. Its main themes are the mutual influences of people and environment, and the recent history and current issues in the area. Mobile maritime cultures flourished throughout the Hebrides from prehistoric times, including Mesolithic builders of wheelhouses, coracle-borne monastic travellers, Norse in longships and Lords of the Isles in birlinns. A prominent feature of the recent history of the Hebrides has been depopulation. The history and heartbreak of this phenomenon, experienced in differing degrees in rural areas throughout Europe from the mid-18th century, is clearly shown in aerial photographs and discussed in the accompanying text. Today's Hebridean landscapes have been heavily modified by various forms of human land use; current land-management options and controversies are also discussed in the context of photographs that draw attention to the various issues involved.


1. Rats treated with disodium ethane-1-hydroxy-1,1-diphosphonate for 14 days developed rickets and impaired intestinal calcium transport, even when receiving large amounts of cholecalciferol (vitamin D 3 ). 2. Vitamin d-deficient rats treated with the diphosphonate, and irrespective of the duration of such treatment, responded initially to a single intravenous dose of cholecalciferol with a normal production of 1,25-dihydroxycholecalciferol. 3. This normal response was followed within 2 days by an apparent inhibition of the renal biosynthesis of 1,25-dihydroxycholecalciferol. It is inferred that the impaired intestinal transport of calcium, in diphosphonate-treated rats receiving vitamin D, is due to a deficiency of this renal metabolite. 4. Inhibition of the synthesis of 1,25-dihydroxycholecalciferol could not be attributed to a direct action of the drug on the renal 1-hydroxylase, but appeared to be determined by the initial normal response to vitamin D. 5. The mechanisms possibly involved in producing this effect are discussed.


Why has the production of public murals in London declined in recent decades? Can mural making be reclaimed as a critical art form? What is the relationship between public surface and public space?

This new publication focuses on ten key murals in London – ranging from the well-known and visible such as The Battle of Cable Street in East London to the forgotten and hidden – to examine how these public paintings have changed over time and how the spaces around them have transformed. The murals are presented through newly-commissioned photographs, each accompanied by a text which draws on and reflect on the broader questions of the project. How does making a mural in a local community alter artistic decision making? Why confront the difficulties of making an image collectively? How have changes in the distribution of art funding in recent decades affected mural production?

Reclaim the Mural marks the end of two year's research by the art collective The Work In Progress (Benedict Drew, Emma Hart, Dai Jenkins, Dean Kenning and Corinna Till), who were commissioned as part of the Whitechapel Gallery's programme of new art beyond the gallery. This publication brings together their findings in order to disseminate and share their ideas, and provoke further questions.

With an introduction by the curators of the project and an essay by writer Owen Hatherley, Reclaim the Mural offers a unique insight into a long-term, artist-led project. It is the only publication which looks critically at the legacy of the mural and community arts movement of the late seventies and provides an important analogy with contemporary questions surrounding the social function of art.


1. In peripheral arterial insufficiency, leg blood flow during exercise is reduced. The aim of this study was to investigate the metabolic response in different muscle types during exercise at reduced versus normal exercise blood flow. 2. A modified rat hindlimb perfusion model was used. Muscle metabolites and distribution of labelled microspheres were analysed in the soleus and the gastrocnemius muscles during exercise induced by sciatic nerve stimulation. 3. Blood flow distribution between the soleus and the gastrocnemius muscles (per unit weight) was 1.7: 1 at rest, and this ratio did not change significantly during exercise at reduced flow. 4. There was a more pronounced decrease in the [phosphocreatinel, the [glycogenl and the [ATPI/[ADPl ratio as well as a more pronounced increase in the [lactate] and the [lac-tatel/[pyruvatel ratio in the gastrocnemius muscle during exercise at reduced blood flow as compared with values obtained at normal exercise flow. In the soleus muscle the difference between the two conditions was confined to an increased [lactatel/[pyruvatel ratio. 5. The results show that a muscle composed mainly of fast-twitch fibres with a high glycolytic and low oxidative capacity is much more susceptible to a reduced exercise flow than a muscle composed of slow-twitch, oxidative fibres. It is suggested that claudicating pain is related to these metabolic changes and it is concluded that pain most probably originates in type I1 fibres.


This article assesses the feasibility and benefits of converting the Iranian heavy water research reactor, IR-40, from using natural uranium to low-enriched uranium fuel. Based on neutronics calculations for a detailed model of the two reactor configurations, a conversion would result in a smaller core with a subsequent reduction and degradation of plutonium production. It is argued that the proposed conversion will provide Iran with a research reactor that is better suited for scientific experiments and radioisotope production than in its original configuration. It is proposed to introduce the converted IR-40's fuel consumption requirements as a natural cap for Iran's future enrichment efforts.


Ernst Walter Mayr was a person of the twentieth century, having missed only a few years at the beginning of that century and lived into a few years of the twenty–first. He was a naturalist all of his life which established the foundation for his career as an evolutionary biologist. Often called the 'Darwin of the twentieth century', Ernst Mayr was clearly one of the best–known evolutionary biologists of his time, being one of the major architects of the modern evolutionary synthesis of 1937–48 and serving as the major founder of the Society for the Study of Evolution and of its journal Evolution. Although he was born and educated in Germany, Ernst was an American scientist, having worked at the American Museum of Natural History (AMNH) and the Museum of Comparative Zoology, Harvard University, for 74 of his 100 years. Almost all of his publications were in the area of evolutionary biology; he published very few papers in functional biology. The most technical tool that he used was a Dictaphone. Ernst was truly a non–technical person and complained in his later years about libraries putting their catalogues in an electronic form because he did not know how to type – he did not even know the location of the keys on the keyboard – which delayed him greatly finding books he did not know. Computers were out of the question. He was outgoing, sought out interesting people whether they were important or not, talked to them, listened to what they said, read intensively, and thought deeply about what he took in. He had an amazing memory, but more importantly he could readily put the bits of knowledge together into new and significant ideas. He was a real teacher and simply could not allow someone to someone to leave with wrong ideas. Ernst had strongly held ideas and was firm in them; hence many people considered him to be overly dogmatic. He was interested in what was correct and not necessarily who was correct. He would argue strongly for his ideas, but he would change his position readily if he was convinced of the opposing stance. One had to be certain of one's facts and logic in any discussion with Ernst, which prevented many students and co–workers from discussing controversial ideas with him, something that made him sad. I can recall clearly his statement that 'My bark is worse than my bite.'


Christopher Schmidt-Nowara's book, Slavery, Freedom, and Abolition in Latin America and the Atlantic World, addresses the fact that Latin America has always been a place of great struggles and triumphs. While inconsistency and danger have always had a stronghold in this place, serious traditions have developed as well. Slavery is one of the most apparent examples of this; an analysis of how it functioned is highly revealing of the historical past. Without it, the development of Latin America would have been far less productive. It was an economic gold mine that was integrated into society and that was why people clung to it so much. Slavery was so resilient in Latin America because it worked well and was a key component of Latin American identity that people did not want to give up. This is evident by analyzing the progression of slavery and its termination. This article is available in Constructing the Past: http://digitalcommons.iwu.edu/constructing/vol14/iss1/12


We define a $k$-plex to be a partial latin square of order $n$ containing $kn$ entries such that exactly $k$ entries lie in each row and column and each of $n$ symbols occurs exactly $k$ times. A transversal of a latin square corresponds to the case $k=1$. For $k>n/4$ we prove that not all $k$-plexes are completable to latin squares. Certain latin squares, including the Cayley tables of many groups, are shown to contain no $(2c+1)$-plex for any integer $c$. However, Cayley tables of soluble groups have a $2c$-plex for each possible $c$. We conjecture that this is true for all latin squares and confirm this for orders $n\leq8$. Finally, we demonstrate the existence of indivisible $k$-plexes, meaning that they contain no $c$-plex for $1\leq c


In recent years, large amounts of data have accumulated with the application of database systems. Meanwhile, the requirements of applications have not been confined in the simple operations, such as search and retrieval, because these operations were not helpful in finding the valuable information from the databases. The hidden knowledge is hard to be handled by the present database techniques, so a great wealth of knowledge concealed in the databases is not developed and utilized mostly.

Data mining aimed at finding the essential significant knowledge by automatic process of database. DM technique was one of the most challenging studies in database and decision-making fields. The data range processed was considerably vast from natural science, social science, business information to the data produced from scientific process and satellite observation. The present focuses of DM were changed from theories to practical application. Where the database existed, there were many projects about DM to be studied on.

The paper concentrated on the research about data information in credit card by DM theories, techniques and methods to mine the valuable knowledge from the card. Firstly, the basic theories, key algorithms of DM techniques were introduced. The emphases were focused on the decision tree algorithms, neural networks, X-means algorithm in cluster and Apriori algorithm in association rule by understanding the background of bank and analyzing the knowledge available in the credit card. A preliminary analysis of credit card information, Industry and Business Bank at Tianjin Department, was performed based on the conversion and integration of data warehouse. The combined databases including information of customers and consumptive properties were established in accordance with the idea of data-warehouse. The data were clustered by iT-means algorithm to find valuable knowledge and frequent intervals of transaction in credit card. Back propagation neural networks were designed to classify the information of credit card, which played an important role in evaluation and prediction of customers. In addition, the Apriori algorithm was achieved to process the abovementioned data, which could establish the relations between credit information of customers and consumption properties, and to find the association rule among credit items themselves, providing a solid foundation for further revision of information evaluation.

Our work showed that DM technique made great significance in analyzing the information of credit card, and laid down a firm foundation for further research in the retrieval information from the credit card.


Credit derivatives are among the most important new financial instruments, but also among the most complicated. Each individual issuer is continuously exposed to default risk, and default intensity looking forward is not constant. It typically has a term structure, as revealed in the CDS market. A portfolio of risky bonds, as in a CDO, aggregates the individual risks, and now the correlations among them also become important. CDO tranches then redistribute and split up this aggregate exposure among a set of new securities. Evaluating the resulting tranche exposures requires a model for the individual default risks and their correlations, but even in the industry-standard Gaussian copula model, the problem is computationally intractable without heroic simplifying assumptions. The plainest vanilla model assumes correlations are equal for all pairs of credits. Then, analogous to the way an implied volatility can be extracted from an option's market price, the implied correlation can be extracted from a CDO tranche price. But, as with implied volatility, the resulting tranche correlations differ widely for different tranches, leading to the use of "base correlation," a different implied correlation concept. Base correlation is still inconsistent with the model it is derived from, but it is not quite as badly behaved as tranche correlations. In this article, Hull and White offer an alternative approach that considerably reduces the inconsistencies in calibrating a copula to a set of CDO tranche prices. The secret is to make default intensities and recovery rates stochastic, rather than requiring a single value. By imposing the restrictions that the single-name CDS and the CDO tranches must all be priced by the model just as they are in the market, and that the probabilities for the set of possible individual default intensities must sum to 1 and exhibit maximum smoothness, Hull and White are able to imply tranche correlations that are much better behaved than the standard approach. The last part of the article extends their procedure in a number of directions, to nonstandard attachment points, bespoke portfolios, and CDO-squared securities.


OBJECTIVE
Evaluate the effect of a digital Diabetes Prevention Program (dDPP) on chronic disease risk factors in a workplace population.

METHODS
dDPP participants were employees and spouses with BMI ≥24 kg/m and prediabetes or diabetes (n = 84). Annual change in risk factors before and after dDPP were assessed in the dDPP group and in a retrospectively identified matched control group drawn from those who participated in a dDPP after the conclusion of this study (n = 252).

RESULTS
In the dDPP group, body weight, BMI, fasting glucose, triglycerides, total cholesterol and LDL-cholesterol decreased in the post-dDPP period compared with the pre-dDPP period (P < 0.05). In the control group, no difference between the annual change before and after dDPP was observed (P > 0.37).

CONCLUSION
The dDPP was effective in reducing risk factors for chronic disease in a workplace setting.


Obesity is defined as a BMI greater than 25 kg/m 2 . Once thought to simply be a nutritional disorder, obesity has become a major health concern characterized by a state of constant low-grade inflammation caused by chronic adiposity. This state of inflammation is characterized by circulating inflammatory mediators, such as IL-6, leptin, and TNF- α , as well as varying levels of glucose-regulating hormones produced by obese adipose tissue. When left untreated, obesity can lead to a number of diseases including, but not limited to, cardiovascular disease, metabolic syndrome, neurodegeneration, type II diabetes mellitus, chronic kidney disease, and infertility. The distribution of adiposity differs in men and women, and these differences, along with the differences in sex hormones and sex hormone levels, can exacerbate or attenuate the course of disease pathology. Obesity can also be exacerbated by stress, which can worsen disease pathogenesis. In this review, we will explore how obesity affects inflammation and disease and how sex can affect the course of these diseases.


Purpose: The paper aims to identify the actions that foster the development of positive relationships between employees and the company and help build internal relational capital. The authors also attempted to describe the patterns of formation of intra-organizational relations by identifying the actions that contribute the most to the development of internal relational capital. Design/Methodology/Approach: Two studies conducted in 2018-2020 focused on the importance of relational competencies in creating company value and the role of leadership. The first study concentrated on the managers (N=10), whereas the second one focused on the analyzed companies' employees (N=185). The obtained information was used to perform structural analysis, based on structural indicators expressed as percentage values. Factor analysis was also carried out as part of the data analysis to determine the relationships between factors. The principal component analysis was used. Findings: The results indicate that in the process of creation and development of intellectual capital in an enterprise, the role of a leader involves mainly the establishment of values desired for the company's success, creation of a corporate culture that helps to accomplish goals, and assistance in reaching the targets by employees, as well as support for workers and their activity. The analyzed enterprises are engaged in developing proper internal relations and apply different methods to build relations between the company and the employees. Practical Implications: The results indicate the directions for building internal relations. Identification of the actions that demonstrate a greater impact on the development of positive relationships between employees and the company and those with a lesser impact. Originality/Value: Concentration on effective relational management and creation of relational capital are the key elements of modern leadership. The development of positive relationships between employees and the company contributes to the company's relational capital, which considerably affects an enterprise's growth and competitive position.


The overlap stage is one of the most time- and space-consuming steps in de novo genome assembly. The huge size of output of Next Generation Sequencing (NGS), represented by small segments of multiple copies of the original genome, creates a serious computational challenge. The target is to find overlaps between each pair of sequences (reads) in order to build an overlap-based graph which constitutes the input for the assembly stage in which longer sequences (contigs) are sent to output. Finding overlaps between each pair of the input reads can be performed by solving the all-pairs suffix prefix problem (APSP) for these sequences. Such a problem, if not addressed effectively by designing new algorithms, data structures, and parallel processing techniques, can create an obstacle to the target of making genome assembly possible even with limited resources. This work presents a survey for previously presented solutions for APSP. We demonstrate and classify these techniques. Showing recent results regarding the time and space consumption for these solutions, we draw a conclusion regarding the best direction to tackle this critical problem. All-pairs suffix prefix is a well-known computer science problem. For a group of sequences G = {S1, S2, S3, …. Sk), finding all pairs suffix prefix is to find the longest suffix prefix match for each ordered pair in G. For instance, let G = {AACCGT, TAAAC, ACCCTA}. The solution to all-pairs suffix prefix for G is: (1,2) = {T}, {1,3} = {}, (2,1) = {AAC}, (2,3) = {AC}, {3,1} = {A} and (3,2} = {TA}. The first optimal solution for APSP was introduced by Gusfield et al. (D. Gusfield, 1992). The algorithm was based on the generalized suffix tree and takes O(n+k2) time, where n is the total length of all k strings. The suffix tree data structure is one of the most important tools for string matching and its applications in bioinformatics. A suffix tree of a sequence S is an index structure in which each suffix of S is stored as a path from the root to a leaf. Obviously many suffixes will share partial path before they end in different leaves. Despite the fact that suffix tree's performance in solving many genome analysis problems is considered optimal, suffix tree is expensive in term of space. A pointer-type suffix tree typically requires O(n log n) space, whereas the original text over an alphabet of size requires only O(n log) bits. In addition, suffix tree has a bad locality of memory reference, which causes a remarkable slowdown in cached processor architectures. A practically faster and less space-consuming solution for APSP was presented by Ohlebusch and Gog in 2010 (E. Ohlebusch and S. Gog, 2010), using the enhanced suffix array (M. Abouelhoda, 2004). Suffix array has emerged as a substitute to suffix tree in order to avoid its high space consumption, and to achieve better locality. The suffix array SA of a string S is an array of integers including the positions of the lexicographically sorted suffixes of S; i.e., for any two integers 0 i' < i'' < n, S[SA[i']] is lexicographically less than S[SA(i'')]. Several indices were introduced in the last decade as compressed versions of suffix trees and suffix arrays. Those indices were considered a miracle since they don't just offer indexed searching, but also extract any text substring from the original text. With these self-index data structures, the original text is unnecessary and can be discarded. The term self-index highlights the fact that text is not stored explicitly but it can be derived from the index. FM index and RLCSA are examples for compressed suffix array, while Sadakane tree is a good example for compressed suffix tree. Simpson and Durbin (J.T. Simpson and R.Durbin, 2012) used the FM index (P. Ferragina, 2004) to solve APSP in an indirect way as follows. The index is constructed for all strings after concatenating them in one string. The index is then queried by the reads, one by one, to find prefix-suffix matches. The time complexity of this algorithm is not as optimal as the one of (D. Gusfield, 1992), because one examines more suffixes than the output size. (This limitation stems also from the fact that the FM index lacks structural information to run the algorithms of (D. Gusfield, 1992) or (E. Ohlebusch and S. Gog, 2010) on it.). However, its space consumption is much less than that of the previous algorithms. The resulting assembler was called SGA. Rachid et al. (M. H. Rachid Q. M., 2014) presented two solutions to solve APSP using a Sadakane suffix tree. The Sadakane suffix tree is a self-index and fully functional in a similar way to the uncompressed version of suffix tree. It offers the typical suffix tree operations such as checking if a node is a leaf, moving to the next sibling, using a suffix link, or even performing lowest common ancestor queries which can be expensive in term of time with other compressed data structure such as FM. Rachid et al. (M. H. Rachid Q. M., 2014) took advantage of the different components of this tree to solve APSP. The authors also utilized these components in building two different parallel implementations of these solutions. Rachid et al. (M. Haj. Rachid, 2014) also presented a solution to APSP using RLCSA. RLCSA is a compressed suffix array, which is introduced in (J. Siren, 2008), (J.Siren, 2010), and (V. Makinen, 2009). Both solution achieved considerable space reduction, but with a big slowdown. Readjoiner (G. Gonnella & S. kurtz, 2012) was recently proposed as an efficient genome assembler that, in the overlap stage, finds suffix-prefix matches with a minimal length l by grouping all relevant suffixes in buckets. Each bucket is identified by a common prefix for all suffixes inside it. Then, after sorting suffixes inside each bucket, it finds suffix-prefix matches using the lcp-intervals concept which is introduced in (M.I. Abouelhoda, 1994). The overlap stage in Readjoiner achieved best time and space consumption over all earlier solutions. Rachid and Malluhi (M. H. Rachid Q. M., 2015) presented a solution, called SOF, for APSP using a compact prefix tree. A prefix tree is a tree in which every read is represented by one path from the root to a leaf. The internal nodes represent common prefixes between reads. SOF could not achieve better results than Readjoiner using a single thread; however it shows better scalability and better time and space consumption in a multithreading environment. Figures 1 and 2 show the time and space consumptions for 7 different solutions to APSP when running on randomly generated data (M. H. Rachid Q. M., 2015). Figure 1. Time consumptions for 7 solutions running on randomly generated data Figure 2. Space consumptions for 7 solutions running on randomly generated data We conclude that using suffix tree/array-based solutions, with standard or compressed forms, is not the best direction to solve APSP, despite the fact that they may possess an optimal time complexity. It turns out that other techniques which are based on LCP interval can achieve practically superior results in term of time without the large space which a suffix tree/array requires. Bibliography D. Gusfield, G. L. (1992). An efficient algorithm for the all pairs suffix-prefix problem. Inf. Process. Lett, 41(4):181–185. E. Ohlebusch and S. Gog. (2010). Efficient algorithms for the all-pairs suffix-prefix problem and the all-pairs substring-prefix problem. Inf. Process. Lett, 110(3):123–128. G. Gonnella, & S. kurtz. (2012). Readjoiner: a fast and memory efficient string graph-based sequence assembler. BMC Bioinformatics, 13:82. J. Siren, N. V. (2008). Run-Length Compressed Indexes Are Superior for Highly Repetitive Sequence Collections. in Amihood Amir; Andrew Turpin & Alistair Moffat, pp. 164–175. J. Siren. (2010). Sampled Longest Common Prefix Array. CoRR abs. J. T. Simpson and R. Durbin. (2012). Efficient de novo assembly of large genomes using compressed data structures. Genome research, 22(3):549–556. M. Abouelhoda, S. K. (2004). Replacing suffix trees with enhanced suffix arrays. Journal of Discrete Algorithms, 53–86. M. H. Rachid, Q. M. (2014). Using the sadakane compressed suffix tree to solve the all-pairs suffix-prefix problem. BioMed research international. M. H. Rachid, Q. M. (2015). A practical and scalable tool to find overlaps between sequences. BioMed Research International, 12. M. Haj. Rachid, Q. M. (2014). A space-efficient solution to find the maximum overlap using a compressed suffix array. Biomedical Engineering (MECBME), 329–333. M. I. Abouelhoda, S. K. (1994). Replacing Suffix Trees with Enhanced Suffix Arrays. Journal of Discrete Algorithms, 2, 53–86. P. Ferragina, G. M. (2004). An alphabet-friendly fm-index. In SPIRE, 150–160. V. Makinen, G. N. (2009). Storage and Retrieval of Individual Genomes. in Serafim Batzoglou, ed., 'RECOMB', Springer., pp. 121–137.


The neurotrophins are secreted growth factors that play a range of roles in the development and maintenance of the vertebrate nervous system through binding to two classes of receptors, the shared p75 neurotrophin receptor and the Trk receptor tyrosine kinase. Neurotrophins exist as dimers, and a crystal structure of the neurotrophin, nerve growth factor (NGF), bound to a ligand-binding domain of Trk has a 2:2 complex, which suggests that receptor dimerization may be involved in the activation mechanism. Now He and Garcia (see the Perspective by Zampieri and Chao) have determined the structure of NGF bound to the extracellular domain of p75 at 2.4 Å resolution. In the structure, an NGF dimer is bound to a single p75 monomer, and this allosteric binding prevents binding of a second p75. Signaling may thus occur through the disassembly of p75 dimers, which would potentially allow NGF-p75 complexes to engage the Trk receptor and to modulate its signaling. X. He, K. C. Garcia, Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science 304, 870-875 (2004). [Abstract] [Full Text] N. Zampieri, M. V. Chao, The p75 NGF receptor exposed. Science 304, 833-834 (2004). [Summary] [Full Text]


The purpose of this study was to find out what it is that motivates staff to work with people with mental disabilities. There is currently very little research on how employees perceive their work with people with mental disabilities. There is even less research to explain their motivation, and when it comes to housing, the literature - and the article studies proved that there is nothing about the motivation of the work housing. The data collection method used was semi-structured qualitative research interviews which were analyzed using thematic analysis. Study results have been divided into five different endings themes: to understand and get to know another human being, personal development, to mean something to another person, a demanding job that needs to be discussed, to provide the best assistance, the staff must have the right materials and knowledge with them. The main conclusion to be drawn from this study is that it is the people that are most important in motivating the staff. The motivation seems to be in order to understand, to know, help and support another person in getting a better life.Keywords: motivation, people, personal development


Onion (Allium cepa L.) is the third most valuable vegetable crop worldwide and the third most produced in Brazil. The knowledge of the nature and the value of the relationship between the traits of interest is very important, since it is possible to select a main trait, with low heritability or difficult measurement, obtaining higher genetic gain faster than with direct selection. The aim of this work was to estimate the genotypic, phenotypic and environmental correlations between the characteristics of the plant, the bulb and seed production in onion segregating populations obtained from different breeding methods. Most of the estimations of the genetic correlations (rg) were higher than the phenotypic (rp) and the environmental (re) ones. The genotypic, phenotypic and environmental correlation coefficients for plant and bulb characteristics were low, except for plant vigour and its components (plant height, neck diameter and plant architecture). The phenotypic and genotypic correlations revealed an association between the traits related to the plant vigour in onion, nevertheless, it was not reflected in the bulb and seed production, in the two years evaluated. The traits "Seed setting" and "Resistance in Alternaria" can be useful in the indirect selection for "Seed mass per umbel


Highly reliable interleaved memory systems for uniprocessor and multiprocessor computer architectures are presented. The memory systems are divided into groups. Each group consists of several banks and each bank has several modules. The error model is defined at the memory-module level. A module is faulty if any single or multiple faults result in loss of the entire module. Spare modules, as well as spare banks, are included in the systems to enhance reliability and availability. A faulty module is replaced by a spare module within a bank first, and, if the bank has no redundancy remaining for the faulty module, the whole bank will be replaced by a spare bank at the next higher level. The structure of the reconfigurable memory system is designed in such a way that the replacement of faulty modules (banks) by spare modules (banks) will not disturb memory references if each bank (group) has at most two spare modules (banks). If there are more than two spare modules (banks) in a bank (group), a second-level address translator is designed which can prohibit references to faulty modules by address remapping. The address translator can be implemented with a CAM or switches. Analysis results show that the system reliability can be significantly improved with little hardware overhead. Also, a typical system with one redundant row of modules has the highest cost-effectiveness during its useful lifetime period. User transparency in memory access is retained.


Transfers of technology to least developed countries (LDCs) are often hindered by lack of absorptive capacity on the receiving party, the possibility of imitation, and relatively thin markets for the licensed product. We propose a licensing model that considers these problems. A licensor must decide on the amount of know-how to costly transfer to the licensee, taking into account that this transfer may prompt the introduction of an imitation product. We study how this a¤ects know- how transfers and the form of scheduled payments that support these transfers.


Is it possible to trade with bandits? When government is absent, the superior strength of some agents makes it cheaper for them to violently steal what they desire from weaker agents than to use trade to obtain what they want. Such was the case with middlemen who interacted with producers in late precolonial west central Africa. In the face of this threat, producers employed two mechanisms to make exchange with middlemen possible. On the one hand, they used credit to alter middlemen's cost‐benefit structure of engaging in plunder versus trade. On the other hand, producers demanded tribute from traveling traders as a risk premium. By transforming traveling traders' incentive from banditry to peaceful trade and reducing producers' costs associated with interacting with middlemen, these mechanisms enhanced both parties' ability to capture the gains from exchange.


With the development of a toxic bait (HOGGONE®) for the control of invasive wild pig (IWP; Sus scrofa) populations in the United States, there is a need to develop a bait station to mitigate potential effects on nontarget species. Our objective was to identify characteristics of a bait station that can successfully exclude raccoons (Procyon lotor)—a ubiquitous and dexterous nontarget species—while facilitating bait consumption by IWPs that exhibit group-feeding behaviors. We evaluated abilities of captive raccoons (n = 19) and IWPs (n = 41) to open the lids of prototype resistance assessment bait stations (RABS) under various levels of resistance (range = 1.1–18.1 kg) at research facilities in Colorado and Texas, USA, during July–August 2014. We found that similar proportions (0.65) of individual raccoons and IWPs in our tests opened lids with 0–1.4 kg resistance, which decreased as resistance increased. No raccoons opened lids with ≥13.6 kg of resistance. However, equal proportions (0.45) of IWPs opened lids with 13.6 kg and 18.1 kg, and a greater proportion (0.73) secondarily accessed RABS after other IWPs opened them. Scrounging behaviors of IWPs (i.e., aggressively taking access to food from less dominate IWPs) increased as the levels of resistance increased, but similar proportions of animals gained access. These results suggest that a threshold-weight-of-resistance of 13.6–18.1 kg on hinged lids excludes raccoons and allows access by IWPs. Furthermore, bait stations designed to allow multiple IWPs to feed simultaneously may be preferred because of group feeding behaviors. Field evaluations are required to evaluate the exclusion of other nontarget species (e.g., white-tailed deer [Odocoileus virginianus], black bears [Ursus americanus], and coyotes [Canis latrans]), potential scrounging behaviors by nontargets, and bait consumption by IWPs. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.


Mobile technology has significant potential to help revolutionize personal wellness and the delivery of healthcare. Mobile phones, wearable sensors, and home-based tele-medicine devices can help caregivers and individuals themselves better monitor and manage their health. While the potential benefits of this "mHealth" technology include better health, more effective healthcare, and reduced cost, this technology also poses significant security and privacy challenges. In this paper we propose Amulet, an mHealth architecture that provides strong security and privacy guarantees while remaining easy to use, and outline the research and engineering challenges required to realize the Amulet vision.


Concern about the EU's 'democratic deficit' is misplaced. Judged against prevailing standards in existing advanced industrial democracies, rather than those of an ideal plebiscitary or parliamentary democracy, the EU is democratically legitimate. Its institutions are tightly constrained by constitutional checks and balances: narrow mandates, fiscal limits, super-majoritarian and concurrent voting requirements and separation of powers. There is little evidence that the EU impacts an unjustifiable neo-liberal bias on EU policy. The apparently disproportionate insulation of EU institutions reflects the subset of functions they perform – central banking, constitutional adjudication, civil prosecution, economic diplomacy and technical administration – which are matters of low electoral salience commonly delegated in national systems, for normatively justifiable reasons. Efforts to expand participation in the EU, even if successful, are thus unlikely to greatly expand meaningful deliberation. On balance, the EU redresses rather than creates biases in political representation, deliberation and output.


Judgment aggregation is an abstract framework for studying collective decision making by aggregating individual opinions on logically related issues. Important types of judgment aggregation methods are those of scoring and distance-based methods, many of which can be seen as generalizations of voting rules. An important question to investigate for judgment aggregation methods is how hard it is to find a collective decision by applying these methods. In this article we study the complexity of this "winner determination" problem for some scoring and distance-based judgment aggregation procedures. Such procedures aggregate judgments by assigning values to judgment sets. Our work fills in some of the last gaps in the complexity landscape for winner determination in judgment aggregation. Our results reaffirm that aggregating judgments is computationally hard and strongly point towards the necessity of analyzing approximation methods or parameterized algorithms in judgment aggregation.


MicroRNAs (miRNAs) are an extensive class of regulatory RNA whose specific functions in animals are generally unknown. Although computational methods have identified many potential targets of miRNAs, elucidating the spatial expression patterns of miRNAs is necessary to identify the sites of miRNA action. Here, we report the spatial patterns of miRNA transcription during Drosophila embryonic development, as revealed by in situ hybridization to nascent miRNA transcripts. We detect expression of 15 "stand-alone" miRNA loci and 9 intronic miRNA loci, which collectively represent 38 miRNA genes. We observe great variety in the spatial patterns of miRNA transcription, including preblastoderm stripes, in aspects of the central and peripheral nervous systems, and in cellular subsets of the mesoderm and endoderm. We also describe an intronic miRNA (miR-7) whose expression pattern is distinct from that of its host mRNA (bancal), which demonstrates that intronic miRNAs can be subject to independent cis-regulatory control. Intriguingly, the expression patterns of several fly miRNAs are analogous to those of their vertebrate counterparts, suggesting that these miRNAs may have ancient roles in animal patterning.