bluuebunny/crossref_metadata_2025 huggingface dataset:
Designating Places and Populations as Medically Underserved: A Proposal for a New Approach
Authors: Ricketts Thomas C , Goldsmith Laurie J , Holmes George Mark , Randolph Randy, M.R.P , Lee Richard , Taylor Donald H , Ostermann Jan
Published: August 2007

This article describes the development of a theory-based, data-driven replacement for the Health Professional Shortage Area (HPSA) and Medically Underserved Area (MUA) designation systems. Data describing utilization of primary medical care and the distribution of practitioners were used to develop estimates of the effects of demographic and community characteristics on use of primary medical care. A scoring system was developed that estimates each community's effective access to primary care. This approach was reviewed and contributed to by stakeholder groups. The proposed formula would designate over 90% of current geographic and low-income population HPSA designations. The scalability of the method allows for adjustment for local variations in need and was considered acceptable by stakeholder groups. A data-driven, theory-based metric to calculate relative need for geographic areas and geographically-bounded special populations can be developed and used. Its use, however, requires careful explanation to and support from affected groups.
The Telehealth Divide: Disparities in Searching Public Health Information Online
Authors: Schmeida Mary , McNeal Ramona S
Published: August 2007

This article explores e government inequalities to searching Medicare and Medicaid information online. Telehealth, a branch of e government, can bring public health service and insurance information to the citizen. The Centers for Medicare and Medicaid Services website, among others, has critical information for potential beneficiaries and recipients of services. Using Pew survey data and multivariate regression analysis we find people in most need of Medicare and Medicaid information online (the elderly and poor) are accessing it, and people with years of online experience are strong proponents of online searches. Despite being less likely to have broadband services, individuals in rural areas were not found to be less likely to search for information online. In conclusion, some disparities are narrowing as the elderly and poor in need of access to public health insurance are searching for it online. However, people without Internet access and experience (perhaps the oldest and poorest) remain disadvantaged with respect to accessing critical information that can link them to needed health care services.
Neighborhood Clinics: An Academic Medical Center—Community Health Center Partnership
Authors: Silberberg Mina , Yarnall Kimberly S. H , Johnson Fred , Sangvai Devdutta , Patel Rupal , Yaggy Susan D
Published: August 2007

This report describes a clinic run by a federally-qualified health center and an academic medical center. The clinic expands the community's primary care capacity, combining advantages of big and small settings, and of its dual affiliation. Survey data suggest the clinic prevents health care delays and lowers emergency department use.
Disparities in Breast Cancer Treatment among American Indian, Hispanic and Non-Hispanic White Women Enrolled in Medicare
Authors: Wilson Robin Taylor , Adams-Cameron Meg , Burhansstipanov Linda , Roubidoux Marilyn A , Cobb Nathaniel , Lynch Charles F , Edwards Brenda K
Published: August 2007

Because racial/ethnic disparities in breast cancer survival have persisted, we investigated differences in breast cancer treatment among American Indian, Hispanic, and non-Hispanic White (NHW) women. Surveillance, Epidemiology and End Results data linked to Medicare claims in New Mexico and Arizona (1987–1997) among enrollees aged 65 and older were used to identify treatment, treatment interval, and mortality risk associated with delays in care. We identified 2,031 women (67 American Indian, 333 Hispanic and 1,631 NHW women with time to treatment information. Treatment intervals from diagnosis to surgery (all stages, 18 versus 4 days, p
The Democracy Barometers(Part I): Authoritarian Nostalgia in Asia
Authors: Chang Yu-tzung , Chu Yun-han , Park Chong-Min
Published: August 2007

Abstract: From Bangkok to Manila, Taipei, Seoul, and Ulaanbaatar, East Asia's third-wave democracies are in distress. Data from the first and second Asian Barometer Surveys can help us systematically to assess the extent of normative commitment to democracy that citizens feel in Japan, South Korea, Taiwan, Mongolia, the Philippines, and Thailand. Compared to levels of popular support for democracy, strength of authoritarian detachment, and satisfaction with the performance of democracy observed in other regions, our six East Asian democracies appear on a par with similarly situated societies elsewhere in the world. The lesson is that this form of government must win citizens' support through better performance.
The Decline of the African Military Coup
Authors: Clark John Frank
Published: August 2007

This study tests the proposition that liberalizing African states may avoid coups d'etat and other forms of military intervention in their politics. It hypothesizes that one way for African states to gain legitimacy is by following a trajectory of gradual liberalization. The study shows that this legitimacy, in turn, tends to inoculate African states against military intervention. Many African regimes, on the other hand, have experienced an "authoritarian drift" after nominal transitions to "democracy." Unlike the regimes governing liberalizing states, "electoral authoritarian" regimes—ones that fall prey to authoritarian drift—become more vulnerable to both civil war and military coup.
Exchange: The Sequencing “Fallacy”
Authors: Mansfield Edward D. , Snyder Jack
Published: August 2007

Abstract: Countries taking the initial steps from dictatorship toward electoral politics are especially prone to civil and international war. Yet states endowed with coherent institution’s such as a functioning bureaucracy and the elements needed to construct a sound legal system, have often been able to democratize peacefully and successfully. Consequently, whenever possible, efforts to promote democracy should try to follow a sequence of building institutions before encouraging mass competitive elections. Democratizing in the wrong sequence not only risks bloodshed in the short term, but also the mobilization of durable illiberal forces with the capacity to block democratic consolidation over the long term.
Personalizing Power in Uganda
Authors: Mwenda Andrew M
Published: August 2007

A dozen years after the adoption of Uganda's new constitution, the democratization process has been thrown into reverse. Uganda today is sliding backward toward a system of one-man rule engineered by the recently reelected President Yoweri Museveni, who has now been in power for more than two decades. Due to Museveni's use of force and intimindation on the one hand, and his manipulation of patronage on the other, the stakeholders whom one would naturally expect to denounce the backsliding have been silent.
Comment: How Will China Democratize?
Authors: Pei Minxin
Published: August 2007

Abstract: Given the mixed signals and trends in China, it may be premature to identify a specific timeframe within which China will become Free or even Partly Free on the Freedom House scale. A more fruitful intellectual exercise might be to ask not when but how the Middle Kingdom could become Free. No one should underrate the will and skill that the ruling Chinese Communist Party will put into keeping its grip on power.
The Institutionalization of Political Power in Africa
Authors: Posner Daniel N , Young Daniel J
Published: August 2007

Across sub-Saharan Africa, formal institutional rules are coming to matter much more than they used to, and have displaced violence as the primary source of constraints on executive behavior. From decolonization in the early 1960s through the 1980s, most African rulers left office through a coup, assassination, or some other form of violent overthrow. Since 1990, however, the majority have left through institutionalized means—chiefly through voluntary resignation at the end of a constitutionally defined term or by losing an election. While institutional rules may not yet always determine outcomes in Africa today, such rules are consistently and dependably affecting the strategies through which those outcomes are reached.
The Democracy Barometers (Part I): Learning to Support New Regimes in Europe
Authors: Rose Richard
Published: August 2007

Abstract: Using New Europe Barometer public opinion surveys from 13 postcommunist countries, this article shows that with the passage of time citizens in undemocratic as well as democratic regimes tend to accept their political system; however, they do so for different reasons. Democratic regimes can gain positive support from reform-minded democrats and those who reject undemocratic alternatives. By contrast, undemocratic regimes depend more on resigned acceptance from citizens who do not think there is any alternative, thus, for better or worse, making their new regime the only game in town.
The Democracy Barometers (Part I): The Rise of Populism and the Left in Latin America
Authors: Seligson Mitchell A.
Published: August 2007

Abstract: AmericasBarometer data point to some overall trends that merit careful attention. The ideological center of gravity in Latin America is, by world standards, slightly to the right, yet attitudes are moving to the left. Ideological cleavages in Latin America, long after the Cold War's end, still line up along a distinct left-right dimension, and voters support parties consistent with their ideological orientations. The gap between left and right is very narrow, however, in some countries like Costa Rica, but strikingly wide in other countries such as Chile, El Salvador, and Nicaragua.
Comment: China’s Long March to Freedom
Authors: Yang Dali L.
Published: August 2007

Abstract: Yang highlights several factors that augur well for freedom in China. These factors include growing elite discourse on human rights and democracy as well as a massive expansion of tertiary education that will make a new generation more capable of articulating its interests. International factors include the expansion of democracy in Asia and China's aspirations to be a responsible global power in a world in which the leading powers are democracies. Ultimately China's political transformation will not be determined by the top elite alone but will be subject to negotiation and contestation among diverse interests.
Beyond "Pabulum for the Undergraduates": The Development of the Princeton Theological Seminary Library in the Nineteenth Century
Authors: Paulus Michael J
Published: August 2007

In the early nineteenth century Protestant denominations began establishing postgraduate professional schools to train ministers for the new republic of the United States. These new schools provided the only substantive opportunities for advanced studies in antebellum America and figured prominently in American culture. One of the earliest and most important of these schools was Princeton Theological Seminary, the plan for which called for and depended on "a complete theological library" that would facilitate advanced instruction and research. This article examines how Princeton's theological library was developed in the nineteenth century to realize this goal and provides insights into an academic culture that preceded and paralleled the advent of the modern research university and library in the United States.
The Bushranger's Voice: Peter Carey's True History of the Kelly Gang (2000) and Ned Kelly's Jerilderie Letter (1879)
Authors: Eggert Paul
Published: August 2007

There is an umbilical cord of outlaw folkloric tradition that joins Rolf Boldrewood's 1880s bushranger novel Robbery Under Arms and Peter Carey's Booker Prize-winning novel True History of the Kelly Gang (2000). Carey has done again what Boldrewood so innovatively achieved: the invention, or reinvention, of the bushranger's voice. But the more tantalising manifestation of the common outlaw tradition, for Carey, was the real-life bushranger Ned Kelly's Jerilderie Letter (1879). The relationship between the Letter and Carey's novel interrupts an easy postmodern take on his work: this interruption is the subject of the essay. It teases out the paradox of the novel's being simultaneously both postmodern-quotational and, in the old-fashioned sense, an act of imaginative engagement with a significant past, a historical tale in fact.
Wildean Philosophy with a Needle and Thread: Consumer Fashion at the Origins of Modernist Aesthetics
Authors: Fortunato Paul L.
Published: August 2007

Oscar Wilde was a consumer modernist. His modernist aesthetics drove him into the heart of the mass culture industries of 1890s London, particularly the journalism and popular theater industries. Wilde was extremely active among these industries: as a journalist at the Pall Mall Gazette; as magazine editor of the Woman's World; as commentator on dress and design through both of these; and finally as a fabulously popular playwright. Because he makes the desire to impact a mass audience so central, the primary elements of Wilde's consumer aesthetic are superficial ornament and ephemeral public image—both of which he links to the theatrical. His concern with the surface and with the ephemeral was, ironically, a foundational element of what became twentieth-century modernism—thus we can call Wilde's aesthetic a consumer-modernism, a root and branch of modernism that was largely erased (just as Wilde was erased from literary history by the early modernists).
Just Look at That Post-Colonial Shuffle!
Authors: Marrouchi Mustapha
Published: August 2007

The essay is an embrace not only of a life lived on the edge but of an anxiety—an anxiety about the post-colonial sense of self being swamped and smothered in Jamaica Kincaid, whose narrative charts an existence remarkably open to breeze, birds, and rainfall in the Caribbean, to the arrival of daylight and evening. The narrative is also strangely, unselfconsciously, enclosed even if it examines the experience of the goings-on of life, crystallizing something that is amorphous and resistant to crystallization. Kincaid performs this embrace brilliantly and passionately. Her endeavor to tell of dislocation, childhood, deracination, love, and death is not, really, a nostalgic one, in spite of all she says about loss, uprooting, and the act of returning; her elegiac notes are her most strained. The narrative has the hard-headed exuberance of a 19th-century novel even if it centers on "failure" as an integral part of modernist creativity. Like a heroine of dubious energy, Kincaid keeps inventing and reinventing herself, bruising herself as she looks for acceptance–and it is to this drive, this desire, that my essay is attuned.
A Long Lost Sister of Proto-Austronesian?: Proto-Ongan, Mother of Jarawa and Onge of the Andaman Islands
Authors: Blevins Juliette
Published: August 2007

This paper applies the comparative method to two related languages of the southen Andaman Islands, Jarawa and Onge, leading to the reconstruction of a proto-language termed "Proto-Ongan" (PON). The same method is used to argue that Proto-Ongan may be related to Proto-Austronesian (PAN). Lexical and grammatical evidence suggests that Proto-Ongan and Proto-Austronesian are sisters, daughters of a Proto-Austronesian-Ongan (PAO). The implications of this discovery are wide-ranging, from potential solutions to problems in PAN grammar, to new hypotheses regarding ancient speaker migrations. While few of these implications are examined here, an extended Austronesian phylogeny is proposed in the hope that it will seed new avenues of research, and highlight the potential importance of Andamanese studies in understanding Austronesian prehistory.
Òma Lóngh Historical Phonology
Authors: Blust R. A
Published: August 2007

The phonology of Óma Lóngh Kenyah as described by Soriente (2006) shows strinking typological difference from its nearest relatives. Contrary to a pattern of avoidance that is almost universal in Austronesian languages, it has developed final palatals, including voiceless unreleased palatal stop (written -j), and a palatal nasal (written -ny). In violation of universal tendencies in phonological systems, it has also innovated a voiceless velar nasal (but no other voiceless nasals) in final position. Out of a Proto-Kenyah six-vowel system in which tense mid vowels occurred only word-finally, it has developed three new vowels and an unusual system of soube vowel harmony that requires both High-Mid avoidance and Tense-Lax agreement. Even more surprisingly, a typologically bizarre connection between the tenseness/laxness of the penultimate vowel and the shape of the final syllable is present in one subclass of bases, but emerges clearly only through a historical analysis. Together, these innovations add to an already impressive picture of north-central Borneo as a "hot spot" for rapid phonological change, include changes that do not appear to be phonetically motivated.
Is Kazukuru Really Non-Austronesian?
Authors: Dunn Michael , Ross Malcolm
Published: August 2007

Kazukuru is an extinct language, originally spoken in the inland of the western part of the island of New Georgia, Solomon Islands, and attested by very limited historical sources. Kazukuru has generally been considered to be a Papuan, that is, non-Austronesian, language, mostly on the basis of its lexicon. Reevaluation of the available data suggests a high likelihood that Kazukuru was in fact an Oceanic Austronesian language. Pronominal paradigms are clearly of Austronesian origin, and many other aspects of language structured retrievable from the limited data are also congruent with regional Oceanic Austronesian typology. The extent and possible causes of Kazukuru lexical deviations from the Austronesian norm are evaluated and discussed.
Three-participant Events in Oceanic Languages
Authors: Margetts Anna
Published: August 2007

In this study I investigate the linguistic strategies available in Oceanic languages for the encoding of events with three participants (such as expressions of 'sending', 'giving', 'showing', 'telling', or doing something for someone's benefit). The notion of three-participant events is traditionally associated with the concept of ditransitive clauses, but there are, in fact, a variety of other strategies found cross-linguistically, and only some of these involve ditransitive constructions. Languages may differ considerably in which of these methods of encoding they productively use. In the present study I explore which of the strategies are used in the Oceanic language group. This may be a first step toward establishing whether language families or groups differ in their preferences for certain strategies and whether such preferences correlate with other typological features. While in some strategies all three event participants are encoded by syntactic means, in other strategies the involvement of a third participant is essentially evoked by pragmatics. The Oceanic language group seems to show a greater preference for such pragmatic strategies than is familiar from the study of the better-known European languages.
Missing Complement Clause Subjects in Malagasy
Authors: Potsdam Eric , Polinsky Maria
Published: August 2007

This paper presents and analyzes a biclausal construction in the Austronesian language Malagasy in which the subject of a complement clause is not expressed but is interpreted as coreferential with a higher noun phrase: Manantena Rabei [mba/fa hividy fiara Øi] 'Rabei hopes that Øi will buy a car.' We show that there are two different structures here depending upon the choice of complementizer. With the complementizer mba, the construction instantiates finite control: an obligatory referential dependency between an unexpressed subject in a finite clause and a higher antecedent. With the complementizer fa, despite some apparent similarities, the construction is not control. We propose instead an NP Drop analysis in which the missing subject is a null pronominal licensed by an independent process of topic drop.
Another Look at the Marking of Plural Personal Noun Constructions in Austronesian Languages
Authors: Reid Lawrence Andrew
Published: August 2007

In a recent note in this journal, Robert Blust, using data from Philippine and Formosan languages, proposes a functional difference for Proto-Austronesian between the forms of genitive common noun phrase markers, such that PAN *nu marked 'genitive of common nouns', while PAN *na marked 'genitive of plural personal nouns'. This paper examines the Philippine and Formosan evidence for these reconstructions and concludes that the evidence provided is the result of convergent development in the languages cited, and cannot be considered evidence for the proposed reconstructions. Alternate reconstructions that better account for the Philippine evidence are proposed.
An Unusual Passive in Western Oceanic: The Case of Vitu
Authors: Berg René van den
Published: August 2007

Passive constructions are rare in Melanesia and none is reconstructed for Proto-Oceanic. This paper reports on a passive in Vitu, a Meso-Melanesian language spoken in West New Britain, Papua New Guinea, describing its structural properties (some of which are unusual) and attempting to provide a diachronic scenario through which it may have arisen.
Home Video and the "TV Problem": Cultural Critics and Technological Change
Authors: Dawson Max
Published: August 2007

This article resituates the emergence of the first home video technologies during the 1960s and early 1970s within the context of contemporary debates over the state of American television. It traces the influence that cultural intermediaries—namely, the journalists who covered television for publications like the New York Times and Saturday Review—exerted on the cultural meanings of this nascent technology in this period. For a number of these critics, home video represented a potential technological solution to the aesthetic and moral shortcomings of American commercial television. Tracking these critics’ interventions in the negotiations over this new technology’s meanings and uses enriches our understanding of home video’s past. More importantly perhaps, it highlights some of the ways in which critics have historically mobilized their cultural capital to subtly shape the trajectory of technological change.
Beyond Men and Machines: New Contributions to the History of Polar Exploration
Authors: Oslund Karen
Published: August 2007

This essay is a review of the recent literature on polar exploration, focusing closely on two books, S.A. Andrée: The Beginning of Polar Aviation, 1895–1897, by Günther Sollinger, and The Coldest Crucible: Arctic Exploration and American Culture, by Michael F. Robinson. While Robinson uses the public perception of American Arctic explorations to illuminate developments in the political and cultural history of the United States, Sollinger focuses on a single Arctic explorer, the Swede Salomon August Andrée, who tried to reach the North Pole by balloon in 1897. While the essay judges both books to be worthwhile contributions to the literature on polar exploration, it points out the fundamentally conservative approach of both studies, which reflects the field as a whole. Therefore, the essay concludes by calling for scholars of polar exploration to broaden their approach conceptually by engaging more actively with the literature in the history of travel and the history of technology.
The Exhibiting Dilemma
Authors: Skramstad Harold
Published: August 2007

A continuing dilemma of exhibition design is how to convey coherent content through a medium that is engaged in a unique and different way by each individual exhibition viewer. This dilemma is exacerbated by a lack of critical study of the exhibition design process and the lack of a rich critical literature of exhibition critiques, although in recent years there has been an increased interest in understanding the special nature of the medium of exhibitions. David Dernie’s Exhibition Design is a thoughtful addition to the critical literature of exhibition design in which he attempts to articulate several approaches to the use of exhibition space: “narrative space,” “performative space,” and “simulated experience.” His approaches are of special interest to designers of science and technology exhibitions. Dernie’s critical framework and his use of a large number of case studies provide a provocative addition to the literature of exhibition design.
Ultrastructural aspects of fibre development during the stone groundwood process: New insights into derived pulp properties
Authors: Fernando Dinesh , Rosenberg Peter , Persson Erik , Daniel Geoffrey
Published: August 2007

A study was performed on stone groundwood (SGW) pulps produced on a pilot scale. The behaviour of selected juvenile and mature Norway spruce wood samples was investigated. As revealed by standard tests, sheets formed from juvenile wood showed improved light scattering properties, improved tear and tensile strength, and higher sheet density compared to those formed from mature wood. Scanning electron microscopy indicated that the differences are likely related to the manner of fibre processing and development at the ultrastructural level. Mature wood fibres showed greater fibre end breakage, a smaller long-fibre fraction, enhanced S1 fibrillation and frequently open fibres. In contrast, juvenile fibres had a 14% higher long-fibre fraction and showed typical S2 fibrillation. Fibre development of juvenile wood showed fibrillation features similar to those previously reported for thermomechanical pulp fibres. In both cases, the structural hierarchy of the wood fibre cell wall and the microfibril angle of S2 and S1 layers govern cell-wall splitting and fibrillation progression. The superior quality of the fibre furnish prepared from juvenile fibres compared to mature fibres with SGW pulping may offer an alternative process for more effective utilisation of raw materials such as top logs rich in juvenile wood.
Lignin modification in the initial phase of softwood kraft pulp delignification with polyoxometalates (POMs)
Authors: Bujanovic Biljana , Ralph Sally A. , Reiner Richard S. , Atalla Rajai H.
Published: August 2007

Commercial softwood kraft pulp with kappa number 30.5 (KP30.5) was delignified with polyoxometalates (POM, Na5(+2)[SiV1(-0.1)MoW10(+0.1)O40]), and POM-treated kraft pulp of kappa number 23.6 was obtained (KPPOM,23.6). Residual lignin from pulps was isolated by mild acid hydrolysis and characterized by analytical and spectral methods to gain insight into lignin reactions taking place during the initial delignification phase. Lignin from POM-delignified pulp was isolated in lower yield. Comparative analysis of residual lignins (RL-KP30.5, RL-KPPOM,23.6) showed that POM leads to products enriched in carbonyl/carboxyl groups and carbohydrates. POM lignins have a lower molecular mass and a lower content of phenolic hydroxyl and methoxyl groups. Based on these results and FTIR spectra, we suggest that aromatic ring cleavage and quinone formation occur during POM delignification. The degree of lignin-cellulose association increases after POM delignification. Lignin-cellulose association was found to be partially unstable under mild alkaline conditions, as residual lignin isolated after alkaline extraction of KPPOM,23.6 pulp (RL-KPPOM/NaOH) exhibited lower glucose content, higher Klason lignin content, and less extraneous material.
Stabilization of peracetic acid with aspartic acid diethoxy succinate (AES)
Authors: Popov Evgeny , Välisaari Jouni , Vuorenpalo Veli-Matti , Hietapelto Vesa , Aksela Reijo , Eloranta Jussi
Published: August 2007

Stabilization of peracetic acid (PAA) by aspartic acid diethoxy succinate (AES) was studied by electron spin resonance, UV/Vis spectroscopy, electrospray ionization time-of-flight mass spectrometry and oxygen evolution measurements. The results indicate that Mn(II)-AES complexes may exist in both monomeric and dimeric forms. Dimerization is proposed to proceed via formation of an oxygen bridge between two Mn(II)-AES complexes. The equilibrium between these two forms depends strongly on pH, the monomeric form being favored under acidic conditions, while conditions close to neutral pH favor the dimeric form. In the presence of PAA, the dimer form was oxidized and finally yielded MnO2. Oxygen evolution measurements were carried out to demonstrate the efficiency of AES in stabilizing PAA solutions containing small amounts of Mn(II) impurities under acidic conditions.
Fluorescence spectroscopy for chromophore studies on bleached kraft pulps
Authors: Liukko Sirje , Tasapuro Ville , Liitiä Tiina
Published: August 2007

Fluorescence techniques are highly sensitive and, since aromatic lignin is the most likely source of natural pulp fluorescence, they are suitable for detailed investigation of residual lignin in bleached pulps. Such investigations are important to our understanding of the bleachability and brightness reversion of pulps. In this study, the effect of bleaching on pulps was evaluated using fluorescence spectra of two softwood kraft pulps bleached in six elemental chlorine-free and totally chlorine-free sequences. Fluorescence spectra were recorded in each bleaching stage using four different instrument settings. In general, pulp fluorescence at excitation wavelengths of 270 and 350 nm increased as bleaching proceeded. Below a certain lignin content, however, pulp fluorescence measured at an excitation wavelength of 430 nm decreased with the residual lignin content. Carbonyl groups have a quenching effect on fluorescence, and the formation of carbonyl groups after oxygen and ozone delignification induced a decrease in pulp fluorescence. The increase in pulp fluorescence after peroxide bleaching stages was due to the removal of carbonyl groups. Reactions of chromophores during brightness reversion also had an effect on pulp fluorescence. These findings demonstrate that fluorescence spectroscopy provides an interesting tool for pulp bleaching studies.
Munc18-1: Sequential Interactions with the Fusion Machinery Stimulate Vesicle Docking and Priming
Authors: Gulyás-Kovács Attila , de Wit Heidi , Milosevic Ira , Kochubey Olexiy , Toonen Ruud , Klingauf Jürgen , Verhage Matthijs , Sørensen Jakob B.
Published: August 2007

Exocytosis of secretory or synaptic vesicles is executed by a mechanism including the SNARE (solubleN-ethylmaleimide-sensitive factor attachment protein receptor) proteins. Munc18-1 is a part of this fusion machinery, but its role is controversial because it is indispensable for fusion but also inhibits the assembly of purified SNAREsin vitro. This inhibition reflects the binding of Munc18-1 to a closed conformation of the target-SNARE syntaxin1. The controversy would be solved if binding to closed syntaxin1 were shown to be stimulatory for vesicle fusion and/or additional essential interactions were identified between Munc18-1 and the fusion machinery. Here, we provide evidence for both notions by dissecting sequential steps of the exocytotic cascade while expressing Munc18 variants in the Munc18-1 null background. In Munc18-1 null chromaffin cells, vesicle docking is abolished and syntaxin levels are reduced. A mutation that diminished Munc18 binding to syntaxin1in vitroattenuated the vesicle-docking step but rescued vesicle priming in excess of docking. Conversely, expressing the Munc18-2 isoform, which also displays binding to closed syntaxin1, rescued vesicle docking identical with Munc18-1 but impaired more downstream vesicle priming steps. All Munc18 variants restored syntaxin1 levels at least to wild-type levels, showing that the docking phenotype is not caused by syntaxin1 reduction. None of the Munc18 variants affected vesicle fusion kinetics or fusion pore duration. In conclusion, binding of Munc18-1 to closed syntaxin1 stimulates vesicle docking and a distinct interaction mode regulates the consecutive priming step.
Localized Activation of p21-Activated Kinase Controls Neuronal Polarity and Morphology
Authors: Jacobs Tom , Causeret Frédéric , Nishimura Yoshiaki V. , Terao Mami , Norman Adele , Hoshino Mikio , Nikolić Margareta
Published: August 2007

In the developing forebrain, neuronal polarization is a stepwise and initially reversible process that underlies correct migration and axon specification. Many aspects of cytoskeletal changes that accompany polarization are currently molecularly undefined and thus poorly understood. Here we reveal that the p21-activated kinase (Pak1) is essential for the specification of an axon and dendrites. In hippocampal neurons, activation of Pak1 is spatially restricted to the immature axon despite its uniform presence in all neurites. Hyperactivation of Pak1 at the membrane of all neurites or loss of Pak1 expression disrupts both neuronal morphology and the distinction between an axon and dendrites. We reveal that Pak1 acts on polarity in a kinase-dependent manner, by affecting the F-actin and microtubule cytoskeleton at least in part through Rac1 and cofilin. Our data are the first to demonstrate the importance of localized Pak1 kinase activation for neuronal polarization and differentiation.
Competing Interactions between Micro-RNAs Determine Neural Progenitor Survival and Proliferation after Ethanol Exposure: Evidence from anEx VivoModel of the Fetal Cerebral Cortical Neuroepithelium
Authors: Sathyan Pratheesh , Golden Honey B. , Miranda Rajesh C.
Published: August 2007

The fetal brain is sensitive to a variety of teratogens, including ethanol. We showed previously that ethanol induced mitosis and stem cell maturation, but not death, in fetal cerebral cortex-derived progenitors. We tested the hypothesis that micro-RNAs (miRNAs) could mediate the teratogenic effects of ethanol in a fetal mouse cerebral cortex-derived neurosphere culture model. Ethanol, at a level attained by alcoholics, significantly suppressed the expression of four miRNAs, miR-21, -335, -9, and -153, whereas a lower ethanol concentration, attainable during social drinking, induced miR-335 expression. A GABAAreceptor-dependent mechanism mediated miR-21, but not miR-335 suppression, suggesting that divergent mechanisms regulate ethanol-sensitive miRNAs. Antisense-mediated suppression of miR-21 expression resulted in apoptosis, suggesting that miR-21 is an antiapoptotic factor. miR-335 knockdown promoted cell proliferation and prevented death induced by concurrently suppressing miR-21, indicating that miR-335 is a proapoptotic, antimitogenic factor whose actions are antagonistic to miR-21. Computational analyses identified two genes,Jagged-1, a Notch-receptor ligand, and embryonic-lethal abnormal vision,Drosophila-like 2 (ELAVL2), a brain-specific regulator of RNA stability, as presumptive targets of three of four ethanol-sensitive micro-RNAs. Combined knockdown of miR-335, -21, and -153 significantly increasedJagged-1mRNA. Furthermore, ethanol induced bothJagged-1andELAVL2mRNA. The collective suppression of micro-RNAs is consistent with ethanol induction of cell cycle and neuroepithelial maturation in the absence of apoptosis. These data identify a role for micro-RNAs as epigenetic intermediaries, which permit teratogens to shape complex, divergent developmental processes, and additionally demonstrate that coordinately regulated miRNAs exhibit both functional synergy and antagonism toward each other.
Synaptic Anchorage of AMPA Receptors by Cadherins through Neural Plakophilin-Related Arm Protein–AMPA Receptor-Binding Protein Complexes
Authors: Silverman Joshua B. , Restituito Sophie , Lu Wei , Lee-Edwards Laveria , Khatri Latika , Ziff Edward B.
Published: August 2007

Cadherins function in the adhesion of presynaptic and postsynaptic membranes at excitatory synapses. Here we show that the cadherin-associated protein neural plakophilin-related arm protein (NPRAP; also called δ-catenin) binds via a postsynaptic density-95 (PSD-95)/discs large/zona occludens-1 (PDZ) interaction to AMPA receptor (AMPAR)-binding protein (ABP) and the related glutamate receptor (GluR)-interacting protein (GRIP), two multi-PDZ proteins that bind the GluR2 and GluR3 AMPAR subunits. The resulting cadherin–NPRAP–ABP/GRIP complexes serve as anchorages for AMPARs. Exogenous NPRAP that was bound to cadherins at adherens junctions of Madin-Darby canine kidney cells recruited ABP from the cytosol to form cadherin–NPRAP–ABP complexes, dependent on NPRAP interaction with the ABP PDZ domain 2. The cadherin–NPRAP–ABP complexes also bound GluR2. In cultured hippocampal neurons, dominant-negative mutants of NPRAP designed to disrupt tethering of ABP to NPRAP–cadherin complexes reduced surface levels of endogenous GluR2, indicating that interaction with cadherin–NPRAP–ABP complexes stabilized GluR2 at the neuronal plasma membrane. Cadherins, NPRAP, GRIP, and GluR2 copurified in the fractionation of synaptosomes and the postsynaptic density, two fractions enriched in synaptic proteins. Furthermore, synaptosomes contain NPRAP–GRIP complexes, and NPRAP localizes with the postsynaptic marker PSD-95 and with AMPARs and GRIP at spines of hippocampal neurons. Thus, tethering is likely to take place at synaptic or perisynaptic sites. NPRAP also binds PSD-95, which is a scaffold for NMDA receptors, for AMPARs in complexes with auxiliary subunits, the TARPs (transmembrane AMPA receptor regulator proteins), and for adhesion molecules. Thus, the interaction of scaffolding proteins with cadherin–NPRAP complexes may anchor diverse signaling and adhesion molecules at cadherins.
Angiotensin-Converting Enzyme Converts Amyloid β-Protein 1–42 (Aβ1–42) to Aβ1–40, and Its Inhibition Enhances Brain Aβ Deposition
Authors: Zou Kun , Yamaguchi Haruyasu , Akatsu Hiroyasu , Sakamoto Takaaki , Ko Mihee , Mizoguchi Kazushige , Gong Jian-Sheng , Yu Wenxin , Yamamoto Takayuki , Kosaka Kenji , Yanagisawa Katsuhiko , Michikawa Makoto
Published: August 2007

The abnormal deposition of the amyloid β-protein (Aβ) in the brain appears crucial to the pathogenesis of Alzheimer's disease (AD). Recent studies have suggested that highly amyloidogenic Aβ1–42is a cause of neuronal damage leading to AD pathogenesis and that monomeric Aβ1–40has less neurotoxicity than Aβ1–42. We found that mouse and human brain homogenates exhibit an enzyme activity converting Aβ1–42to Aβ1–40and that the major part of this converting activity is mediated by the angiotensin-converting enzyme (ACE). Purified human ACE converts Aβ1–42to Aβ1–40as well as decreases Aβ1–42/Aβ1–40ratio and degrades Aβ1–42and Aβ1–40. Importantly, the treatment of Tg2576 mice with an ACE inhibitor, captopril, promotes predominant Aβ1–42deposition in the brain, suggesting that ACE regulates Aβ1–42/Aβ1–40ratioin vivoby converting secreted Aβ1–42to Aβ1–40and degrading Aβs. The upregulation of ACE activity can be a novel therapeutic strategy for AD.
Match–Mismatch Processes Underlie Human Hippocampal Responses to Associative Novelty
Authors: Kumaran Dharshan , Maguire Eleanor A.
Published: August 2007

The hippocampus has long been proposed to play a critical role in novelty detection through its ability to act as a comparator between past and present experience. A recent study provided evidence for this hypothesis by characterizing hippocampal responses to sequence novelty, a type of associative novelty where familiar items appear in a new temporal order. Here, we ask whether a hippocampal match–mismatch (i.e., comparator) mechanism operates selectively to identify the violation of predictions within the temporal domain or instead also underlies the processing of associative novelty in other domains (e.g., spatial). We used functional magnetic resonance imaging and a repetition paradigm in which subjects viewed sequences of objects presented in distinct locations on the screen and performed an incidental target detection task. The left hippocampus exhibited a pattern of activity consistent with that of an associative match–mismatch detector, with novelty signals generated only in conditions where one contextual component was novel and the other repeated. In contrast, right hippocampal activation signaled the presence of objects in familiar locations. Our results suggest that hippocampal match–mismatch computations constitute a general mechanism underpinning the processing of associative novelty. These findings support a model in which hippocampal mismatch signals rely critically on the recall of previous experience, a process that only occurs when novel sensory inputs overlap significantly with stored representations. More generally, the current study also offers insights into how the hippocampus automatically represents the spatiotemporal context of our experiences, a function that may relate to its role in episodic memory.
Context Familiarity Enhances Target Processing by Inferior Temporal Cortex Neurons
Authors: Mruczek Ryan E. B. , Sheinberg David L.
Published: August 2007

Experience-dependent changes in the response properties of ventral visual stream neurons are thought to underlie our ability to rapidly and efficiently recognize visual objects. How these neural changes are related to efficient visual processing during natural vision remains unclear. Here, we demonstrate a neurophysiological correlate of efficient visual search through highly familiar object arrays. Humans and monkeys are faster at locating the same target when it is surrounded by familiar compared with unfamiliar distractors. We show that this behavioral enhancement is driven by an increased sensitivity of target-selective neurons in inferior temporal cortex. This results from an increased “signal” for target representations and decreased “noise” from neighboring familiar distractors. These data highlight the dynamic properties of the inferior temporal cortex neurons and add to a growing body of evidence demonstrating how experience shapes neural processing in the ventral visual stream.
Functional Imaging of Primary Visual Cortex Using Flavoprotein Autofluorescence
Authors: Husson T. Robert , Mallik Atul K. , Zhang Jing X. , Issa Naoum P.
Published: August 2007

Neuronal autofluorescence, which results from the oxidation of flavoproteins in the electron transport chain, has recently been used to map cortical responses to sensory stimuli. This approach could represent a substantial improvement over other optical imaging methods because it is a direct (i.e., nonhemodynamic) measure of neuronal metabolism. However, its application to functional imaging has been limited because strong responses have been reported only in rodents. In this study, we demonstrate that autofluorescence imaging (AFI) can be used to map the functional organization of primary visual cortex in both mouse and cat. In cat area 17, orientation preference maps generated by AFI had the classic pinwheel structure and matched those generated by intrinsic signal imaging in the same imaged field. The spatiotemporal profile of the autofluorescence signal had several advantages over intrinsic signal imaging, including spatially restricted fluorescence throughout its response duration, reduced susceptibility to vascular artifacts, an improved spatial response profile, and a faster time course. These results indicate that AFI is a robust and useful measure of large-scale cortical activity patterns in visual mammals.
Mobilization Techniques in Subjects With Frozen Shoulder Syndrome: Randomized Multiple-Treatment Trial
Authors: Yang Jing-lan , Chang Chein-wei , Chen Shiau-yee , Wang Shwu-Fen , Lin Jiu-jenq
Published: August 2007

Background and Purpose

The purpose of this study was to compare the use of 3 mobilization techniques—end-range mobilization (ERM), mid-range mobilization (MRM), and mobilization with movement (MWM)—in the management of subjects with frozen shoulder syndrome (FSS).

Subjects

Twenty-eight subjects with FSS were recruited.

Methods

A multiple-treatment trial on 2 groups (A-B-A-C and A-C-A-B, where A=MRM, B=ERM, and C=MWM) was carried out. The duration of each treatment was 3 weeks, for a total of 12 weeks. Outcome measures included the functional score and shoulder kinematics.

Results

Overall, subjects in both groups improved over the 12 weeks. Statistically significant improvements were found in ERM and MWM. Additionally, MWM corrected scapulohumeral rhythm significantly better than ERM did.

Discussion and Conclusion

In subjects with FSS, ERM and MWM were more effective than MRM in increasing mobility and functional ability. Movement strategies in terms of scapulohumeral rhythm improved after 3 weeks of MWM.
High-efficiency wide-band metal-dielectric resonant grating for 20 fs pulse compression
Authors: Flury M. , Tonchev S. , Fechner R. , Schindler A. , Parriaux O.
Published: August 2007

More than 95% average efficiency TE-polarisation diffraction over a 200 nm wavelength range centred at 800 nm is obtained by a metal-dielectric grating structure with non-corrugated mirror. 98% maximum -1st order diffraction efficiency and a wide band top-hat spectrum are demonstrated experimentally opening the way to high-efficiency Chirped Pulse Amplification of femtosecond pulses as short as 20 fs.
Differential Treatment Effects of Subgroup Analyses in Phase 3 Oncology Trials From 2004 to 2020
Authors: Sherry Alexander D. , Hahn Andrew W. , McCaw Zachary R. , Abi Jaoude Joseph , Kouzy Ramez , Lin Timothy A. , Minsky Bruce , Fuller C. David , Meirson Tomer , Msaouel Pavlos , Ludmir Ethan B.
Published: March 2024

Importance

Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited.

Objective

To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials.

Design, Setting, and Participants

This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov.

Main Outcomes and Measures

Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard and odds ratios. Multiplicity of testing control was recorded. Differential treatment effect claims were rated using the Instrument for Assessing the Credibility of Effect Modification Analyses. Linear and logistic regressions evaluated associations with outcomes.

Results

Among 785 trials, 379 studies (48%) enrolling 331 653 patients reported a subgroup analysis. The forest plots of 43% of trials (156 of 363) were missing visual elements impeding interpretability. While 4148 subgroup effects were evaluated, only 1 trial (0.3%) controlled for multiple testing. On average, trials that did not meet the primary end point conducted 2 more subgroup effect tests compared with trials meeting the primary end point (95% CI, 0.59-3.43 tests; P = .006). A total of 101 differential treatment effects were claimed across 15% of trials (55 of 379). Interaction testing was missing in 53% of trials (29 of 55) claiming differential treatment effects. Trials not meeting the primary end point were associated with greater odds of no interaction testing (odds ratio, 4.47; 95% CI, 1.42-15.55, P = .01). The credibility of differential treatment effect claims was rated as low or very low in 93% of cases (94 of 101).

Conclusions and Relevance

In this cross-sectional study of phase 3 oncology trials, nearly half of trials presented a subgroup analysis in their primary publication. However, forest plots of these subgroup analyses largely lacked essential features for interpretation, and most differential treatment effect claims were not supported. Oncology subgroup analyses should be interpreted with caution, and improvements to the quality of subgroup analyses are needed.
Effect of Feminizing Hormone Therapy on QTc Interval
Authors: Angus Lachlan M. , Lin Tina , Leemaqz Shalem Y. , Cheung Ada S.
Published: March 2024

This secondary analysis of a randomized clinical trial investigates the effect of spironolactone and cyproterone acetate hormone therapy on the QT interval corrected for heart rate among transgender women and nonbinary or transfeminine individuals.