With attractive pinkish-white flowers and lush green foliage, the Madagascar rosy periwinkle appears at first to be an innocuous, decorative plant. Belying its appearance, the plant has incredibly potent qualities. In the early 1950s, the pharmaceutical giant Eli Lilly & Company began conducting research on the periwinkle, until then grown largely by poverty-stricken indigenous communities. Inspired by its use traditional medicine, researchers at Eli Lilly eventually isolated two extracts--vinblastine and vincristine. Both extracts have become powerful drugs, one to treat childhood leukemia, and the other to treat Hodgkins' Disease. Together, these drugs generate over US$200 million in revenue for Eli Lilly each year, no part of which is seen or even heard of by the people of Madagascar. [ILLUSTRATION OMITTED] The story of Eli Lilly and the rosy periwinkle is one example that relevant NGOs label as "biopiracy," a term used to describe the appropriation, by outside forces, of legal rights over indigenous knowledge. This type of traditional knowledge (TK), including but not limited to native lore about plants and animals, is scantily protected under existing international intellectual property (IP) regimes. Furthermore, indigenous communities tend to be located in poorer countries in the "Global South," where governments cannot easily afford to regulate or protect local rights to indigenous biodiversity. In order to protect the rights of the governments and peoples of these countries, the current system must be adapted, with new laws created that recognize value of traditional knowledge. The question arises, however, of whether or not knowledge about indigenous biodiversity can be considered intellectual property. The end product, a compound developed from an original plant sample, might have a completelely different purpose than the original status of the plant in traditional knowledge. At the very least, however, benefit-sharing agreements between drug patent-holders and source countries is not only a moral issue in terms of uniform protection of rights, but at a more fundamental level, is necessary for protecting and promoting the livelihoods of the world's poor. International Standards: The West and the Rest The current basis for international intellectual property law resides in a treaty signed by WTO member states, the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). The TRIPS agreement is a basic framework that protects the intellectual property rights of individuals and corporations across WTO nations. However, the standards of TRIPS stem from those of richer, developed nations. Pushed through the WTO by the US, European countries, and Japan, the agreement as a whole is generally viewed by advocates of developing countries as a forced concession to the developed world. Though fought and debated for a decade, by the beginning of 2005, all developing countries were bound to comply to TRIPS intellectual property standards. The agreement, thus far, has mostly served to protect the interests of large, multinational corporations based in the developed world. Particularly with regard to prescription drugs, TRIPS has protected large pharmaceutical countries to the detriment of the citizens of poorer nations, who in many cases have the most need for such drugs but are the least able to afford them. The irony, then, comes full circle. In some cases, such as that of the rosy periwinkle, the indigenous people who provided the initial source of knowledge about a medicine are among the least likely to benefit from the resulting drugs, much less even hear about them or reap any monetary benefits at all. Though in recent years, the issue of protecting traditional knowledge has risen in prominence among lawyers and activists alike, no effective legal mechanisms yet exist that proactively provide support for holders of TK. The 1992 Convention on Biological Diversity is the one treaty that came close to recognizing the rights of traditional knowledge holders by declaring that "traditional lifestyles" must be protected. …


The Western legal tradition portrays itself as a tradition of rationality. Although this tradition has its roots in the academic treatment of law at the medieval university, the medieval juridical mannerisms seem to be anathema to the Weberian 'formal rationality.' Scholasticism has become the synecdoche for the problems we moderns have when trying to access medieval thought. Medieval Scholastic jurisprudence seems prima facie strangely formalistic, guided by ambitions that are incomprehensible to the 'modern mind'. Yet medieval jurisprudence is not as remote from us as it might seem at first glance. This paper aims to demonstrate that what connects the medieval and the modern jurist are aspects of legal discourse that cannot be explained in 'rational' terms. To this end, the paper focuses on the 'legal aesthetics' of the Scholastic jurists, exemplified by an inquiry into the doctrine of 'interesse', one of the most controversial areas of the law of damages.


Two earlier computations of the optimal truncation of Gaussian beams for a simple, focused, coherent lidar that used an incoherent backscatter target with identical circular transmitter and receiver apertures differ because they refer to different receiver geometries. The definitions of heterodyne and systemantenna efficiencies are reviewed in light of the discrepancy and are used to compare the optical performance of systems with apertures illuminated by beam profiles that are not Gaussian. The heterodyne efficiency is less than 0.5 for all cases considered here.


Although one of the simplest and powerful approaches for the demodulation of a single fringe pattern with closed fringes is the regularized phase-tracking (RPT) technique, this technique has two important drawbacks: its sensibility at the fringe-pattern modulation and the time employed in the estimation. We present modifications to the RPT technique that consist of the inclusion of a rough estimate of the fringe-pattern modulation and the linearization of the fringe-pattern model that allows the minimization of the cost function through stable numerical linear techniques. With these changes, the demodulation of nonnormalized fringe patterns is made with a significant reduction in the processing time, preserving the demodulation accuracy of the original RPT method.


In Subversive Voices, Evelyn Jaffe Schreiber investigates the intersection of identity and culture as manifested in the novels of William Faulkner and Toni Morrison. Drawing on the psychoanalytic theory of Jacques Lacan as well as on various cultural studies theories, Schreiber offers provocative new insights into these two writers and what their work reveals about the possibilities of social change. Schreiber considers how blacks and women, through their subversive voices and articulation of difference, produce change despite the psychic and cultural structures that would determine identity. The author begins her examination of these marginalized voices by analyzing the patriarchal structure depicted in Faulkner s Go Down, Moses. She goes on to trace the subversive voices of women in the Snopes trilogy before considering the emergent voices of blacks in Faulkner s work generally, as well as specifically in Intruder in the Dust. In the second half of the book, Schreiber analyzes the articulation of difference that Morrison presents through the black and female characters of The Bluest Eye, Song of Solomon, Beloved, and Paradise. In Faulkner s work, Schreiber argues, nostalgia provides a screen that preserves the power of patriarchal structures and serves to eroticize the other for the dominant culture by using marginalized others to fulfill the desire for an imagined wholeness. Yet, in spite of this screen, agency or empowerment does emerge for these marginalized voices in Faulkner. In Morrison s novels, the absence of a nostalgic screen highlights these subversive voices: the dominant culture s eroticized, imagined other becomes a threatening entity and gains agency. Schreiber suggests that meaningful action and change can occur through encounters with what Lacan calls the real, an awareness of the nothingness at the core of identity. Recognition of this nothingness allows the reality of the other to manifest itself and have agency in the social world. The works of both Faulkner and Morrison reveal whether obliquely or directly how subversive voices emerge to expose this lack. Such exposure then creates a form of self-awareness that can lead to cultural transformation. The Author: Evelyn Jaffe Schreiber is an assistant professor of English at George Washington University. Her articles have appeared in the Faulkner Journal, Style, Mississippi Quarterly, and other publications."


Background: Psoriasis is a chronic inflammatory dermatosis associated with psychological morbidity. Like mental illness, it is also associated with stigma. Very few studies from India have evaluated stigma experienced by patients with psoriasis. Aim of the Study: To study stigma in patients with psoriasis (in the form of internalized stigma, perceived stigma, and social-participation-restriction stigma) and its relationship with demographic and clinical variables. Methodology: 104 patients with psoriasis assessed on the internalized stigma of mental illness scale (ISMIS), explanatory model interview catalogue stigma scale, participation scale (P-scale), perceived social support, total score of Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD-7) scale, Dermatology Life Quality Index, and Psoriasis disability index. Results: On ISMIS, overall, 27.9% had experienced stigma. On domains, majority of the participants experienced discrimination (52.9%) followed by stigma resistance (51.9%), stereotype (26.0%), social withdrawal (24.1%), and alienation (23.1%). Majority of them reported mild restriction. As per the evaluation by a qualified psychiatrist, about 30% of the participants had at least one psychiatric diagnosis. On comparison, those with the presence of co-morbid psychiatric illness experienced a higher level of stigma on each domain of ISMIS except discrimination and stigma resistance. Lower social support was associated with higher stigma in all the domains. All the domains of ISMIS except discrimination and stigma resistance were associated with a higher level of anxiety and depression, poor quality of life, and higher disability. Conclusion: The patients with psoriasis experience a significant amount of stigma and stigma is associated with the presence of psychiatric morbidity, lower social support, higher restriction, and more disability.


Consistent evaluation of the {sup 232}Th capture cross section is performed in the energy range from 4 keV to 5 MeV. The Hauser-Feshbach-Moldauer theory and coupled channel optical model are employed. Total, differential scattering, fission, and inelastic scattering data are consistently reproduced as a major constraint for the capture cross-section estimate. Average resonance parameters are obtained, which are consistent with the capture cross-section database.


With the development of the Internet, more and more people actively interact with others via online social networks. Potentially, people can hide themselves in the dark and continually gather information from other users from the Internet. To assist individual users to protect their privacy and security, in this study a computational approach for abnormal attention detection will be presented. The proposed approach can detect abnormal attention from the local view of a user, without invading other people's privacy. We then move on to focus on the online interpersonal surveillance which is an excessive, unreciprocated and persistent attention. We address the issue of interpersonal surveillance by asking the question, "who is surveiling you through social networking?". This is a challenging question, as interpersonal surveillance is a victim-defined behaviour and often occurs without a visible trace. Viewing a network as interconnected agents who interact through posting and reading information, we provide a measure to quantify the level of attention a person pays towards another from a global view. This measure allows us to capture online interpersonal surveillance. Through theoretical and experimental analyses, we show that our method distinguishes and detects online interpersonal surveillance.


The present paper defends Augustine's claim that time is ontologically dependent on the world. My proof is accomplished by establishing two sub-proofs. First, I argue that time requires change by criticizing Shoemaker's argument for the counterclaim that time does not require change. Second, I go on to show that there is no source of change apart from the created universe. I conclude that if we grant the traditional theistic assumption that the created universe has a beginning and an end, then since time is ontologically dependent on the world, time cannot extend from the infinite past into the infinite future. And if time does not extend from the infinite past into the infinite future, then a temporal God has a beginning and endures for only a finite period of time. This implausible consequence gives us reason to believe that God is eternal.


An understanding of the neurocognitive and neurobiological underpinnings of body dysmorphic disorder (BDD) is important in differentiating BDD from related disorders, namely obsessive–compulsive disorder and psychotic disorders. Similar cognitive anomalies in executive function, spatial visual processing and memory (bias to process detailed visual information) have been found in BDD and obsessive–compulsive disorder samples, while schizophrenia patients display more pervasive cognitive deficits. Emotional hyperactivity and misinterpretation of emotion in others have been found in BDD, with similar results to obsessive–compulsive disorder samples. Neuroimaging has shown abnormalities in the prefrontal cortex, visual cortex, caudate nucleus and right amygdala in BDD patients. These findings are consistent with the neurocognitive profile. This field of research is in its infancy. However, the bias towards detailed visual analysis may be an important clue when investigating the neurobiological basis of BDD, and could explain why individuals exhibit focused attention on one aspect of their own appearance. Emotional hyperarousal caused by amygdala pathology may reinforce a perception of negative physical appearance.


Given the importance of water-mediated hydrophobic interactions in a wide range of biological and synthetic self-assembly processes, it is remarkable that both the sign and the magnitude of the hydrophobic interactions between simple amphiphiles, such as alcohols, remain unresolved. To address this question, we have performed Raman hydration-shell vibrational spectroscopy and polarization-resolved femtosecond infrared experiments, as well as random mixing and molecular dynamics simulations. Our results indicate that there are no more hydrophobic contacts in aqueous solutions of alcohols ranging from methanol to tertiary butyl alcohol than in random mixtures of the same concentration. This implies that the interaction between small hydrophobic groups is weaker than thermal energy fluctuations. Thus, the corresponding water-mediated hydrophobic interaction must be repulsive, with a magnitude sufficient to negate the attractive direct van der Waals interaction between the hydrophobic groups.


Using data on economic values and attitudes for various nations from the World Value Study, I show that the strength of values associated with market success does not appear to have a significant impact on the rate of economic growth in a sample of developing and developed market economies. I also show that such values do not seem related to the economic system and have an ambiguous relation to the overall level of economic development. These negative results suggest that, contrary to common belief, knowledge about such values does not seem very useful in helping us understand economic growth or differences in levels of economic development or economic systems in various countries.


We study incentives for information sharing (about uncertain future demand for final output) among firms in imperfectly competitive markets for farm output. Information sharing generally leads to increases in expected total welfare but may reduce expected firm profits. Even when expected firm profits increase, information sharing does not represent equilibrium behavior because firms face a prisoner's dilemma in which it is privately rational for each firm to withhold information, given that other firms report truthfully. This equilibrium can be overcome if firms commit to simultaneously reporting their information and if reports are verifiable. We argue that agricultural bargaining associations serve both these roles.


The Gender Transformative and Responsible Agribusiness Investments in South East Asia (GRAISEA) programme works to promote women's economic empowerment in agricultural value chains. The agricultural sector is heavily reliant on women workers, but these women do not have equal access to resources – only 12 percent of the three million landowners in Asia are women, for example. Together with the Institute for Social Enterprise for Asia and its partners, GRAISEA documented the stories of women who have been empowered by partnerships in the Philippines and Thailand. This case study tells their stories and presents a set of benchmarks for how transformational partnerships can be implemented in agricultural value chains.


Nowadays, pharmaceutical mobile applications are widely used. Several features and functionality play an important role to support the real needs of users especially in primary medication. Users' behaviors in the modern world have changed where users may prefer to access drug information using search engines via the Internet rather than consulting with professionals like pharmacists, doctors or experts. However, the drug information that users retrieve from the internet sources may provide inaccurate, incomplete or unreliable information. The questions are: can we decrease this phenomenon? Suppose that we are applying an application to a content provider, which application functionalities are suitable for users and support their real needs? Can the application encourage users to gather drug information via the application instead of searching via the internet sites? The proposed study aimed to develop a Pharmacy Assistant Mobile Application (PAMA) based on necessarily required features and functionalities which are designed and operate on the iOS operation system. The application performance has been tested and measured regarding the graphic user interface and the system acceptance level. The experimental results have been reviewed and an issue has been found which needs to be considered as an important factor when developing a healthcare mobile application for the real uses.


We reflect on China's economic performance from the perspective of the experiences of a broad panel of countries. We formulate an econometric framework building on standard growth regressions that allows us to measure the impact of various factors on economic growth and growth variability. As China has become more and more integrated into the world's economic and financial landscape, we devote special attention to measures of (de jure) financial openness. We also document how the real effects of openness are impacted by financial development, political risk, and the quality of institutions. Standard growth regressions cannot explain China's extraordinary growth experience and we fail to find an important role for foreign trade and foreign direct investment. In contrast, the sheer volume of investment has played a significant role in China's growth. As China's per capita GDP continues to grow, it must find sustainable sources of growth. We identify a more efficient financial sector, less state ownership higher quality of government institutions and full financial openness as important factors. Interaction analysis suggests that the beneficial effects of financial openness first require further financial and institutional development. China is less of an outlier in its growth variability experience but achieved high growth with surprisingly low growth volatility.


Cholecystokinin (CCK) is a gastrointestinal satiety signal released from the duodenum to terminate feeding, via CCK1 receptors. CCK2 receptors are considered to be involved in anxiety. CCK2 receptor knockout mice have increased body weight and food intake. Little is known regarding the effects of CCK2 receptor deficiency on adipose distribution and hypothalamic feeding regulators such as neuropeptide Y (NPY), a powerful stimulator of feeding. Adult (10 week) CCK2 receptor knockout and wild‐type mice were anaesthetized and killed by decapitation. Brain sections, organs and fat tissue were dissected. Plasma leptin, insulin and brain NPY content were measured by radioimmunoassay. Female CCK2 receptor knockout mice weighed more than control mice (22.0 ± 0.2 vs. 19.9 ± 0.4 g, P < 0.05), with this difference being less marked in male mice (26.4 ± 0.4 vs. 25.6 ± 0.6 g). Fat masses in all locations sampled were significantly smaller in CCK2 receptor knockout mice of both genders (P < 0.05), resulting in lower plasma leptin and insulin levels. NPY concentrations were significantly increased in arcuate nucleus and anterior hypothalamus in both male and female CCK2 receptor knockout mice, and total hypothalamic NPY content was increased by 7 and 9% in males and females, respectively (P < 0.05). CCK2 receptor deletion was associated with increased body weight and hypothalamic NPY content, but reduced fat masses and plasma leptin and insulin. Increased NPY might contribute to increased food intake in CCK2 receptor knockout mice. Further work needs to focus on the metabolic changes.


Abstract

Background: Although electroconvulsive therapy (ECT) is the most potent treatment for severely major depressive disorder (MDD), little is known about the neural mechanism of ECT in MDD patients. The frontal pole (Fp) plays an important role in integrating social, emotional, and cognitive processes. However, the exact role of Fp, especially at the sub-regional level, response for ECT in MDD remains largely unknown.

Methods and Findings: We combined voxel-based morphometry and resting-state functional connectivity (RSFC) to investigate the structural and functional alterations in Fp sub-regions to explore the mechanism of ECT in 23 MDD patients before and after ECT. Structurally, we found increased gray matter volume (GMV) of the left Fp1 and left Fp2 in MDD patients after ECT. Functionally, we found decreased RSFC between the left Fp1 and right cerebellum, left fusiform gyrus, and between right Fp1 and left fusiform gyrus, as well as increased RSFC between right Fp1 and left angular gyrus, left cuneus, and between right Fp2 and left cuneus in MDD patients after ECT. Furthermore, we also found significant associations between the changes of the GMV/RSFC and the therapeutic efficacy or side effects of ECT in MDD patients.

Conclusion: These results showed that the ECT can distinctly modulate GMV and RSFC of Fp at subregional level in MDD patients, which provide a novel view to understand the mechanism of ECT and may help us optimize the ECT procedures for improving therapeutic efficacy
and reducing side effects.


In this book, the author surveys the internal structures of three classes of bu-yu, complexpredicate structures, in Mandarin. They are traditionally termed as jieguo-'resultative' bu-yu, keneng'potential' bu-yu, and miaoshu'descriptive' bu-yu. They all consist of P(redicate)1 and P(redicate)2. The author offers a finer categorization within and without these bu-yu structures that differ in formation, aspect marking, negation, and A-not-A question formation. His analysis of P1 and P2 incorporation explains why in jieguo bu-yu, only P2 is under the scope of negation and why an intransitive P2 can now assign case. He argues that keneng bu-yu is derived from jieguo bu-yu, based on the similarities in their interpretations, the transitivity of their P2's, and the optionality in their object topicalization and pro-drop. He proposes, however, that keneng bu-yu is a serial-verb construction, the infix de being an analytical morpheme for both potentiality and causativity. A successive cyclic analysis accounts for the idiosyncrasy in keneng buyu A-not-A question, which takes the form of P1-DE-P2-P1-not-P2, different from the normal A-not-A questions. He divides miaoshu bu-yu into descriptives, resultatives, and causatives, depending on the nature of their P2. When P2 is an individual-level predicate, we have descriptives, with P2 being the main predicate. When P2 is a stage-level predicate, we have resultatives or causatives. Resultatives has either subject-control or complex clausal structure, based on the finiteness of P2. Causatives have ECM. The de in descriptives is argued to be a nominalizer, which explains the peculiar P1-copying effect. The de in resultatives is argued to be a complementizer like English 'that'. The de in causatives is argued to be a prepositional complementizer like English 'for' that introduces an infinitive complement.


To better understand the biotic and abiotic factors that control soil CO2 efflux, we compared seasonal and diurnal variations in simultaneously measured forest-floor CO2 effluxes and soil CO2 concentration profiles in a 54-year-old Douglas fir forest on the east coast of Vancouver Island. We used small solid-state infrared CO2 sensors for long-term continuous real-time measurement of CO2 concentrations at different depths, and measured half-hourly soil CO2 effluxes with an automated non-steady-state chamber. We describe a simple steady-state method to measure CO2 diffusivity in undisturbed soil cores. The method accounts for the CO2 production in the soil and uses an analytical solution to the diffusion equation. The diffusivity was related to air-filled porosity by a power law function, which was independent of soil depth. CO2 concentration at all depths increased with increase in soil temperature, likely due to a rise in CO2 production, and with increase in soil water content due to decreased diffusivity or increased CO2 production or both. It also increased with soil depth reaching almost 10 mmol mol � 1 at the 50-cm depth. Annually, soil CO2 efflux was best described by an exponential function of soil temperature at the 5-cm depth, with the reference efflux at 10 8 C( F 10) of 2.6 mmol m � 2 s � 1 and the Q10 of 3.7. No evidence of displacement of CO2-rich soil air with rain was observed. Effluxes calculated from soil CO2 concentration gradients near the surface closely agreed with the measured effluxes. Calculations indicated that more than 75% of the soil CO2 efflux originated in the top 20 cm soil. Calculated CO2 production varied with soil temperature, soil water content and season, and when scaled to 10 8C also showed some diurnal variation. Soil CO2 efflux and concentrations as well as soil temperature at the 5-cm depth varied in phase. Changes in CO2 storage in the 0‐ 50 cm soil layer were an order of magnitude smaller than measured effluxes. Soil CO2 efflux was proportional to CO2 concentration at the 50-cm depth with the slope determined by soil water content, which was consistent with a simple steadystate analytical model of diffusive transport of CO2 in the soil. The latter proved successful in calculating effluxes during 2004. # 2005 Elsevier B.V. All rights reserved.


Abstract. The Mid-Brunhes Transition (MBT) began ∼ 430 ka with an increase in
the amplitude of the 100 kyr climate cycles of the past 800 000 years. The
MBT has been identified in ice-core records, which indicate interglaciations
became warmer with higher atmospheric CO2 levels after the MBT, and
benthic oxygen isotope (δ18O) records, which suggest that
post-MBT interglaciations had higher sea levels and warmer temperatures than
pre-MBT interglaciations. It remains unclear, however, whether the MBT was a
globally synchronous phenomenon that included other components of the climate
system. Here, we further characterize changes in the climate system across
the MBT through statistical analyses of ice-core and δ18O
records as well as sea-surface temperature, benthic carbon isotope, and dust
accumulation records. Our results demonstrate that the MBT was a global event
with a significant increase in climate variance in most components of the
climate system assessed here. However, our results indicate that the onset of
high-amplitude variability in temperature, atmospheric CO2, and sea
level at ∼430 ka was preceded by changes in the carbon cycle, ice
sheets, and monsoon strength during Marine Isotope Stage (MIS) 14 and MIS 13.


This Essay addresses the following questions: What jurisdictions should govern cyberspace problems? Are cyberspace problems different from those in the tangible world? If so, what are the implications for governance? We conclude that the judicial response to cyberspace governance has been mostly correct. After some adaptation problems (an early learning curve), courts have generally followed common law analogs to cyberspace problems. In other words, those problems are not treated as unique unless there is something special about the internet that suggests different resolutions are needed. There certainly is nothing to suggest that American courts or legislatures are trying to occupy the field of cyberspace law.


Diarrheal disease is one of the leading middle income countries. This study examined diarrheal diseases among children in Uasin Gishu County's childcare institutions per age, sex, duration of a child in a childcare institution, and use of soap in hand washing after visiting the toilet. The study involved 202 children between ages 6 to 20 years old. There were65.8% boy child and 34.2 girls, 71.3% of these children were between 6-15 years old. The study found 64.4% children used soap to wash hands after toilet. Use of soap in hand washing increased with increase in children's age, with a girl using soap more in hand washing at the rate of 84.1% compared to a boy child. The study learned that 90.1% children had suffered from diarrheal diseases within 28 days where61.4% boys had suffered from diarrhea. Chi-square analysis showed a significant relationship between diarrheal diseases and children's age (P<0.001) while there was a significant relationship between diarrhea andgender (P<0.001). It was concluded that the prevalence of diarrheal diseases in Uasin Gishu County child care institutions was 90.1% and that boys were affected more than the girls. Health education on use of soap in hand-washing after toilet should be intensified as a means of decreasing diarrheal diseases.


Fortification of food with folic acid to reduce the number of neural tube defects was introduced 10 y ago in North America. Many countries are considering whether to adopt this policy. When fortification is introduced, several hundred thousand people are exposed to an increased intake of folic acid for each neural tube defect pregnancy that is prevented. Are the benefits to the few outweighed by possible harm to some of the many exposed? In animals, a folic acid-rich diet can influence DNA and histone methylation, which leads to phenotypic changes in subsequent generations. In humans, increased folic acid intake leads to elevated blood concentrations of naturally occurring folates and of unmetabolized folic acid. High blood concentrations of folic acid may be related to decreased natural killer cell cytotoxicity, and high folate status may reduce the response to antifolate drugs used against malaria, rheumatoid arthritis, psoriasis, and cancer. In the elderly, a combination of high folate levels and low vitamin B-12 status may be associated with an increased risk of cognitive impairment and anemia and, in pregnant women, with an increased risk of insulin resistance and obesity in their children. Folate has a dual effect on cancer, protecting against cancer initiation but facilitating progression and growth of preneoplastic cells and subclinical cancers, which are common in the population. Thus, a high folic acid intake may be harmful for some people. Nations considering fortification should be cautious and stimulate further research to identify the effects, good and bad, caused by a high intake of folic acid from fortified food or dietary supplements. Only then can authorities develop the right strategies for the population as a whole.


This contribution describes the analytical performance resulting from modifications to the source of a Nu Instruments 'Nu Plasma' high resolution Multi Collector Inductively Coupled Plasma Mass Spectrometer (MC-ICP-MS). Key advances in the 'enhanced sensitivity' (HR-ES) setup include changes to the geometry of the skimmer and sampler cones, re-design of the interface pumping system and modifications to the source lens. Comparison of both solution and laser-ablation data acquired on the same instrument before and after the modifications indicates that the sensitivity is improved by 80–125% in solution mode and 70–95% in laser-ablation mode. Analyses of standard solutions and reference zircon suggest no loss in accuracy. For laser ablation, the practical result is that for a given ablated volume, the HR-ES modification increases the precision with which individual isotopic measurements (e.g. U–Th/Pb, Hf) can be made. Conversely, for a required precision it reduces the amount of material needed by ∼2×, thereby significantly increasing the spatial resolution of in situ isotope MC-ICP-MS measurements.


The importance of the knowledge-base in regional and urban competition is generally recognised, although causal relations between urban and regional economic growth and knowledge level are far from clear. This paper presents the first analysis of the strength, interrelations and nodality of the global research centres. The data are records in the Science Catation Index 1997-99 of papers produced by authors from the 40 largest `greater' urban regions of the world as measured by research output. The network of research co-operation depends on nationality, distance and other factors. The top-level nodes in the co-operation network of the world are London, Geneve-Lausanne and the San Francisco Bay Area. In absolute number of co-authored papers, Los Angeles, Boston and New York constitute a second level and, when observed links are related to expected links, the second level combines Amsterdam-Hague-Rotterdam-Utrecht, Paris, Basel-Mulhouse-Freiburg and Copenhagen-Lund. As expected, the networks of citation are, by contrast, very independent of distance, but not of nationality. The primary categories of research centres for the total number of citings presented are San Diego, Seattle, Boston, New York and the San Francisco Bay Area. When we turn to the international data-set, it is Mannheim-Heidelberg, Geneve-Lausanne, Basel-Mulhouse-Freiburg and Cambridge which are in the lead.


Modern prediction problems arising in multilabel learning and learning to rank pose unique challenges to the classical theory of supervised learning. These problems have large prediction and label spaces of a combinatorial nature and involve sophisticated loss functions. We offer a general framework to derive mistake driven online algorithms and associated loss bounds. The key ingredients in our framework are a general loss function, a general vector space representation of predictions, and a notion of margin with respect to a general norm. Our general algorithm, Predtron, yields the perceptron algorithm and its variants when instantiated on classic problems such as binary classification, multiclass classification, ordinal regression, and multilabel classification. For multilabel ranking and subset ranking, we derive novel algorithms, notions of margins, and loss bounds. A simulation study confirms the behavior predicted by our bounds and demonstrates the flexibility of the design choices in our framework.


The workhorse model of optimal taxation strongly recommends tagging, but its use in policy is limited. I argue that this puzzle is a symptom of a more fundamental problem. Conventional theory neglects the diverse normative criteria with which, as extensive evidence has shown, most people evaluate policy. In particular, if the classic principle of Equal Sacrifice augments the standard Utilitarian criterion, optimal tagging is limited. Calibrated simulations of optimal policy with normative diversity of this type simultaneously match three features of U.S. policy: substantial income redistribution; rejection of gender, race, and height tags; and acceptance of a blindness tag. Additional implications increase the appeal of this revision to conventional theory.


A novel Internet protocol (IP) transmission and routing is proposed over coherent multiple array (M-ary) frequency shift keying optical code-division multiple-access (FSK-OCDMA) network with incoherent demodulation. The architecture also benefits from the use of the co-channel interference canceller. In contrast to wavelength-division multiple-access (WDMA), a fewer set of wavelengths are needed as a result of M-ary source coding. As the spreading codes, double-padded modified prime codes (DPMPC) have been employed. The performance has been analyzed in terms of the users' channel utilization in the network and compared with common incoherent pulse-position modulation technique. The results indicate that this architecture is very power efficient and enhances the network capacity. With the advantage of shorter code length, DPMPC also improves the throughput. It is shown that for a maximum bit-rate, the network performance can be improved by reducing the channel utilization. Since each IP packet is buffered only at the edge of this network, the buffer delay is considerably reduced. The novel encoder adjusting time management reduces the switching time notably rather than traditional routing. Our analytical investigation clearly indicates that this OCDMA technique can be an excellent candidate for the future ultra-fast high bit-rate optical IP networks.


Stuttering is an intermittent and involuntary speech disorder overtly characterized by syllable repetitions phoneme prolongations and postural fixations that disrupt the natural flow of speech. Overt stuttering is reduced by 60-100% as the person who stutters produces speech while perceiving an ongoing second speech signal. The purpose of the current investigation was to further examine mechanisms of stuttering inhibition during perception of second speech signals. To do this the researcher conducted two experiments examining the level of inhibition during temporal-spatial alignment alterations and level of inhibition during hierarchically difficult scripted telephone conversations under combined altered auditory feedback signals. The first study examined temporal-spatial alignments of speakers during choral and shadow speech. Choral speech is when two speakers talk in approximate simultaneity. This effect is believed to be the most powerful inhibitor of stuttering reducing it 90-100%. A slightly less powerful inhibitor of stuttering is shadow speech which is historically defined as the person who stutters lagging or shadowing behind a fluent speakers utterance. Reductions under shadow speech typically range from 80-90%. Interestingly prior to the current investigation empirical analysis of output from people who stutter (PWS) when maintaining the lead speaker position during shadow speech had yet to be evaluated. This temporal-spatial alignment most mimics delayed auditory feedback with a second speaker. Experiment I included four conditions: 1) choral speech 2) shadow speech with the person who stutters maintaining the lead speaker position 3) shadow speech with the person who stutters maintaining the lag speaker position and 4) baseline. Nine participants who stutter verbally read 300 syllable passages while a second fluent speaker read the same passage and maintained close temporal-spatial alignments during choral conditions and three to four word separations during shadow speech conditions. Stuttering frequency was significantly reduced 95% during choral speech and approximately 80% during both shadow speech conditions. Results challenge notions put forth by previous hypotheses regarding reductions in stuttering during perception of second signals. Experiment II examined stuttering inhibition during scripted telephone conversations under altered auditory feedback. As with the lag shadow speech condition altered auditory feedback and more specifically delayed auditory feedback presents a second speech signal along with ongoing speech. Delayed auditory feedback and frequency-altered feedback generate second speech signals from the speakers' initial speech productions. Reductions in stuttering frequency under altered auditory feedback typically range from 60-80%. These reductions occur during the presentation of one signal and one combination of signals across a variety of settings; specifically telephone conversations which are judged to be one of the most hierarchically difficult situations for people who stutter. The second experiment examined nine people who stutter during 15 scripted telephone conversations under baseline one combination of DAF and FAF (i.e. 50 ms delay and ½ octave shift up respectively; 1 COMBO) and two combinations of DAF and FAF (i.e. 1 COMBO plus 200 ms delay and ½ shift down respectively; 2 COMBO). Stuttering was significantly inhibited during both altered feedback conditions (i.e. 63% during 1 COMBO and 74% during 2 COMBO). Furthermore significant reductions in stuttering frequency during the 2 COMBO conditions as compared to the 1 COMBO indicated that presentation of increased gestural information enhances the inhibitory effects. Results from both studies challenge notions put forth by previous models of stuttering reduction during the perception of second signals. The findings that stuttering was reduced to similar extents during both lead and lag conditions in Experiment I and that more robust stuttering inhibition occurred during the COMBO II condition in Experiment II challenge fundamental notions from previous reduction theories during the perception of second signals. Furthermore these findings support the flexible and dynamic gestural percepts hypothesized in the Gestural Model of Stuttering Inhibition. It is likely that increased gestural information alters mirror neuron system activation patterns which enables a more efficient and effective release of the central neural block that is stuttering therefore increasing inhibitory effectiveness from the perception of second signals.


ABSTRACT The late stages of human breast cancer development are poorly understood complex processes associated with the expression of genes by cancers that promote specific tumorigenic activities, such as angiogenesis. Here, we describe the identification of periostin as a mesenchyme-specific gene whose acquired expression by human breast cancers leads to a significant enhancement in tumor progression and angiogenesis. Undetectable in normal human breast tissues, periostin was found to be overexpressed by the vast majority of human primary breast cancers examined. Tumor cell lines engineered to overexpress periostin showed a phenotype of accelerated growth and angiogenesis as xenografts in immunocompromised animals. The underlying mechanism of periostin-mediated induction of angiogenesis was found to derive in part from the up-regulation of the vascular endothelial growth factor receptor Flk-1/KDR by endothelial cells through an integrin αvβ3-focal adhesion kinase-mediated signaling pathway. These findings demonstrate the presence of a novel mechanism by which tumor angiogenesis is acquired with the expression of a mesenchyme-specific gene as a crucial step in late stages of tumorigenesis.


Abstract The French Institut de Radioprotection et de Sûreté Nucléaire (IRSN) and the German Gesellschaft für Anlagen und Reaktorsicherheit mbH (GRS) have been jointly developing for several years a system of calculation codes (or "integral" code), ASTEC (Accident Source Term Evaluation Code), to simulate the complete scenario of a hypothetical severe accident in a nuclear light water reactor from the initiating event through the possible radiological release of fission products out of the containment, the so-called "source term." Very intensive validation work has been performed in recent years by IRSN and GRS on the V1 versions by comparison of code calculations with results of more than 160 international experiments. Complementary validation was performed by 30 partners of the SARNET European Network of Excellence in the 6th Framework Programme of the European Commission, where ASTEC is considered the European reference code. The global status of validation is good for most phenomena, as shown by several examples that are described in this paper, and even very good on fission product behavior. The main need for modeling improvement concerns reflooding of a degraded core, due to the lack in ASTEC V1 of any dedicated model, and intensive efforts will focus on this topic in the next years. Molten core concrete interaction models are at the state of the art, but new experiments under way in the international frame and a better understanding of physical mechanisms are necessary to make further progress. Version V2.0 of the new ASTEC series, released mid-2009, takes benefit of the previous very intensive validation of the ICARE2 IRSN mechanistic code since its core degradation models have now been implemented. Validation will continue in the SARNET network from 2009 to 2013.


Ecological theory does not currently allow precise predictions of the consequences of ecological restoration. Ecological restoration and species enhancement projects could be profitably used to test theoretically based predictions, but only if theory were first applied to develop quantita- tive predictions suitable for testing. Here, we review what is known about factors limiting population size and production of the American lobster Homarus americanus, and use that information to con- struct a demographic life-table model of population dynamics. We then use the model to evaluate alternative options for enhancing lobster population size and production. Because this species repre- sents an example of a population subjected to intense human exploitation as a target of commercial fisheries, which has stimulated much research on its biology, demographic modeling is facilitated. Furthermore, intervention into the fishery provides a viable restoration option available only to exploited species. We apply the economic concept of discounting (of future pay-back in the form of restoration, analogous to being paid interest on a loan) to allow quantification of the scale of restora- tion needed to compensate for both the magnitude of the estimated loss of American lobsters and the time lags between loss and restoration following a major oil spill. Quantification of benefits is rarely performed for restoration projects to guide compensation for natural resource damages caused by en- vironmental incidents. The methods and approach developed here can help address this past failure in order to provide compensating ecological and human services equal to those lost. The approach represents a significant step forward in conceptually and quantitatively addressing restoration needs. The methods may be applied to other species, especially those that are exploited by humans, but also others that can feasibly be restored to mitigate impacts of adverse environmental events.


This contribution presents a balance of the research performed in some national and international projects concerning the history of seismology with a view to the scientific and historical use of scientific correspondence between earth science scholars. We also present some of the contents of the scientific correspondence studied in the course of those projects. As many scholars and observatories, above all in the 19th century, operated in different sectors of the earth sciences at the same time, we highlight the importance of a coordinated collaboration between scholars and relevant institutions and in valorising the epistolary assets produced by the earth sciences observation networks.


In this paper we provide a classification of fundamental group elements representing simple closed curves on the punctured Klein bottle, Simi-lar to the Birman-Series classification of curves on the punctured torus [1]. In the process, an explicit description of the mapping class group is given. We then apply this to give a counterexample to the simple loop conjecture for representations from the Klein bottle group to PGL (2 , R ) .


Our paper presents the general overview of the current geophysical results, which helps to improve the geophysical image and the lithospheric structure of the Carpathian-Pannonian Basin region. Two different geophysical methods have been applied for the study of the structure and composition of the lithosphere as well as for determination of the lithospheric thermal structure. Firstly, integrated 2D modeling of gravity, geoid, topography and surface heat flow data was performed. Secondly, based on the results of the CELEBRATION 2000 seismic experiment, a large-scale 3D lithospheric gravity model was developed. The resulting map of the lithospheric thickness shows important variations in lithospheric thickness across the chain as well as along strike of the Carpathian arc. The sediment stripped gravity map is characterized by minima in the Eastern Alps and Western Carpathians. The maxima are observed in the Pannonian Back-arc Basin system, Bohemian Massif, Fore-Sudetic Monocline, Bruno-Silesian unit (BSU), Lublin Trough and partly in the Holy Cross Mts. and Malopolska unit. The Western Carpathian gravity minimum is a result of the interference of two main gravity effects. The first one comes from the low-density sediments of the Outer Western Carpathians and Carpathian Foredeep. The second one is due to the thick low-density upper and middle crust, reaching up to 25 km. The sediment stripped anomaly in the Pannonian Back-arc Basin system is characterized by gravity high that is a result of the gravity effect of the anomalously shallow Moho. The most dominant feature of the complete stripped gravity map is the abrupt change of the positive anomalies along the Pieniny Klippen Belt zone. The complete residual anomaly of the Pannonian Back-arc Basin system and the Western Carpathian orogen is characterized by a long-wavelength gravity low. The lowest values are associated with the thick low-density upper and middle crust of the Inner Western Carpathians. The European Platform is characterized by significantly denser crust with respect to the less dense crust of the microplates ALCAPA and Tisza-Dacia. That is why we suggest that the European platform represents consolidated, while the Carpathian-Pannonian Basin region un-consolidated crust.


Background: Although most implantable cardioverter defibrillator (ICD) patients cope well, fears about receiving ICD shocks have been identified as a major determinant of psychological distress. The relationships among ICD-related concerns, receipt of defibrillating shocks, and symptoms of anxiety and depression have not been investigated. Our objectives were to (1) describe ICD-related concerns, and (2) examine whether the relationships between receipt of defibrillating shocks and psychological distress were mediated by patients' concerns related to their ICD. Methods and Results: All Swedish ICD-recipients were invited to this cross-sectional correlational study; 3,067 completing the survey (55% response). Their mean age was 66+11 years, and 80% were male. One third (35%) had received defibrillating shocks, and 26% had high ICD-related concerns. Regression analyses demonstrated that having received at least one shock significantly predicted symptoms of anxiety and depression (OR 1.58 and OR 3.04, respectively). The association between receipt of shocks and psychologically distress were mediated by high ICD-related concerns which explained 68% of the relationship between shocks and symptoms of anxiety,and 54% of the relationship between shocks and symptoms of depression, see Figure 1. Conclusion: Having high ICD-related concerns has a bigger impact on psychological distress than receipt of an actual shock. Screening for ICD-related concerns in clinical practice may identify patients at risk of psychological distress, which could provide a specific target for intervention. Interventions tailored to individual patients' needs can - besides addressing device-related education and anxiety about shocks - also include relaxation and stress management, cognitive restructuring, social support and/or group discussions, and exercise programs.


Aggression, especially male-male aggression, has been well documented in many taxa to be caused by an increase of the sex hormone, testosterone. However, in birds the link between testosterone and aggression is equivocal. Studies on this subject have produced contradictory results leading some to investigate other mechanisms that may be responsible for this increase in aggression. We examined aggressive behavior in Mountain Chickadess, Poecile gambeli, that were injected with either adrenocorticotropin hormone (ACTH), which causes an acute rise in corticosterone, or saline control solution. We found that ACTH birds were faster to return to the nest and would get closer to a speaker playing a male Mountain Chickadee song. However, we did not see any difference in number of songs sang between the groups. These results suggest that corticosterone levels and the HPA axis play a role in mounting an aggressive response to a perceived intruder.


The Euclidean concentration inequality states that, among sets with fixed volume, balls have $r$-neighborhoods of minimal volume for every $r>0$. On an arbitrary set, the deviation of this volume growth from that of a ball is shown to control the square of the volume of the symmetric difference between the set and a ball. This sharp result is strictly related to the physically significant problem of understanding near maximizers in the Riesz rearrangement inequality with a strictly decreasing radially decreasing kernel. Moreover, it implies as a particular case the sharp quantitative Euclidean isoperimetric inequality from \cite{fuscomaggipratelli}.


The Principles of Beautiful Web Design is the ideal book for people who can build websites, but are seeking the skills and knowledge to visually enhance their sites.This book will teach you how to:Understand what makes "good design," from discovery through to implementationUse color effectively, develop color schemes, and create a paletteCreate pleasing layouts using grids, the rule of thirds, and symmetryEmploy textures: lines, points, shapes, volumes, and depthApply typography to make ordinary designs look greatChoose, edit, and position effective imageryAnd lots more...This easy-to-follow guide is illustrated with beautiful, full-color examples, and will lead you through the process of creating great designs from start to finish. The third edition of this book has been greatly revised and now features:Updated and expanded coverage of mobile and responsive web design (RWD)A new sample projectNew sections on user interface and icon designCommon user-interface patterns and resources


Translation of IP addresses to domain names is an optional feature of
DNS. Many sites implement it in someway, many others do not implement
it at all. Over time, some myths have developed regarding reverse DNS
mapping. The goal of this document is to to identify best practices,
illuminate false assumptions and to report on the status of reverse
DNS facilities so that DNS Administrators and operators can make
informed decisions about the options for DNS reverse mapping.


This book provides an ideal introduction for anyone wondering whether to study law or those who are simply curious to know more about it. It is not confined to English law, but deals with the Western tradition of law as a whole. It outlines the key problems of constitutional law and the law of property, contracts, treaties, crimes and torts. It also explains the importance of law of forms, procedures, and interpretation and examines how law relates to government, history, and justice. In this way it vividly brings out the intellectual and practical fascination of the subject. The book is easy to read and the chapters are self-contained. Where possible, technical terms are avoided. When unavoidable, they are explained both in the text and in a glossary at the end of the book. The author is a leading lawyer, legal historian, and legal philosopher. During his career in Oxford he taught many hundreds of students and it is from this experience that the book is drawn.


Geometric skinning techniques, such as smooth blending or dual-quaternions, are very popular in the industry for their high performances, but fail to mimic realistic deformations. Other methods make use of physical simulation or control volume to better capture the skin behavior, yet they cannot deliver real-time feedback. In this paper, we present the first purely geometric method handling skin contact effects and muscular bulges in real-time. The insight is to exploit the advanced composition mechanism of volumetric, implicit representations for correcting the results of geometric skinning techniques. The mesh is first approximated by a set of implicit surfaces. At each animation step, these surfaces are combined in real-time and used to adjust the position of mesh vertices, starting from their smooth skinning position. This deformation step is done without any loss of detail and seamlessly handles contacts between skin parts. As it acts as a post-process, our method fits well into the standard animation pipeline. Moreover, it requires no intensive computation step such as collision detection, and therefore provides real-time performances.


The aim of this study was to examine the effectiveness of cross-functional knowledge conversion within Taiwanese high-technology small and medium-sized enterprise's (SME) new product development (NPD) teams. An analysis of 107 Taiwanese high-technology SMEs' management characteristics found a complex knowledge structure is better adopted for cross-functional knowledge conversion during the NPD period than existing or simple knowledge structure models. In addition, a Processual strategy moderated the relationships between organisational knowledge structures and four-all steps within knowledge conversion to knowledge transfer; in contrast, Classical strategy was shown only to have moderated effects during the planning and developing stage of the NPD period.
Following Blackler's (1995) organisational theory, this study also found the socialisation and externalisation stages require both knowledge features from communication-intensive organisation and symbolic-analyst-dependent organisation within the NPD team's knowledge conversion. Knowledge features from a knowledge-routinised organisation are required at the combination stage; and finally, the knowledge features from an expert-dependent organisation are required at the internalisation stage.
Observed strategies can be categorised as being Classical or Processual oriented (Whittington, 1993). This study describes how the strategy moderates the relationship between the organisational knowledge structures and the four knowledge-creation steps, socialisation, externalisation, combination and internalisation for NPD teams. Results showed that the requirement upon strategy differed among stages within the NPD period. During the transfer process, Processual strategy moderated the relationships between organisational knowledge structures and steps within conversion to knowledge transfer during the planning, developing, marketing and commercialisation stages of the NPD period even the negative moderating effects showed in some stages. In contrast, Classical strategy was shown only to have negative moderating effects during the planning and developing stage.
Survey results also showed that the highly formalised communication model and periodic meetings advocated by Song et al (1996 & 2002) were gradually replaced by a bounded transfer and less formalised approach.
However this study does not find that a consistent approach to strategy, using either PS or CS is likely to smooth the NPD process between marketing and R & D in high technology Taiwanese firms. It is possible that other schools, such as the Evolutionary or Systemic schools suggested by Whittington may fit more closely than the two tested in this study; and this will be the topic of further investigation. However, it is clear that different stages require contradictory processes and outcome routines; thus it is likely that conflict and inconsistency is actually the normal by-product of successful NPD's knowledge conversion.


These twelve previously unpublished essays present innovative and practical ideas for addressing the harmful effects of sprawl. Sprawl is not only an ongoing focus of specialized magazines like Dwell ; indeed, Time magazine has cited orecycling the suburbso as the second of oTen Ideas Changing the World Right Now.o While most conversations on sprawl tend to focus on its restriction, this book presents an overview of current thinking on ways to fix, repair, and retrofit existing sprawl. Chapters by planners, geographers, designers, and architects present research grounded in diverse locales including Phoenix, Arizona; Seattle, Washington; Dublin, Ohio; and the Atlanta, Georgia, and Washington, D.C. metro areas. The authors address head-on the most controversial aspects of sprawluissues of power and control, justice and equity, and American attitudes about regulating private development. But they also put these issues in practical contexts, bringing in examples of redesign that are already occurring around the country, including the retrofitting of corridors and the repurposing of cul-de-sacs. Whether fixing sprawl requires a ocultural shifto in thinking or a ocoordinated efforto by local government, these essays testify that a combination of forethought and creative thinking will be needed.


A classical nova is an eruption on the surface of a white dwarf in an accreting binary system. The material ejected from the white dwarf surface generally forms an axisymmetric shell. The shaping mechanisms of nova shells are probes of the processes that take place at energy scales between planetary nebulae and supernova remnants. We report on the discovery of nova shells surrounding the post-nova systems V4362 Sagittarii (1994) and more limited observations of DO Aquilae (1925). Distance measurements of $0.5\substack{+1.4 \\ -0.2}$ kpc for V4362 Sgr and 6.7 ± 3.5 kpc for DO Aql are found based on the expansion parallax method. The growth rates are measured to be 0.07 arcsec yr−1 for DO Aql and 0.32 arcsec yr−1 for V4362 Sgr. A preliminary investigation into the ionization structure of the nova shell associated with V4362 Sgr is presented. The observed ionization structure of nova shells depends strongly on their morphology and the orientation of the central component towards the observer. X-ray, IR, and UV observations as well as optical integral field unit spectroscopy are required to better understand these interesting objects.


Apatite-type oxide-ion conductors have attracted considerable interest as potential fuel cell electrolytes. Atomistic modelling techniques have been used to investigate oxygen interstitial sites, protonic defects and water incorporation in three silicate and three germanate-based apatite-systems, namely La8Ba2(SiO4)6O2, La9.33(SiO4)6O2, La9.67(SiO4)6O2.5, La8Ba2(GeO4)6O2, La9.33(GeO4)6O2, and La9.67(GeO4)6O2.5. The simulation models reproduce the complex experimental structures for all of these systems. The interstitial defect simulations have examined the lowest energy configuration and confirm this site to be near the Si/GeO4 tetrahedra. The water incorporation calculations identify the O–H protonic site to be along the O4 oxygen channel as seen in naturally occurring hydroxy-apatites. The results also show more favourable and exothermic water incorporation energies for the germanate-based apatites. This is consistent with recent experimental work, which shows that Ge-apatites take up water more readily than the silicate analogues.


We propose a tree-based procedure inspired by the Monte-Carlo Tree Search that dynamically modulates an importance-based sampling to prioritize computation, while getting unbiased estimates of weighted sums. We apply this generic method to learning on very large training sets, and to the evaluation of large-scale SVMs.

The core idea is to reformulate the estimation of a score - whether a loss or a prediction estimate - as an empirical expectation, and to use such a tree whose leaves carry the samples to focus efforts over the problematic "heavy weight" ones.

We illustrate the potential of this approach on three problems: to improve Adaboost and a multi-layer perceptron on 2D synthetic tasks with several million points, to train a large-scale convolution network on several millions deformations of the CIFAR data-set, and to compute the response of a SVM with several hundreds of thousands of support vectors. In each case, we show how it either cuts down computation by more than one order of magnitude and/or allows to get better loss estimates.


The Internet is undergoing substantial changes from a communication and browsing infrastructure to a medium for conducting business and marketing a myriad of services. The World Wide Web provides a uniform and widely-accepted application interface used by these services to reach multitudes of clients. These changes place the Web server at the center of a gradually emerging e-service infrastructure with increasing requirements for service quality and reliability guarantees in an unpredictable and highly-dynamic environment. This paper describes performance control of a Web server using classical feedback control theory. We use feedback control theory to achieve overload protection, performance guarantees, and service differentiation in the presence of load unpredictability. We show that feedback control theory offers a promising analytic foundation for providing service differentiation and performance guarantees. We demonstrate how a general Web server may be modeled for purposes of performance control, present the equivalents of sensors and actuators, formulate a simple feedback loop, describe how it can leverage on real-time scheduling and feedback-control theories to achieve per-class response-time and throughput guarantees, and evaluate the efficacy of the scheme on an experimental testbed using the most popular Web server, Apache. Experimental results indicate that control-theoretic techniques offer a sound way of achieving desired performance in performance-critical Internet applications. Our QoS (Quality-of-Service) management solutions can be implemented either in middleware that is transparent to the server, or as a library called by server code.


This article starts from a twofold distinction: that between corpora as documentation tools and corpora as a source of materials for the translation classroom, and that between corpus-based and corpus-driven approaches. Then a pedagogic framework for translator training is outlined in which the notion of objective is central and a task-based methodology is used. Within such a framework, four kinds of corpus-related tasks are presented and illustrated: cloze tests based on a bilingual corpus, multiple choice exercises based on a learner corpus, translation of short passages yielded by the concordancer and concordance analysis. The first three are corpus-based, whereas the last one is more corpus-driven and can be used to promote autonomous learning and discovery strategies.


CONTEXT
The 329,000 hip fractures that annually occur in the United States are associated with high morbidity, mortality, and cost. Identification of those at high risk is a step toward prevention.

OBJECTIVE
To develop an algorithm to predict the 5-year risk of hip fracture in postmenopausal women.

DESIGN, SETTING, AND PARTICIPANTS
A total of 93,676 women who participated in the observational component of the Women's Health Initiative (WHI), a multiethnic longitudinal study, were used to develop a predictive algorithm based on commonly available clinical features. Selected factors that predicted hip fracture were then validated by 68,132 women who participated in the clinical trial. The model was tested in a subset of 10,750 women who had undergone dual-energy x-ray absorptiometry (DXA) scans for bone mass density assessment.

MAIN OUTCOME MEASURE
The prediction of centrally adjudicated hip fracture, measured by the area under the receiver operator characteristic (ROC) curves.

RESULTS
During a mean (SD) follow-up of 7.6 (1.7) years, 1132 hip fractures were identified among women participating in the observational study (annualized rate, 0.16%), whereas during a mean follow-up of 8.0 (1.7) years, 791 hip fractures occurred among women participating in the clinical trial (annualized rate, 0.14%). Eleven factors predicted hip fracture within 5 years: age, self-reported health, weight, height, race/ethnicity, self-reported physical activity, history of fracture after age 54 years, parental hip fracture, current smoking, current corticosteroid use, and treated diabetes. Receiver operating characteristic curves showed that the algorithm had an area under the curve of 80% (95% confidence interval [CI], 0.77%-0.82%) when tested in the cohort of different women who were in the clinical trial. A simplified point score was developed for the probability of hip fracture. Receiver operating characteristic curves comparing DXA-scan prediction based on a 10% subset of the cohort and the algorithm among those who participated the clinical trial were similar, with an area under the curve of 79% (95% CI, 73%-85%) vs 71% (95% CI, 66%-76%).

CONCLUSION
This algorithm, based on 11 clinical factors, may be useful to predict the 5-year risk of hip fracture among postmenopausal women of various ethnic backgrounds. Further studies are needed to assess the clinical implication of the algorithm in general and specifically to identify treatment benefits.


Since the formal launch of the renminbi trade settlement scheme in 2009, renminbi internationalization has made impressive inroads. The progress in renminbi trade settlement is especially impressive. However, Hong Kong, China's offshore renminbi deposits failed to make significant progress as expected. The question of how far renminbi internationalization can go has become a common concern in the international financial community. This paper argues that the sheer size of the People's Republic of China's (PRC) trade and the convenience of using the renminbi for transaction settlements is one contributing factor, but that exchange rate arbitrage and interest rate arbitrage matter also. As well, a fundamental constraint for renminbi internationalization is the PRC's capital controls. Before fully opening up its capital account and making the renminbi freely convertible, however, the PRC needs first to put its own house in order, most importantly making the renminbi exchange rate flexible. While the renminbi can and will become a major international currency eventually, the road to internationalization is bound to be long and bumpy.


Wentsaiboea renifolia D. Fang & D. H. Qin, a new genus and species of Gesneriaceae from Guangxi, China, is described and illustrated. This genus is similar to Dolicholoma D. Fang & W. T. Wang in the shape of stigma, but differs by having leaves reniform, palmately nerved and base cordate, corolla obliquely campanulate, corolla lobes rounded, and both stamens and staminodes adnate to corolla tube near base. It is also similar to Chiritopsis W. T. Wang in the habit, but differs by having leaves palmately nerved, corolla tube campanulate and abaxially swollen, and stigma hippocrepiform.


In Recognition as Key for Reconciliation the authors emphasize that in dangerous times it is essential for human beings to understand our interdependency on each other if we, our children and future generations are to survive and thrive.


For much of Africa the 20th century was overshadowed by the experience of colonial rule, with politcal independence arriving for most people only in the last 50 years. "The Short Century" is a broad survey of cultural life in Africa from the independence movements through the post-colonial era to the end of apartheid in 1994. Expansive, wide-ranging and illustrated, this book studies achievements in all areas of the performing and fine arts, photography, literature, theatre, architecture, music and film. "The Short Century" includes the works of over 50 artists from the paintings of Mancona and Sekoto during the '50s, through the drawings and theatre projects of William Kentridge up to the installations and video works of Kay Hassan and Oladele A. Bamgboye. The great writers of the continent - Soyinka, Senghor and Cesaire amongst others - Africa's filmmakers, architects and musicians, all of whom left their mark on the process of decolonization, are studied here in depth. Renowned historians and cultural philosophers discuss the background of developments and analyze the ideological strategies employed by Western colonial powers to preserve their grip on African countries and peoples. A chapter on photojournalism supplemented by a detailed chronology of events and political movements presents the main stages of Africa's political history. A comprehensive anthology in the appendix contains some 30 historical documents, such as essays, speeches and political manifestos, shedding light on the key issues of the period.


Background: Hydroxychloroquine can improve most underlying coronary risk factors; however, there are a few studies on the effects of hydroxychloroquine on blood glucose and insulin resistance. The current study aimed to assess the effects of hydroxychloroquine on blood glucose control status as well as on level of lipid profile and inflammatory biomarkers in prediabetic patients. Materials and Methods: In a randomized, double-blinded, controlled trial, 39 consecutive patients who were suffering from prediabetes and were referred to the Isfahan Endocrinology Center in January 2013 were randomly assigned to receive hydroxychloroquine (6.5 mg/kg/day) (n = 20) or placebo (n = 19) for 12 weeks. The biomarker indices and anthropometric parameters were tested before and after completion of treatment. Results: In both groups of patients receiving hydroxychloroquine and placebo, except for serum level of insulin that was significantly elevated after treatment by hydroxychloroquine, the changes in other parameters remained insignificant. Both groups experienced increase of insulin level, but this change was considerably higher in those groups receiving hydroxychloroquine. The group receiving hydroxychloroquine experienced reduction of glucose at 60 min of Oral Glucose Tolerance Test (OGTT) test after intervention, while the placebo group experienced increase of blood glucose at the same time. Conclusion: The use of hydroxychloroquine may increase the serum insulin level in patients with prediabetic states who are at risk of developing diabetes mellitus.


This article analyzes and criticizes the temporal orientation of Catherine Lu's theory of colonial redress in Justice and Reconciliation in World Politics. Lu argues that colonial historic injustice can, with few exceptions, justify special reparative measures only if these past injustices still contribute to structural injustice in contemporary social relations. Focusing on Indigenous peoples, I argue that the structural injustice approach can and should incorporate further backward looking elements. First, I examine how Lu's account has backward-looking elements not present in other structural injustice accounts. Second, I suggest how the structural injustice approach could include additional backward-looking features. I presuppose here, with Lu, that all agents connected to an unjust social structure have a forwardlooking political responsibility to reform this structure, regardless of their relation (or lack thereof) to victims or perpetrators of historic injustice. However, I suggest that agents with connections to historic injustice can occupy a social position that makes them differently situated than other agents within that same structure, leading to differences in how these agents should discharge their forward-looking responsibility and differentiated liability for failure to do so. Third, I argue that Lu obscures the importance of rectifying material dispossession. Reparations, pace Lu, can be justified beyond a minimum threshold of disadvantage. Theorists of settler colonialism and Indigenous scholars show how the dispossession of Indigenous land can be seen as a structure that has not yet ended. I conclude by arguing that rectification can be a precondition for genuine reconciliation.


CD99 is a 32 kDa transmembrane protein whose high expression characterizes Ewing sarcoma (ES), a very aggressive pediatric bone tumor. In addition to its diagnostic value, CD99 has therapeutic potential since it leads to rapid and massive ES cell death when engaged with specific antibodies. Here a novel mechanism of cell death triggered via CD99 is shown, leading, ultimately, to the appearance of macropinocytotic vescicles. Anti-CD99 mAb 0662 induces MDM2 ubiquitination and degradation, which causes not only a p53 reactivation but also the IGF-1R induction and its subsequent internalization; CD99 results internalized together with IGF-1R inside endosomes, but then the two molecules display a different sorting: CD99 is degraded, while IGF-1R is recycled on the surface, causing, as a final step, the up-regulation of RAS-MAPK. High-expressing CD99 mesenchymal stem cells show mild Ras induction but no p53 activation and escape cell death, but in presence of EWS/FLI1 mesenchymal stem cells expressing CD99 show a stronger Ras induction and a p53 reactivation, leading to a significant cell death rate. We propose that CD99 triggering in a EWS/FLI1-driven oncogenetic context creates a synergy between RAS upregulation and p53 activation in ES cells, leading to cell death. Moreover, our data rule out possible concerns on toxicity related to the broad CD99 expression in normal tissues and provide the rationale for the therapeutic use of anti-CD99 MAbs in the clinic.


We investigate a two-dimensional low F-number dual micro-axilens array with binary structures based on a rigorous electromagnetic theory. The focal characteristics of a binary dual micro-axilens array (BDMA), including axial performances (focal depth and focal shift) and transverse performances (focal spot size and diffraction efficiency), have been analyzed in detail for different F-numbers, different incident polarization (TE and TM) waves, and different distances between micro-axilens. Numerical results reveal that the interference effect of a BDMA is not very evident, which is useful for building a BDMA with a high fill factor, and the focal characteristics of a BDMA are sensitive to the polarization of an incident wave. The comparative results have also shown that the diffraction efficiency of a BDMA will increase and the focal spot size of a BDMS will decrease when the F-number increases, for both TE polarization and TM polarization, respectively. It is expected that this investigation will provide useful insight into the design of micro-optical elements with high integration.


Subjective evaluations are critical for assessing the perceptual realism of sounds in audio-synthesis driven technologies like augmented and virtual reality. However, they are challenging to set up, fatiguing for users, and expensive. In this work, we tackle the problem of capturing the perceptual characteristics of localizing sounds. Specifically, we propose a framework for building a general-purpose quality metric to assess spatial localization differences between two binaural recordings. We model localization similarity by utilizing activation-level distances from deep networks trained for direction of arrival (DOA) estimation. Our proposed metric (DPLM) outperforms baseline metrics on correlation with subjective ratings on a diverse set of datasets, even without the benefit of any human-labeled training data.


ABSTRACT Predators of extant decapod crustaceans are fairly well known, but unlike many other invertebrate clades, not much is known regarding predation evidence found on fossil decapods. Herein, we provide an overview of such predation and expand upon this through an extensive study of fossil decapod specimens from multiple museum collections. Thus far most examples of predation come from drill holes and stomach contents; bite marks, incisions or irregular holes, and possible regurgitated material are also known. The currently recognized predators of decapods in the fossil record are fish, plesiosaurs, ammonites, octopods, and gastropods. We also provide new evidence of unambiguous drill-hole predation in decapods, based on 33,593 nonmoldic Cenozoic (middle Eocene–Holocene) decapod remains originating from Europe, Asia, and North America, indicating that drilling predation in decapods is more common than currently recognized. Drill holes attributed to octopods (ichnotaxon Oichnus ovalis) and gastropods (O. simplex and O. paraboloides) were found in carapaces and appendages from the Pliocene of the Netherlands, the Pleistocene and Pliocene of the United States (Florida), and the Pleistocene and early Miocene of Japan. Six drill holes attributed to octopods were found in epifaunal and semiburrowing crabs; three drill holes attributed to gastropods were discovered in semiburrowing and epifaunal crabs, and in a burrowing mud shrimp; and the producer of two other drill holes in epifaunal crabs is unknown. Other possible drill holes occur in decapods from the Holocene and early Miocene of Japan and the late Eocene of the United States. Drill-hole predation intensities in decapod faunas by stratigraphic formation are low (≤2.7%), at least in part due to multiple biases such as preservation and molting.


OBJECTIVE--To establish what is known about the role of feedback of statistical information in changing clinical practice. DESIGN--Review of 36 studies of interventions entailing the use of statistical information for audit or practice review, which used a formal research design. SUBJECTS--Papers identified from computer searches of medical and health service management publications, of which 36 describing studies of interventions designed to influence clinical care and including information feedback from clinical or administrative data systems were reviewed. MAIN OUTCOME MEASURES--Evidence for effect of information feedback on change in clinical practice. RESULTS--Information feedback was most likely to influence clinical practice if it was part of strategy to target decision makers who had already agreed to review their practice. A more direct effect was discernable if the information was presented close to the time of decision making. The questions of the optimum layout and quantity of information were not addressed; the 36 papers were insufficient for defining good formats for information to be used for audit or quality assurance. CONCLUSIONS--Given the cost of information processing and the current emphasis on closing the audit loop in the health services, it is important that the use of information in the audit process should be critically evaluated.


Concave compositions are compositions (i.e. ordered partitions) of a number in which the parts decrease up to the middle summand(s) and increase thereafter. Perhaps the most surprising result is for even length, concave compositions where the generating function turns out to be the quotient of two instances of the pentagonal number theorem with variations of sign. The false theta function discoveries also lead to new facts about concatenatable, spiral, self-avoiding walks.


Abstract. Narrative evidence contained within historical documents
and inscriptions provides an important record of climate variability for
periods prior to the onset of systematic meteorological data collection. A
common approach used by historical climatologists to convert such
qualitative information into continuous quantitative proxy data is through
the generation of ordinal-scale climate indices. There is, however,
considerable variability in the types of phenomena reconstructed using an
index approach and the practice of index development in different parts of
the world. This review, written by members of the PAGES (Past Global
Changes) CRIAS working group
– a collective of climate historians and historical climatologists
researching Climate Reconstructions and Impacts from the Archives of
Societies – provides the first global synthesis of the use of the index
approach in climate reconstruction. We begin by summarising the range of
studies that have used indices for climate reconstruction across six
continents (Europe, Asia, Africa, the Americas, and Australia) as well as the world's
oceans. We then outline the different methods by which indices are developed
in each of these regions, including a discussion of the processes adopted to
verify and calibrate index series, and the measures used to express
confidence and uncertainty. We conclude with a series of recommendations to
guide the development of future index-based climate reconstructions to
maximise their effectiveness for use by climate modellers and in multiproxy
climate reconstructions.


The problem of reproducing high dynamic range images on devices with restricted dynamic range has gained a lot of interest in the computer graphics community. There exist various approaches to this issue, which span several research areas including computer graphics, image processing, color science, physiology, neurology, psychology, etc. These approaches assume a thorough knowledge of both the objective and subjective attributes of an image. However, no comprehensive overview and analysis of such attributes has been published so far. In this paper, we present an overview of image quality attributes of different tone mapping methods. Furthermore, we propose a scheme of relationships between these attributes, leading to the definition of an overall image quality measure. We present results of subjective psychophysical tests that we have performed to prove the proposed relationship scheme. We also present the evaluation of existing tone mapping methods with regard to these attributes. Our effort is not just useful to get into the tone mapping field or when implementing a tone mapping operator, but it also sets the stage for well-founded quality comparisons between tone mapping operators. By providing good definitions of the different attributes, user-driven or fully automatic comparisons are made possible at all.


Globalization, in its earlier stages, was expected to erode national and ethnic identities. In contrast, ethnicity and ethnic affiliations persisted, growing socially and politically. This paper examines the role of the globalizing new communications technologies on this process, focusing on Diasporas. The study of trans-state networks based on ethnic solidarity, connections and affinities in the framework of social and political science is quite recent. Following a clarification of the distinction between classical and modern Diasporas we analyse a particular case study, that of the Jewish Diaspora. This diaspora was an early adopter of computer-based communications and the Internet for a wide range of purposes. Early events are described including the diffusion of the Internet to Israel, the planning of a Global Jewish Information Network, Israel 2020 macro scenarios for Israel and the Jewish People and the decision on Jewish Peoplehood through communication technologies. A survey of historical systems (Responsa, BBS, and Usenet) follows by a description of the Jewish population and the wide variety of Jewish Web based activities today. These include the Institutional landscape; Jewish media — press, radio, video and blogs; the impact on Jewish religious observance; Jewish genealogy; Online dating; Social networks; Jewish education; Online learning; Jewish Studies and Digital Humanities; Jewish memory. Judaica Europeana supports the activities previously described by aggregating and facilitating the access and the re-use of Jewish digital culture. Europeana is the leading global digital library for cultural heritage as well as a lively eco-system for relevant stakeholders.


The article examines the daily lives of Young Communist League (Komsomol) cadres in the 1920s argue that their ability to establish local authority through consent was often undermined by their everyday conditions. The article treats the emergence of the Komsomol's nomenklatura and cadre appointment system after the Russian civil war, cadre workload, working conditions, health, attitudes, and the Komsomol leadership's efforts to subordinate cadre malfeasance and corruption through public scandal. The article demonstrates that without a sturdy material base upon which to generate consent, local Komsomol cadres often relied on domination to exert their authority over their rank and file members and to some extent the local population. This reliance ultimately perpetuated itself. The more cadres employed coercion, the more the means of consent atrophied, which led them to turn time and again to domination. The use of domination over consent had grave implications on the nature of Bolshevik rule. Often Komsomol cadres were the only representative of the Soviet state in rural localities, and their methods of garnering authority were representative of prevailing trends of Bolshevik governance throughout the 1920s.


The objectives of this thesis are twofold. The first aim is to develop of robust coating procedures for thin supported films onto porous ceramic supports. The second aim is the development of a preparation methodology for high quality porous inorganic membranes, with large membrane surface area.
A robust method is presented for applying a high quality micro-porous silica top layer on a commercial tubular support. The coating method is straightforward and allows for a reproducible coating of large surface area high performance silica membranes.
To improve the surface-to-volume ratio and enhance the mechanical stability, hollow fibers of stainless steel have been developed via a dry wet-spinning process. The morphology of the fibers is predominantly determined during the dry-wet spinning process and can be tuned by changing the spinning conditions and the composition of the spinning mixture. In analogy to their ceramic counterpart the morphology is preserved upon sintering, apart from shrinkage due to densification. The fibers combine a high strength, with a large nitrogen permeance.
The surface-to-volume ratio is further increased by the development of hollow fibers with exceptionally small radial dimensions. Viscous deformation of the green fibers allows for regulated reduction of the macro void volume resulting in a substantial reduction of the outer diameter. Depending on the particle loading different outer diameters (250 – 750 μm) can be achieved, using only a single spinneret with fixed dimensions.
Fibers of other materials were prepared, demonstrating that the method presented in chapter 5 is generic and versatile. It allows for the preparation of a variety of inorganic membranes with small radial dimensions. At low particle concentration, extensive shrinkage of hollow fibers can be achieved above the Tg of the polymer, irrespective of the type and nature of the particles added. Increasing the particle loading results in differences in shrinkage behavior for different powders. A particle specific concentration range can be identified in which extensive shrinkage is observed and fibers with adequate structural integrity are obtained.


SummaryLow-density lipoproteins (LDLs) have an important physiological role in organism transporting cholesterol and other fatty substances to target tissues. However, elevated LDL levels in the blood are associated with the formation of arterial plaques and consequently atherosclerosis. It is therefore important to characterize the intracellular pathways induced upon LDL stimulation as they might be involved in the pathological properties of these lipoproteins. It has been previously found that LDL stimulation of mouse embryonic fibroblasts activates p38 mitogen activated protein kinases (MAPKs). This leads to cell spreading and increase in the wound healing capabilities of the cells. These two responses might occur within atherosclerotic plaques.The aim of this project is to reveal the missing links between LDL particle and activation of p38 MAPK kinase. As previously shown in our lab activation of p38 MAPK kinase by the LDL particles occur independently of classical LDL receptor (LDLR). In this study we have shown that scavenger receptor type Β class I (SR-BI) is responsible for the signal transduction from the LDLs to the p38 MAPK. We have also shown that Mitogen activated kinase kinases (MKKs) that can directly activate ρ 38 MAPK in these conditions are MKK3 and MKK6 but not MKK4. We have also tested some of the intermediate components of the pathway like Ras and PI3 kinase but found that they do not play a role.The data obtained in this study showed a part of molecular mechanism responsible for p38 MAPK activation and subsequent wound healing and can contribute to our knowledge on function of the fibroblasts in the development of the atherosclerotic plaques.Diabetes Mellitus is a condition caused by disordered metabolism of blood glucose level. It is one of the most commonly spread disease in the western world, with the incidence reaching 8% of population in United States. Two most common types of diabetes are type 1 and 2 that differs slightly in the mechanism of the development. However in the basis of both types lies the cell death of pancreatic beta cells. The aim of this work is to improve beta cells survival in different pathophysiological settings. This could be extrapolated to the conditions in which Diabetes develops in humans. We decided to use RasGAP- derived fragment Ν with its strong antiapoptotic effect in beta cells. In our lab we have demonstrated that in the mild stress conditions RasGAP can be cleaved by caspases at the position 455 producing two fragments, fragment Ν and fragment C. Fragment Ν exerts


We present EXOFAST, a fast, robust suite of routines written in IDL that is designed to fit exoplanetary transits and radial velocity variations simultaneously or separately and characterize the parameter uncertainties and covariances with a differential evolution Markov chain Monte Carlo method. We describe how our code incorporates both data sets to derive simultaneously stellar parameters along with the transit and RV parameters, resulting in more self-consistent results on an example fit of the discovery data of HAT-P-3b that is well-mixed in under 5 minutes on a standard desktop computer. We describe in detail how our code works and outline ways in which the code can be extended to include additional effects or generalized for the characterization of other data sets—including non-planetary data sets. We discuss the pros and cons of several common ways to parameterize eccentricity, highlight a subtle mistake in the implementation of MCMC that could bias the inferred eccentricity of intrinsically circular orbits to significantly non-zero results, discuss a problem with IDL's built-in random number generator in its application to large MCMC fits, and derive a method to analytically fit the linear and quadratic limb darkening coefficients of a planetary transit. Finally, we explain how we achieved improved accuracy and over a factor of 100 improvement in the execution time of the transit model calculation. Our entire source code, along with an easy-to-use online interface for several basic features of our transit and radial velocity fitting, are available online at http://astroutils.astronomy.ohio-state.edu/exofast.


Background Tobacco addiction is a complex, multicomponent phenomenon stemming from nicotine's pharmacology and the user's biology, psychology, sociology, and environment. After decades of public denial, the tobacco industry now agrees with public health authorities that nicotine is addictive. In 2000, Philip Morris became the first major tobacco company to admit nicotine's addictiveness. Evolving definitions of addiction have historically affected subsequent policymaking. This article examines how Philip Morris internally conceptualized addiction immediately before and after this announcement. Methods and findings We analyzed previously secret, internal Philip Morris documents made available as a result of litigation against the tobacco industry. We compared these documents to public company statements and found that Philip Morris's move from public denial to public affirmation of nicotine's addictiveness coincided with pressure on the industry from poor public approval ratings, the Master Settlement Agreement (MSA), the United States government's filing of the Racketeer Influenced and Corrupt Organizations (RICO) suit, and the Institute of Medicine's (IoM's) endorsement of potentially reduced risk products. Philip Morris continued to research the causes of addiction through the 2000s in order to create successful potentially reduced exposure products (PREPs). While Philip Morris's public statements reinforce the idea that nicotine's pharmacology principally drives smoking addiction, company scientists framed addiction as the result of interconnected biological, social, psychological, and environmental determinants, with nicotine as but one component. Due to the fragmentary nature of the industry document database, we may have missed relevant information that could have affected our analysis. Conclusions Philip Morris's research suggests that tobacco industry activity influences addiction treatment outcomes. Beyond nicotine's pharmacology, the industry's continued aggressive advertising, lobbying, and litigation against effective tobacco control policies promotes various nonpharmacological determinants of addiction. To help tobacco users quit, policy makers should increase attention on the social and environmental dimensions of addiction alongside traditional cessation efforts.