bluuebunny/crossref_metadata_2025 huggingface dataset:
A Modern Introduction to the Mathematical Theory of Water Waves
Authors: Johnson R. S.
Published: May 2010

The theory of water waves has been a source of intriguing and often difficult mathematical problems for at least 150 years. Virtually every classical mathematical technique appears somewhere within its confines. Beginning with the introduction of the appropriate equations of fluid mechanics, the opening chapters of this text consider the classical problems in linear and non-linear water-wave theory. This sets the ground for a study of more modern aspects, problems that give rise to soliton-type equations. The book closes with an introduction to the effects of viscosity. All the mathematical developments are presented in the most straightforward manner, with worked examples and simple cases carefully explained. Exercises, further reading, and historical notes on some of the important characters in the field round off the book and help to make this an ideal text for a beginning graduate course on water waves.
Modern Romance and Transformations of the Novel
Authors: Duncan Ian
Published: May 2010

Modern Romance examines the relationship between the revival of romance form and the ascendancy of the novel in British literary culture, from 1760 to 1850. The revival of romance as the literary embodiment of a national cultural identity provided a metaphor for the 'authenticity' of the novel itself, set against the changing formations of modern life. The material conditions, cultural status and formal repertoire of prose fiction were given a canonical transformation, leading to the form's nineteenth-century heyday, in Scott's Waverley novels. Ian Duncan's illuminating and innovative study begins with the first identification of modern prose fiction with romance form in the late eighteenth-century Gothic novel, and moves through Scott's highly influential dialectical blend of romance and history, to his relations with his successor in the role of national author, Charles Dickens.
Protestantism in Contemporary China
Authors: Hunter Alan , Chan Kim-Kwong
Published: May 2010

This study investigates the historical and political conditions which have contributed to the state of the Protestant community in China, and the kinds of spirituality and religious life that it has evolved. The authors draw on extensive fieldwork, and offer fascinating insights into the beliefs and practices of a little-documented section of Chinese society. They show that healing, protection, and vengeance by gods have been deep-rooted elements of Chinese religiosity for several hundred years, notions appropriated by Christians who now emphasize the powers of Jesus. Chinese Protestantism is seen to result from an interesting blend of the old and the new, and comparative material is adduced which sets Protestantism side by side with Catholicism and Buddhism, the two religions in China of comparable scope. A wide range of sources are utilized by the authors, and these lead to one of the most complete and detailed surveys of Christianity in China ever produced.
The Physical Basis of Predication
Authors: Newman Andrew
Published: May 2010

In this book about metaphysics the author defends a realistic view of universals, characterizing the notion of universal by considering language and logic, the idea of possibility, hierarchies of universals, and causation. He argues that neither language nor logic is a reliable guide to the nature of reality and that basic universals are the fundamental type of universal and are central to causation. All assertions and predications about the natural world are ultimately founded on these basic universals. A distinction is drawn between unified particulars (which reveal natural principle of unity) and arbitrary particulars (which lack such a principle); unified particulars are the terms of causal relations and thus the real constituents of the world. The world is not made up of events but of unified particulars and basic universals.
The Making of Three Russian Revolutionaries
Authors: Haimson Leopold H.
Published: May 2010

This book presents the life histories, drawn from a series of interviews conducted in the 1960s, of three prominent survivors of the Menshevik party: Lydia Dan, Boris Nicolaevsky, and George Denike. Each of these figures played an important role in the politics of Russia's Social Democracy and eventually in the Menshevik party. The interviews range well beyond politics. They reconstruct, in quasi-anthropological fashion, the childhood and youth of the three figures in the social and culture milieus in which their ideas and attitudes were shaped and in which they played their political roles. Taken together, their recollections form a tableau of a political culture that played a prominent role up to the Revolution, and that was dramatically extinguished in its aftermath.
Optics in the Age of Euler
Authors: Hakfoort Casper
Published: May 2010

According to received historiography, the fundamental issue in eighteenth-century optics was whether light could be understood as the emission of particles, or as the motion of waves in a subtle medium. Moreover, the emission theory of light was supposed to have been dominant in the eighteenth century, backed by Newton's physical arguments. This picture is enriched and qualified by focusing on the origins, contents and reception of the wave theory of light, published by Leonhard Euler in 1746, studied in depth in this 1995 book. Contrary to what has been assumed, the particle–wave debate only starts with Euler. When the emission view of light suddenly became dominant in Germany around 1795, it was new chemical experiments that proved crucial. Reflecting on the mathematical, experimental and metaphysical aspects of physical optics, a general picture of early modern science is outlined in the epilogue to the book.
Motivational Strategies in the Language Classroom
Authors: Dörnyei Zoltan
Published: May 2010

This volume gives an overview of the theory of motivation and applies it to practical skills and strategies, providing new insights into the field of motivational studies and its implications for second-language pedagogy.
The New ICT Ecosystem
Authors: Fransman Martin
Published: May 2010

The ICT sector is crucial as a driver of economic and social growth. Not only is it an important industry in its own right, but it also provides the communication and infrastructure without which modern economies could not function. How does this sector work? Why is it stronger in some countries than in others? What should companies, governments and regulators be doing to enhance its contribution? In The New ICT Ecosystem, Martin Fransman answers these and other questions by developing the idea of the ICT sector as an evolving ecosystem. He shows that some components of the ICT ecosystem, particularly the innovation process, work better in some countries and regions than in others. For example, the Internet content and applications layer of the ecosystem tends to work better in the US than in Europe or Asia. The analysis in this book enables policy makers and regulators to understand why some parts of the ICT ecosystem are underperforming and what can be done to enhance their performance. The previous edition of The New ICT Ecosystem won the 2008–10 Joseph Schumpeter Prize.
A Practical Guide to Private Equity Transactions
Authors: Yates Geoff , Hinchliffe Mike
Published: May 2010

This overview of a complex and often misunderstood subject takes the reader through the issues that are faced throughout the life cycle of a private equity investment, from the identification of an opportunity, through the various stages of the transaction and the lifetime of the investment, to the eventual exit by the investor. The analysis of key documentation and legal issues covers company law, employment law, pensions, taxation, debt funding and competition law, taking into account recent legal developments such as the Companies Act 2006, the recent emergence of private equity in the UK and the challenges faced by the industry as a result of the financial crisis.
Seed Dormancy in Grasses
Authors: Simpson G. M.
Published: May 2010

Grasses are a principal source of food for mankind and play an important role in stabilizing the land surface of much of the globe. Understanding seed dormancy in the Gramineae is therefore of considerable significance to world agriculture and global ecology. This book provides a comprehensive review of the occurrence and explanation of seed dormancy in grasses. Experimental evidence is considered in depth for a single species, the wild oat (Avena fatua), probably the most widely studied species for understanding seed dormancy in the plant kingdom. The evidence for this species is compared with other examples among the Gramineae to reach some general conclusions about the nature of seed dormancy in grasses. Essential reading for all those who need to understand the mechanisms of seed dormancy, this book will be a valuable text for advanced students and professionals in plant physiology, crop science, plant breeding and agronomy.
Medical Decision Making
Authors: Schwartz Alan , Bergus George
Published: May 2010

Decision making is a key activity, perhaps the most important activity, in the practice of healthcare. Although physicians acquire a great deal of knowledge and specialised skills during their training and through their practice, it is in the exercise of clinical judgement and its application to individual patients that the outstanding physician is distinguished. This has become even more relevant as patients become increasingly welcomed as partners in a shared decision making process. This book translates the research and theory from the science of decision making into clinically useful tools and principles that can be applied by clinicians in the field. It considers issues of patient goals, uncertainty, judgement, choice, development of new information, and family and social concerns in healthcare. It helps to demystify decision theory by emphasizing concepts and clinical cases over mathematics and computation.
Morphology and structure of the 1999 lava flows at Mount Cameroon Volcano (West Africa) and their bearing on the emplacement dynamics of volume-limited flows
Authors: SUH C. E. , STANSFIELD S. A. , SPARKS R. S. J. , NJOME M. S. , WANTIM M. N. , ERNST G. G. J.
Published: May 2010

The morphology and structure of the 1999 lava flows at Mount Cameroon volcano are documented and discussed in relation to local and source dynamics. Structures are analysed qualitatively and more detailed arguments are developed on the processes of levee formation and systematic links between flow dynamics and levee–channel interface geometry. The flows have clear channels bordered by four main types of levees: initial, accretionary, rubble and overflow levees. Thermally immature pahoehoe lava units with overflow drapes define the proximal zone, whereas rubble and accretionary levees are common in the distal region bordering thermally mature aa clinker or blocky aa flow channels. Pressure ridges, squeeze-ups and pahoehoe ropes are the prevalent compressive structures. Standlines displayed on clinkery breccias are interpreted to represent levee–channel interactions in response to changing flow levels. These data complement previous knowledge on lava flow morphology, thus far dominated by Etnean and Hawaiian examples.
A Middle–Late Eocene vertebrate fauna (marine fish and mammals) from southwestern Morocco; preliminary report: age and palaeobiogeographical implications
Authors: ADNET SYLVAIN , CAPPETTA HENRI , TABUCE RODOLPHE
Published: May 2010

Recent field work in the southern Moroccan Sahara (‘Western Sahara’), south of the city of ad-Dakhla, has led to the discovery of several new fossiliferous sites with fossil vertebrates in sedimentary deposits previously reported for the Mio-Pliocene. The sedimentology and geological setting of the studied area are briefly reported here, and at least three units have been identified in successive stratigraphical sequences according to their fossil content. The first preliminary list of vertebrate associations is reported and consists mainly of isolated teeth belonging to selachian and bony fishes, a proboscidean tooth currently assigned to ?Numidotheriumsp. and many remains of archaeocete whales (Basilosauridae). At least 48 species of selachians are presently identified; many of them are new and others are recorded in the late Middle Eocene (Bartonian) and Late Eocene (Priabonian) of Wadi Al-Hitan (Egypt) or Wadi Esh-Shallala Formation (Jordan) as in other African localities (e.g.Otoduscf.sokolowi, ‘Cretolamna’ twiggsensis, Xiphodolamia serrata, Misrichthys stromeri, Hemipristis curvatus, Galeocerdocf.eaglesomi, Propristis schweinfurthi), probably indicating a Late Eocene age for unit 2 of the bedrock successions. The evolutionary trend noticeable on the proboscidean tooth is in agreement with such an assumption, by comparison with the close relative species known from the Eocene of Egypt, Libya and Algeria. Indeed, the faunal associations from the Dakhla area clearly demonstrate the erroneous age of these deposits, previously thought to be Mio-Pliocene. It suggests a correlation in age (late Middle Eocene–Late Eocene) and a similar environment with the famous marine deposits from Egypt and Jordan. It opens new opportunities to understand the biogeography and the surprising similarity of landscape between West and Northeast Africa during the Bartonian–Priabonian period.
Plastic bronchitis requiring bronchoscopy
Authors: Hoskison E , Judd O , Dickinson E , Dux A
Published: May 2010

Objective:

We report two cases of plastic bronchitis presenting with acute respiratory failure and mimicking foreign body inhalation.

Method:

The clinical findings, differential diagnoses and radiological investigation are discussed.

Results:

Plastic bronchitis is an uncommon condition, particularly in children. The condition may present to otolaryngologists with symptoms mimicking foreign body inhalation. It is important to consider plastic bronchitis as a differential diagnosis, based on its clinical and radiological signs. Early intervention, in the form of bronchoscopy, can be both diagnostic and therapeutic.

Conclusion:

Plastic bronchitis is uncommon and its clinical and radiological features are non-specific. The recommended management is early bronchoscopy to establish the diagnosis and enable therapeutic intervention.
The China-Russia-Japan Military Balance in Manchuria, 1906–1918
Authors: MASAFUMI ASADA
Published: May 2010

Even after the Russo-Japanese War, Manchuria remained the powder keg of East Asia. In the war's aftermath, three empires, the Qing, the Russian and the Japanese, stationed their troops in Manchuria, in a struggle for military supremacy there. There has already been a considerable amount of research on these military activities. However, previous works have not discussed them from a triangular relationship. This paper contends that the history of modern East Asia cannot be understood until one examines the shift in the military balance in Manchuria from a triangular comparative point of view. The results of such examination show that, in Manchuria, each empire was unable to establish military domination alone, and therefore needed an alliance partner. During the Xinhai Revolution, the Russia-Japan ‘alliance’ wielded overwhelming military power against China. However, after the Russian Revolution in 1917, Japan renounced cooperation with a weakened Russia and built a new partnership with China to advance the Siberian intervention. The military triangle of Russia, China and Japan was unable to create a comprehensive regional security system in Manchuria because what was established was based on mutual distrust and fear.
Generation of Longmuir turbulence and stochastic acceleration in laser beat wave process
Authors: Sharma Prerana , Sharma R.P.
Published: May 2010

This paper investigates the filamentation process of two co-axially propagating laser beams in collisionless plasma. On account of the ponderomotive nonlinearity, two laser beams affect the dynamics of each other, and cross-focusing takes place. The initial Gaussian laser beams are found to have non-Gaussian structures in the plasma. Using the laser beam and the plasma parameters, appropriate for the beat wave process, the filaments of the laser beams have been studied. Using these results, the Langmuir wave excitation at the beat wave frequency (when the laser beams are having filamentary structures) has been studied. The excited LW is modeled with the help of a driven oscillator and it is found that the excited Langmuir wave is not a plane wave; rather it has a turbulent structure. We have obtained the power spectrum of the excited beat wave (Langmuir wave), and calculated the spectral index. The stochastic electron acceleration has been studied in the presence of this Langmuir turbulence and relevance of these results to the beat wave process has been pointed out.
Religion, kinship and godparenthood as elements of social cohesion in Qrendi, a late-eighteenth-century Maltese parish
Authors: CIAPPARA FRANS
Published: May 2010

This micro-study examines the Maltese parish of St Mary's (Qrendi) in the second half of the eighteenth century. First it will be argued that – as in many other contemporaneous communities – migration to other parishes made its population extremely fluid. A second interest lies in the extent to which social distinctions and unruly behaviour further disrupted village solidarity. Finally there will be a consideration of the thesis that such unstable elements were counterbalanced by various integrative ties that bound the Qrendin together, such as charity, the obligations of neighbourliness and an intense devotion to the parish, kinship and godparenthood.
Shaping Knowledge about American Labor: External Advising at the U.S. Bureau of Labor Statistics in the Twentieth Century
Authors: Stapleford Thomas A.
Published: May 2010

Argument

Created in 1884, the U.S. Bureau of Labor Statistics (BLS) has been the major federal source for data in the United States on labor-related topics such as prices, unemployment, compensation, productivity, and family expenditures. This essay traces the development and transformation of formal and informal consulting relationships between the BLS and external groups (including academic social scientists, unions, businesses, and other government entities) over the twentieth century. Though such a history cannot, of course, provide a comprehensive analysis of how political values have shaped the construction of labor statistics during this period, I argue that it can nevertheless provide important insights into the political context for the construction of knowledge about American workers and their living and working conditions.
Philosophy, Environment and Technology
Authors: Cooper David E.
Published: May 2010

A striking feature of philosophy in the century just passed is the scale of attention paid to questions concerning the natural environment and technology—a scale so large that any brief survey of the development, current state and possible future of such attention would degenerate into telegrammatic reportage. I shall indeed address the question why philosophical concern with environment and technology has ‘taken off’, and with some confidence that its answer will enable a reasonable estimate of the central issues which deserve continuing reflection. But that question, too, is unmanageably large as it stands. So I need to do something to restrict it.
Mapping sound-space: the Japanese garden as auditory model
Authors: Fowler Michael
Published: May 2010

Japanese culture, through its art, language and religion, is a result of accumulated flows of knowledge from China and Korea. The traditions of garden design and garden construction, similarly, are ‘a space of flows’ from classical Chinese models though, after centuries of development and refinement, have become distinctly reflective of Japanese culture and aesthetics. The first recorded instance of this knowledge flow reaching Japan appears in the eleventh century. The first treatise on Japanese garden design, Sakuteiki (garden making), is attributed to Tachibana no Toshitsuna, a court official and designer of gardens. Though the treatise contains no illustrations, much of the text is precise, and its content reflective of the cultural and aesthetic predilections of the Confucianist Heien court. Other treatises may have been extant during the Heien period (794–1185), though they are now lost.
ROBUST POLICIES IN A STICKY INFORMATION ECONOMY
Authors: Giuli Francesco
Published: May 2010

This paper analyzes the behavior of a central bank under strong (“Knightian”) uncertainty when the short-run trade-off between output and inflation is represented by the sticky information Phillips curve proposed by Mankiw and Reis [Quarterly Journal of Economics 117(4), 1295–1328 (2002)]. By solving the robust control problem analytically, we show why model uncertainty does not affect the optimal monetary policy response to demand and productivity shocks, whereas it causes a stronger reaction of the monetary policy instrument to a cost-push (i.e., markup) shock. Differently from what occurs in sticky price models, the antiattenuation effect can result in a degree of price level stabilization that is greater or less than that experienced in the rational expectation model, depending on the central bank's degree of conservatism. These results dramatically affect the rationale for delegating monetary policy to a central banker more conservative than the society.
Small trenches. Archaeology and the postcolonial gaze
Authors: Horning Audrey
Published: May 2010

The comments of Nicholas Sarkozy provide a powerful and forceful opening to Dr Richard's article and remind us of the potential significance of academic considerations of colonial legacies in the contemporary world. Dr Richard argues strongly against static conceptualizations of pre-‘Atlantic-era’ Africa and seeks to recast Africans not as victims, but as active ‘producers of history and culture’ (p. 26). In so doing he aligns himself with current trends in critical scholarship on colonial encounters in the Atlantic worlds of the last four centuries, scholarship that overtly criticizes dichotomous understandings of such encounters in favour of approaches that emphasize ambiguity (e.g. Hall 2000; Silliman 2001; 2009; Stahl 2007). Dr Richard's introductory suggestion that we should formulate ‘new questions instead of supplying different answers to the quandaries of an earlier generation of historians’ (p. 3) is clearly applicable to studies of colonial arenas beyond West Africa. In all parts of the world touched by European colonialism (including, of course, Europe itself) the ways in which scholars approach their subjects are very much conditioned by more widely held cultural memories, whatever the relationship of those memories may be to whatever may have occurred in the past.
‘What did the Greeks owe the Orient?’ The question we can't stop asking (even though we can't answer it)
Authors: Marchand Suzanne
Published: May 2010

Reviewing five recent books in German classical and oriental studies, this essay argues that the question of archaic Greece's debts to the Orient remains a particularly lively one in German-speaking Europe. Like their predecessors in previous generations, iconoclastic classicists like Walter Burkert, oriental archaeologists like Ernst Herzfeld (1879–1948) and maverick outsiders like Raoul Schrott have attacked the enraptured view of ‘the Greek miracle’ familiar to those educated in classicalGymnasien. And yet the question of Greek cultural autonomy is still alive, in part because there are too many uncertainties for it to be answered definitively, and in part because it continues to play a role in attempts to define modern European identity.
Roles of COMM-domain-containing 1 in stability and recruitment of the copper-transporting ATPase in a mouse hepatoma cell line
Authors: Miyayama Takamitsu , Hiraoka Daisuke , Kawaji Fumika , Nakamura Emi , Suzuki Noriyuki , Ogra Yasumitsu
Published: May 2010

A novel function of COMMD1 {COMM [copper metabolism MURR1 (mouse U2af1-rs1 region 1)]-domain-containing 1}, a protein relevant to canine copper toxicosis, was examined in the mouse hepatoma cell line Hepa 1-6 with multi-disciplinary techniques consisting of molecular and cellular biological techniques, speciation and elemental imaging. To clarify the function of COMMD1, COMMD1-knockdown was accomplished by introducing siRNA (small interfering RNA) into the cells. Although COMMD1-knockdown did not affect copper incorporation, it inhibited copper excretion, resulting in copper accumulation, which predominantly existed in the form bound to MT (metallothionein). It is known that the liver copper transporter Atp7b (ATP-dependent copper transporter 7β), localizes on the trans-Golgi network membrane under basal copper conditions and translocates to cytoplasmic vesicles to excrete copper when its concentration exceeds a certain threshold, with the vesicles dispersing in the periphery of the cell. COMMD1-knockdown reduced the expression of Atp7b, and abolished the relocation of Atp7b back from the periphery to the trans-Golgi network membrane when the copper concentration was reduced by treatment with a Cu(I) chelator. The same phenomena were observed during COMMD1-knockdown when another Atp7b substrate, cis-diamminedichloroplatinum, and its sequestrator, glutathione ethylester, were applied. These results suggest that COMMD1 maintains the amount of Atp7b and facilitates recruitment of Atp7b from cytoplasmic vesicles to the trans-Golgi network membrane, i.e. COMMD1 is required to shuttle Atp7b when the intracellular copper level returns below the threshold.
Gift-Giving as a Conceptual Framework: Framing Social Behavior in Online Networks
Authors: Skågeby Jörgen
Published: May 2010

This paper explores the use of gift-giving as a theoretical and conceptual framework for analyzing social behavior in online networks and communities. Not only has gift-giving the potential to frame and explain much social media behavior, but reversely, and perhaps more Importantly, mediated social behavior also has the potential to develop gift-giving theory. Information and communication technologies form joint sociotechnical systems where new practices emerge. The paper focuses on describing the academic background of the gifting framework to help develop a deeper, theory-based, understanding of these sociotechnical phenomena. Three themes are prevalent In the gifting literature: other- orientation, social bonding and generalized reciprocity. The paper gives examples of how these themes are enacted by end-users via the use of Information and communication technologies. Finally, sociotechnically embedded economies, called gifting technologies, are Identified and discussed.
Von Bezold Assimilation Effect Reverses in Stereoscopic Conditions
Authors: Soranzo Alessandro , Galmonte Alessandra , Agostini Tiziano
Published: May 2010

Lightness contrast and lightness assimilation are opposite phenomena: in contrast, grey targets appear darker when bordering bright surfaces (inducers) rather than dark ones; in assimilation, the opposite occurs. The question is: which visual process favours the occurrence of one phenomenon over the other? Researchers provided three answers to this question. The first asserts that both phenomena are caused by peripheral processes; the second attributes their occurrence to central processes; and the third claims that contrast involves central processes, whilst assimilation involves peripheral ones. To test these hypotheses, an experiment on an IT system equipped with goggles for stereo vision was run. Observers were asked to evaluate the lightness of a grey target, and two variables were systematically manipulated: (i) the apparent distance of the inducers; and (ii) brightness of the inducers. The retinal stimulation was kept constant throughout, so that the peripheral processes remained the same. The results show that the lightness of the target depends on both variables. As the retinal stimulation was kept constant, we conclude that central mechanisms are involved in both lightness contrast and lightness assimilation.
Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis
Authors: Hakkim Abdul , Fürnrohr Barbara G. , Amann Kerstin , Laube Britta , Abed Ulrike Abu , Brinkmann Volker , Herrmann Martin , Voll Reinhard E. , Zychlinsky Arturo
Published: May 2010

Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients develop autoantibodies to DNA, histones, and often to neutrophil proteins. These form immune complexes that are pathogenic and may cause lupus nephritis. In SLE patients, infections can initiate flares and are a major cause of mortality. Neutrophils respond to infections and release extracellular traps (NETs), which are antimicrobial and are made of DNA, histones, and neutrophil proteins. The timely removal of NETs may be crucial for tissue homeostasis to avoid presentation of self-antigens. We tested the hypothesis that SLE patients cannot clear NETs, contributing to the pathogenesis of lupus nephritis. Here we show that serum endonuclease DNase1 is essential for disassembly of NETs. Interestingly, a subset of SLE patients’ sera degraded NETs poorly. Two mechanisms caused this impaired NET degradation: (i) the presence of DNase1 inhibitors or (ii) anti-NET antibodies prevented DNase1 access to NETs. Impairment of DNase1 function and failure to dismantle NETs correlated with kidney involvement. Hence, identification of SLE patients who cannot dismantle NETs might be a useful indicator of renal involvement. Moreover, NETs might represent a therapeutic target in SLE.
Identification of select glucocorticoids as Smoothened agonists: Potential utility for regenerative medicine
Authors: Wang Jiangbo , Lu Jiuyi , Bond Michael C. , Chen Minyong , Ren Xiu-Rong , Lyerly H. Kim , Barak Larry S. , Chen Wei
Published: May 2010

Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened (Smo) is an important process for regulating stem cell proliferation. The development of Hedgehog-related therapies has been impeded by a lack of US Food and Drug Administration (FDA)-approved Smo agonists. Using a high-content screen with cells expressing Smo receptors and a β-arrestin2-GFP reporter, we identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. These drugs demonstrated an ability to bind Smo, promote Smo internalization, activate Gli, and stimulate the proliferation of primary neuronal precursor cells alone and synergistically in the presence of Sonic Hedgehog protein. Halcinonide, fluticasone, clobetasol, and fluocinonide provide an unprecedented opportunity to develop unique clinical strategies to treat Hedgehog-dependent illnesses.
γ
c
deficiency precludes CD8
+
T cell memory despite formation of potent T cell effectors
Authors: Decaluwe Hélène , Taillardet Morgan , Corcuff Erwan , Munitic Ivana , Law Helen K. W. , Rocha Benedita , Rivière Yves , Di Santo James P.
Published: May 2010

Several cytokines (including IL-2, IL-7, IL-15, and IL-21) that signal through receptors sharing the common γ chain (γ
c
) are critical for the generation and peripheral homeostasis of naive and memory T cells. Recently, we demonstrated that effector functions fail to develop in CD4
+
T cells that differentiate in the absence of γ
c
. To assess the role of γ
c
cytokines in cell-fate decisions that condition effector versus memory CD8
+
T cell generation, we compared the response of CD8
+
T cells from γ
c
+
or γ
c
−
P14 TCR transgenic mice after challenge with lymphocytic choriomeningitis virus. The intrinsic IL-7-dependent survival defect of γ
c
−
naive CD8
+
T cells was corrected by transgenic expression of human Bcl-2. We demonstrated that although γ
c
-dependent signals are dispensable for the initial expansion and the acquisition of cytotoxic functions following antigenic stimulation, they condition the terminal proliferation and differentiation of CD8
+
effector T cells (i.e., KLRG1
high
CD127
low
short-lived effector T cells) via the transcription factor, T-bet. Moreover, the γ
c
-dependent signals that are critical for memory T cell formation are not rescued by Bcl2 overexpression. Together, these data reveal an unexpected divergence in the requirement for γ
c
cytokines in the differentiation of CD4
+
versus CD8
+
cytotoxic T lymphocytes.
In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+T cell inflammation
Authors: Wang Jinguo , Tsai Sue , Shameli Afshin , Yamanouchi Jun , Alkemade Gonnie , Santamaria Pere
Published: May 2010

A current paradigm states that non-antigen-specific inflammatory cues attract noncognate, bystander T cell specificities to sites of infection and autoimmune inflammation. Here we show that cues emanating from a tissue undergoing spontaneous autoimmune inflammation cannot recruit naive or activated bystander T cell specificities in the absence of local expression of cognate antigen. We monitored the recruitment of CD8+T cells specific for the prevalent diabetogenic epitope islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206–214in gene-targeted nonobese diabetic (NOD) mice expressing a T cell “invisible” IGRP206–214sequence. These mice developed islet inflammation and diabetes with normal incidence and kinetics, but their inflammatory lesions could recruit neither naive (endogenous or exogenous) nor ex vivo-activated IGRP206–214-reactive CD8+T cells. Conversely, IGRP206–214-reactive, but not nonautoreactive CD8+T cells rapidly homed to and accumulated in the inflamed islets of wild-type NOD mice. Our results indicate that CD8+T cell recruitment to a site of autoimmune inflammation results from an active process that is strictly dependent on local display of cognate pMHC and suggest that CD8+T cells contained in extralymphoid autoimmune lesions are largely autoreactive.
Quantitative proteomics approach for identifying protein–drug interactions in complex mixtures using protein stability measurements
Authors: West Graham M. , Tucker Chandra L. , Xu Tao , Park Sung Kyu , Han Xuemei , Yates John R. , Fitzgerald Michael C.
Published: May 2010

Knowledge about the protein targets of therapeutic agents is critical for understanding drug mode of action. Described here is a mass spectrometry-based proteomics method for identifying the protein target(s) of drug molecules that is potentially applicable to any drug compound. The method, which involves making thermodynamic measurements of protein-folding reactions in complex biological mixtures to detect protein–drug interactions, is demonstrated in an experiment to identify yeast protein targets of the immunosuppressive drug, cyclosporin A (CsA). Two of the ten protein targets identified in this proof of principle work were cyclophilin A and UDP-glucose-4-epimerase, both of which are known to interact with CsA, the former through a direct binding event (
K

d

 ∼ 70 nM) and the latter through an indirect binding event. These two previously known protein targets validate the methodology and its ability to detect both the on- and off-target effects of protein–drug interactions. The other eight protein targets discovered here, which include several proteins involved in glucose metabolism, create a new framework in which to investigate the molecular basis of CsA side effects in humans.
Structure and identification of ADP-ribose recognition motifs of APLF and role in the DNA damage response
Authors: Li Guang-Yao , McCulloch Richard D. , Fenton Amanda L. , Cheung Melissa , Meng Li , Ikura Mitsuhiko , Koch C. Anne
Published: May 2010

Poly(ADP-ribosyl)ation by poly(ADP-ribose) polymerases regulates the interaction of many DNA damage and repair factors with sites of DNA strand lesions. The interaction of these factors with poly(ADP-ribose) (PAR) is mediated by specific domains, including the recently identified PAR-binding zinc finger (PBZ) domain. However, the mechanism governing these interactions is unclear. To better understand the PBZ-PAR interaction, we performed a detailed examination of the representative PBZ-containing protein involved in the DNA damage response, aprataxin polynucleotide-kinase-like factor (APLF), which possesses two tandem PBZ domains. Here we present structural and biochemical studies that identify Y381/Y386 and Y423/Y428 residues in the conserved C(M/P)Y and CYR motifs within each APLF PBZ domain that are critical for the interaction with the adenine ring of ADP-ribose. Basic residues (R387 and R429 in the first and second PBZ domains, respectively) coordinate additional interactions with the phosphate backbone of ADP-ribose, suggesting that APLF binds to multiple ADP-ribose residues along PAR polymers. These C(M/P)Y and CYR motifs form a basic/hydrophobic pocket within a variant zinc finger structure and are required for APLF recruitment to sites of DNA damage in vivo.
Crystal structure of a junction between two Z-DNA helices
Authors: de Rosa Matteo , de Sanctis Daniele , Rosario Ana Lucia , Archer Margarida , Rich Alexander , Athanasiadis Alekos , Carrondo Maria Armenia
Published: May 2010

The double helix of DNA, when composed of dinucleotide purine-pyrimidine repeats, can adopt a left-handed helical structure called Z-DNA. For reasons not entirely understood, such dinucleotide repeats in genomic sequences have been associated with genomic instability leading to cancer. Adoption of the left-handed conformation results in the formation of conformational junctions: A B-to-Z junction is formed at the boundaries of the helix, whereas a Z-to-Z junction is commonly formed in sequences where the dinucleotide repeat is interrupted by single base insertions or deletions that bring neighboring helices out of phase. B-Z junctions are shown to result in exposed nucleotides vulnerable to chemical or enzymatic modification. Here we describe the three-dimensional structure of a Z-Z junction stabilized by Zα, the Z-DNA binding domain of the RNA editing enzyme ADAR1. We show that the junction structure consists of a single base pair and leads to partial or full disruption of the helical stacking. The junction region allows intercalating agents to insert themselves into the left-handed helix, which is otherwise resistant to intercalation. However, unlike a B-Z junction, in this structure the bases are not fully extruded, and the stacking between the two left-handed helices is not continuous.
Direct role for the RNA polymerase domain of T7 primase in primer delivery
Authors: Zhu Bin , Lee Seung-Joo , Richardson Charles C.
Published: May 2010

Gene 4 protein (gp4) encoded by bacteriophage T7 contains a C-terminal helicase and an N-terminal primase domain. After synthesis of tetraribonucleotides, gp4 must transfer them to the polymerase for use as primers to initiate DNA synthesis. In vivo gp4 exists in two molecular weight forms, a 56-kDa form and the full-length 63-kDa form. The 56-kDa gp4 lacks the N-terminal Cys
4
zinc-binding motif important in the recognition of primase sites in DNA. The 56-kDa gp4 is defective in primer synthesis but delivers a wider range of primers to initiate DNA synthesis compared to the 63-kDa gp4. Suppressors exist that enable the 56-kDa gp4 to support the growth of T7 phage lacking gene 4 (T7Δ4). We have identified 56-kDa DNA primases defective in primer delivery by screening for their ability to support growth of T7Δ4 phage in the presence of this suppressor. Trp69 is critical for primer delivery. Replacement of Trp69 with lysine in either the 56- or 63-kDa gp4 results in defective primer delivery with other functions unaffected. DNA primase harboring lysine at position 69 fails to stabilize the primer on DNA. Thus, a primase subdomain not directly involved in primer synthesis is involved in primer delivery. The stabilization of the primer by DNA primase is necessary for DNA polymerase to initiate synthesis.
Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma
Authors: Maas Coen , Meijers Joost C. M. , Marquart J. Arnoud , Bakhtiari Kamran , Weeterings Cees , de Groot Philip G. , Urbanus Rolf T.
Published: May 2010

The mechanism by which the intrinsic pathway of coagulation contributes to physiological hemostasis is enigmatic. Thrombin activates factor XI, a key zymogen in this pathway, which leads to increased thrombin generation. As thrombin-dependent activation of factor XI in vitro is relatively inefficient, we hypothesized that a physiological cofactor supports this reaction in a plasma environment. We therefore investigated whether the cofactors of coagulation, activated factor V, activated factor VIII, high-molecular weight kininogen, or protein S, influenced activation of factor XI by thrombin. Only activated factor V stimulated activation of factor XI by thrombin in a purified system. Binding studies demonstrated that factor XI specifically interacts with both factor V and factor Va through multiple binding sites. We further investigated this cofactor function of activated factor V in plasma. Depletion of factor V, or the addition of activated protein C, decreased the activation of the intrinsic pathway by thrombin in plasma. However, activated protein C did not exert this effect in the plasma of a homozygous carrier of the prothrombotic factor V Leiden mutation. In conclusion, we propose a role for (activated) factor V as a cofactor in the activation of factor XI by thrombin. These findings offer insights into the coagulation system in both health and disease.
Peter Pan bone cells undermine skeleton
Authors: Leslie Mitch
Published: May 2010

Protein that controls maturation of bone-building cells might be disease culprit.
The structure of the Myo4p globular tail and its function in ASH1 mRNA localization
Authors: Heuck Alexander , Fetka Ingrid , Brewer Daniel N. , Hüls Daniela , Munson Mary , Jansen Ralf-Peter , Niessing Dierk
Published: May 2010

Type V myosin (MyoV)–dependent transport of cargo is an essential process in eukaryotes. Studies on yeast and vertebrate MyoV showed that their globular tails mediate binding to the cargo complexes. In Saccharomyces cerevisiae, the MyoV motor Myo4p interacts with She3p to localize asymmetric synthesis of HO 1 (ASH1) mRNA into the bud of dividing cells. A recent study showed that localization of GFP-MS2–tethered ASH1 particles does not require the Myo4p globular tail, challenging the supposed role of this domain. We assessed ASH1 mRNA and Myo4p distribution more directly and found that their localization is impaired in cells expressing globular tail–lacking Myo4p. In vitro studies further show that the globular tail together with a more N-terminal linker region is required for efficient She3p binding. We also determined the x-ray structure of the Myo4p globular tail and identify a conserved surface patch important for She3p binding. The structure shows pronounced similarities to membrane-tethering complexes and indicates that Myo4p may not undergo auto-inhibition of its motor domain.
TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis
Authors: Noti Mario , Corazza Nadia , Mueller Christoph , Berger Barbara , Brunner Thomas
Published: May 2010

Although tumor necrosis factor (α) (TNF) exerts proinflammatory activities in a variety of diseases, including inflammatory bowel disease, there is increasing evidence for antiinflammatory actions of TNF. In contrast, glucocorticoids (GCs) are steroid hormones that suppress inflammation, at least in part by regulating the expression and action of TNF. We report that TNF induces extraadrenal production of immunoregulatory GCs in the intestinal mucosa during acute intestinal inflammation. The absence of TNF results in a lack of colonic GC synthesis and exacerbation of dextran sodium sulfate–induced colitis. TNF seems to promote local steroidogenesis by directly inducing steroidogenic enzymes in intestinal epithelial cells. Therapeutic administration of TNF induces GC synthesis in oxazolone-induced colitis and ameliorates intestinal inflammation, whereas inhibition of intestinal GC synthesis abrogates the therapeutic effect of TNF. These data show that TNF suppresses the pathogenesis of acute intestinal inflammation by promoting local steroidogenesis.
Invariant NKT cells limit activation of autoreactive CD1d-positive B cells
Authors: Wermeling Fredrik , Lind Sara M. , Jordö Emilie Domange , Cardell Susanna L. , Karlsson Mikael C.I.
Published: May 2010

Faulty activation of autoreactive B cells is a hallmark of autoimmune diseases like systemic lupus erythematosus (SLE). An important feature restricting activation of autoreactive B cells is efficient removal of apoptotic material. Mounting evidence also connects a primary defect in invariant natural killer T (iNKT) cells to autoimmune disease development. However, exactly how this unconventional T cell subset is involved remains to be defined. Here, we identify a suppressive role for iNKT cells in a model where autoantibody production is triggered by an increased load of circulating apoptotic cells, resembling the situation in SLE patients. Absence or reduction of iNKT cells as well as absence of CD1d-expression on B cells, needed for direct iNKT–B cell interaction, leads to increased autoreactive B cell activation and symptoms of disease. The suppression mediated by the iNKT cells is observed before B cell entry into germinal centers and can be rescued by transferring iNKT cells to deficient mice. This links iNKT cells to handling of dying cells and identifies a novel peripheral tolerance checkpoint relevant for autoimmune disease. Thus, these observations connect two clinical observations in SLE patients previously considered to be unrelated and define a new target for immunotherapy.
Inferring the human microRNA functional similarity and functional network based on microRNA-associated diseases
Authors: Wang Dong , Wang Juan , Lu Ming , Song Fei , Cui Qinghua
Published: May 2010

Motivation: It is popular to explore meaningful molecular targets and infer new functions of genes through gene functional similarity measuring and gene functional network construction. However, little work is available in this field for microRNA (miRNA) genes due to limited miRNA functional annotations. With the rapid accumulation of miRNAs, it is increasingly needed to uncover their functional relationships in a systems level.

Results: It is known that genes with similar functions are often associated with similar diseases, and the relationship of different diseases can be represented by a structure of directed acyclic graph (DAG). This is also true for miRNA genes. Therefore, it is feasible to infer miRNA functional similarity by measuring the similarity of their associated disease DAG. Based on the above observations and the rapidly accumulated human miRNA-disease association data, we presented a method to infer the pairwise functional similarity and functional network for human miRNAs based on the structures of their disease relationships. Comparisons showed that the calculated miRNA functional similarity is well associated with prior knowledge of miRNA functional relationship. More importantly, this method can also be used to predict novel miRNA biomarkers and to infer novel potential functions or associated diseases for miRNAs. In addition, this method can be easily extended to other species when sufficient miRNA-associated disease data are available for specific species.

Availability: The online tool is available at http://cmbi.bjmu.edu.cn/misim

Contact:  cuiqinghua@hsc.pku.edu.cn

Supplementary information:  Supplementary data are available at Bioinformatics online.