bluuebunny/crossref_metadata_2025 huggingface dataset:
Houses of the people, kitchens of the great: a Japanese enigma
Authors: Morris Martin
Published: August 2008

The gulf dividing the houses of ruling elites from those in use among the bulk of a population (here referred to as vernacular) is a phenomenon common to many cultures. It reflects the close correlation between the kind of house in which an individual lives and his social status. A grasp of the relationship, between elite and vernacular houses in societies where both exist enhances our understanding of the development of domestic architecture, and our appreciation of the wider historical significance of that development. This paper explores an aspect of the relationship between elite and vernacular houses in seventeenth-century Japan.
Responding to marginalisation
Authors: Powell Christopher
Published: August 2008

Some long-term historical, economic and social circumstances leading to marginalisation of the British architectural profession are described. A mismatch between demand for architectural services and their supply is suggested to have contributed to marginalisation. Possible reasons are advanced for a restrained response to marginalisation by the profession. In particular, aspects of the professional culture connected with insularity and aversion to management are suggested to have been significant. However, while aspects of the professional culture hindered long-term adjustment to changing demand, they also may have helped to support design activity in the shorter term.
Correalism and Equipoise: observations on the sustainable
Authors: Braham William W.
Published: August 2008

Modern environmentalism originates with the recognition of ecological connectivity and the negative effects of technological intervention. This paper examines critical concepts developed by the architect Frederick Kiesler and the critic-historian Sigfried Giedion for their relevance to that discourse. Kiesler's principle of Correalism and Giedion's appeal for Equipoise offer both a prehistory to the current mandates about sustainability and cautions about its limitations. The sustainable is ultimately a social condition that cannot be applied therapeutically nor ever wholly institutionalized.
Reconstructing architectural geometry
Authors: Mark Earl
Published: August 2008

CAD systems provide convenient tools for the creation of simple geometry by direct manipulation on the computer screen. They work well enough for two-dimensional construction, but are often inadequate for creating doubly-curved three-dimensional surfaces. The solution proposed here is to use the in-built programming language provided in most CAD systems for direct creation of geometry. Developed for didactic purposes, the stunning reconstructions of Gothic vaults suggest a method of working likely to be of great value to the geometrically adventurous architect.
Proportional design in L. B. Alberti's Tempio Malatestiano, Rimini
Authors: March Lionel
Published: August 2008

Systems of proportion provoked much controversy in the 1950s. Recent research has moved away from the study of musical theory, to that of number. Applying Classical arithmetic techniques to analyze Alberti's Tempio Malatestiano, this paper demonstrates that its design corresponds to Alberti's system based on geometrical features of the cube depicting ‘natural relationships that cannot be defined as numbers’. For today's practitioners, the paper asserts that architectural works are geometric constructs and reminds them that CAD is based on the arithmeticization of geometry.
Death and rebirth in Chicago: the Du Sable High School Urban Ecology Sanctuary
Authors: Alt Paul
Published: August 2008

Healing gardens have been widely used in healthcare settings, but rarely to heal the psychological illnesses of youth in inner-city neighbourhoods who have lost friends and family to violent deaths. The Urban Ecology Sanctuary in a courtyard of Du Sable High School in Chicago serves as a model of what such a garden might be like, providing places in which young people can reflect upon their loss, regain a sense of purpose, and reconnect to the natural world. This Sanctuary shows how architecture and landscape architecture can buffer the worst effects of social disruption.
Prefabricated brick wall panels: economy or nightmare?
Authors: Louis Michael J.
Published: August 2008

Prefabricated wall systems are becoming a popular element of building construction, lending themselves to streamlining construction schedules and reducing overall construction costs. They also offer the potential for increased quality due to assembly in controlled factory environments. This paper reviews basic principles and concepts for the design of waterproofing systems for prefabricated brick wall panels. Using a project case study, the author shows that failure to adhere to certain proven conventional practices can have serious adverse consequences.
Design participation through the Internet: a case study
Authors: Richens Paul , Trinder Michael
Published: August 2008

Cambridge University and Microsoft are planning a shared computer research and teaching laboratory on a green-field site to the west of the city. The clients wished to use Internet based communication between themselves and their architects, including email, a website and virtual reality. We explain how this is to be achieved, and describe experiences during the first half of a two year project. Particularly successful has been the use of games software (Quake II) for 3D presentation of the emerging building design.
Architectural copyright: recent developments
Authors: Greenstreet Robert , Klingaman Russell
Published: August 2008

This article traces the development of American copyright law as it applies to architectural works from its earliest foundations in the United States Constitution until the enactment of the Architectural Works Copyright Protection Act in 1990. By focusing on the outcomes of the latest legislation through recent case law affecting residential design, the authors evaluate the effectiveness of the protection and illustrate some unintended consequences. In addition, they discuss architectural originality and its relationship to legal protection in the context of individual design freedom.
Erich Mendelsohn and the fourth dimension
Authors: Hart Vaughan
Published: August 2008

In this article the design of Mendelsohn's famous Expressionist tower at Potsdam is shown to have been shaped by the cosmology of Albert Einstein informed, however, by the apparently conflicting occult philosophy of Rudolf Steiner.
Designing the well-tempered institution of 1873
Authors: Cook Jeffrey , Hinchcliffe Tanis
Published: August 2008

The Museum of Natural History in London exemplified the state of environmental services when it was built in 1873. Although the admirable qualities of the building's natural lighting have sometimes been noticed, other aspects of its environmental design have drawn little comment. This paper explores the fabric of the building behind the scenes, related to the integral construction for ventilation. Recent on-site investigations under the floor of the basement, within the attics and elsewhere, reveal the former presence of a comprehensive fresh-air ventilation system of surprising versatility before the advent of electrically-driven fans. Archival documents provide details. The design and performance of such fresh-air systems inform us about the evolution of building services and about the practice of architecture and engineering as distinct professions. And the forgotten knowledge revealed may serve to help in the design of natural and low energy systems for large buildings today.
C. R. Mackintosh: the symbolic geometry of The Hill House
Authors: Gregh Eleanor
Published: August 2008

The first part of this essay analyses in detail key aspects of The Hill House, in order to reveal the organising aesthetic principle that governs it. It would seem that a simple yet infinitely complex system of proportional measure binds a few natural and geometric symbols into a complex whole of profound poetic significance. The second part outlines the possible implications of this discovery for the interpretation and history of the house as an individual work of art, as well as of Mackintosh'soeuvreas a whole. These will be the subject of future research.
Entwicklungspsychopathologie
Authors: Petermann Franz , Noeker Meinolf
Published: September 2008

Entwicklungspsychopathologie vergleicht normale und abweichende Entwicklungsverläufe und beschäftigt sich vor allem mit den Ursachen und dem Verlauf psychischer Störungen. Am Beispiel der Resilienz (= günstiges Entwicklungsergebnis trotz Exposition an widrige Umgebungsbedingungen) wird ein zentrales Konzept der Entwicklungspsychopathologie erläutert. Aktuelle Ergebnisse zur Entwicklungspsychopathologie der ersten Lebensjahre, der Persönlichkeitsstörungen, der Störung des Sozialverhaltens und der Aufmerksamkeitsdefizit/Hyperaktivitätsstörung (ADHS) werden thematisiert.
Resilienz: Funktionale Adaptation an widrige Umgebungsbedingungen
Authors: Noeker Meinolf , Petermann Franz
Published: September 2008

Resiliente Kinder, Jugendliche und Erwachsene sind dadurch gekennzeichnet, dass ihnen eine funktionale Adaptation an widrige, oftmals traumatische Umgebungsbedingungen in einer Weise gelingt, so dass langfristig ein kompensiertes, gesundes psychologisches Funktionsniveau und Entwicklungsergebnis erreicht wird. Im Fokus der Resilienzforschung steht die Identifikation der protektiven Faktoren, die als Moderatormerkmale die Wirkung der Risikofaktoren auf den Outcome lindern oder neutralisieren. An der Entwicklung von Resilienz sind adaptive Systeme auf vier Ebenen beteiligt: personale Kompetenzen des Kindes (Stressverarbeitung, Selbstregulation, Motivation, Lernen), des Familiensystems (Bindung, Interaktion, Erziehung), Ressourcen des sozialen Netzwerkes (Schule, Gleichaltrige) und gesellschaftlich-kulturelle Faktoren (Normen, Werte). Biologische (genetische, endokrine, neurobiologische) Resilienzfaktoren können die Impulskontrolle, Handlungsplanung und Emotionsregulation bei der Stressregulation stärken. Jüngste Befunde belegen, dass eine epigenetische, also erfahrungsabhängige Modulation der Genexpression eine psychopathologische Vulnerabilität verstärken oder reduzieren kann. Ein Modell wird vorgestellt, das die Herausbildung eines resilienten Entwicklungspfades wesentlich als Ergebnis von positiv bewältigten Belastungsepisoden versteht, die das Kind durch die Anwendung funktionaler kognitiver Schemata und kompetenter Bewältigungsfertigkeiten erreicht, die es sich vor allem im Kontext von positiven Eltern-Kind-Interaktionen hat aneignen können. Mit diesem Modell korrespondieren eltern- und kindzentrierte Interventionskonzepte zur Stärkung resilienter Adaptation an stark belastende Umgebungsbedingungen.
Entwicklungspsychopathologie der ADHS
Authors: Schmidt Sören , Petermann Franz
Published: September 2008

Galt die ADHS vor einigen Jahren noch als eine Erkrankung des Kindes- und Jugendalters, so versteht man heute darunter ein Störungsbild über die Lebensspanne. Mit Beginn im Vorschulalter divergieren die Symptome in Abhängigkeit des Alters. Daraus lässt sich ein Modell ableiten, welches diese Veränderungen (Komorbiditäten, Alltagsbeeinträchtigungen) auf der Zeitachse dokumentiert und mit den jeweils gültigen diagnostischen Kriterien in Verbindung bringt. Ausgehend von einer genetischen Prädisposition und einer neurobiologischen Dysregulation sind Faktoren festzustellen, die über die Lebensspanne andauern, sich altersspezifisch verändern oder nur für einen bestimmten Entwicklungsabschnitt gültig sind. Es wird deutlich, dass das Vorschulalter und der Übergang in das Erwachsenenalter die Phasen darstellen, in denen sich die meisten qualitativen Veränderungen feststellen lassen. Dies hat Implikationen für die klinische Praxis, indem diese Veränderungen zu Zwecken der Prävention, des diagnostischen Prozesses und der Therapieplanung herangezogen werden können und somit sowohl dem Anwender eine Hilfestellung bieten, aber auch als Ausgangspunkt für weitere Studien herangezogen werden können.
Sind Aussiedler aggressiver?
Authors: Heubrock Dietmar , Voukava Larissa , Petermann Franz
Published: September 2008

Seit langem bereitet die Kriminalitätsbelastung und -entwicklung junger russlanddeutscher Aussiedler besondere Probleme. Ihnen werden oft Rohheits- und Eigentumsdelikte, nicht selten in Verbindung mit Alkoholkonsum, vorgeworfen. In dieser Studie wurde überprüft, ob Aussiedler eine höhere Aggressivitätsbereitschaft zeigen als Deutsche. Hierzu wurden straffällig gewordene und nichtstraffällige Aussiedler untereinander und mit straffälligen und nichtstraffälligen Deutschen verglichen. Außerdem wurden wegen eines Rohheitsdeliktes straffällig gewordene Aussiedler mit solchen verglichen, die wegen Diebstahls verurteilt worden waren. Die Ergebnisse zeigen, dass sich eine generell erhöhte Aggressivität bei russlanddeutschen Aussiedlern nicht bestätigen ließ. Hinsichtlich verschiedener Aggressivitätsfaktoren fanden sich zwar Unterschiede zwischen den Gruppen, insgesamt sind jedoch die Unterschiede zwischen Delinquenten und Nicht-Delinquenten bedeutsamer als diejenigen zwischen den beiden ethnischen Gruppen. Hinsichtlich der Moderatorvariablen, die zu einer delinquenten Entwicklung junger russlanddeutscher Aussiedler beitragen könnten, fällt sowohl bei der Aussiedler- als auch bei der deutschen Delinquenten-Stichprobe auf, dass die wegen Rohheitsdelikten Verurteilten beider Ethnien in den Bereichen Bildung und Beruf benachteiligt und sozial kaum integriert waren.
Visual Search of Emotional Faces
Authors: Calvo Manuel G. , Nummenmaa Lauri , Avero Pedro
Published: September 2008

In a visual search task using photographs of real faces, a target emotional face was presented in an array of six neutral faces. Eye movements were monitored to assess attentional orienting and detection efficiency. Target faces with happy, surprised, and disgusted expressions were: (a) responded to more quickly and accurately, (b) localized and fixated earlier, and (c) detected as different faster and with fewer fixations, in comparison with fearful, angry, and sad target faces. This reveals a happy, surprised, and disgusted-face advantage in visual search, with earlier attentional orienting and more efficient detection. The pattern of findings remained equivalent across upright and inverted presentation conditions, which suggests that the search advantage involves processing of featural rather than configural information. Detection responses occurred generally after having fixated the target, which implies that detection of all facial expressions is post- rather than preattentional.
The Recall of Information from Working Memory
Authors: Towse John N. , Cowan Nelson , Hitch Graham J. , Horton Neil J.
Published: September 2008

We describe and evaluate a recall reconstruction hypothesis for working memory (WM), according to which items can be recovered from multiple memory representations. Across four experiments, participants recalled memoranda that were either integrated with or independent of the sentence content. We found consistently longer pauses accompanying the correct recall of integrated compared with independent words, supporting the argument that sentence memory could scaffold the access of target items. Integrated words were also more likely to be recalled correctly, dependent on the details of the task. Experiment 1 investigated the chronometry of spoken recall for word span and reading span, with participants completing an unfinished sentence in the latter case. Experiments 2 and 3 confirm recall time differences without using word generation requirements, while Experiment 4 used an item and order response choice paradigm with nonspoken responses. Data emphasise the value of recall timing in constraining theories of WM functioning.
Controlled Processing in Single-Prime Negative Priming
Authors: Chao Hsuan-Fu , Yeh Yei-Yu
Published: September 2008

Negative priming refers to delayed responses to previously ignored distractors. Unlike conventional studies of negative priming in which the attentional selection of a target against its distractors is required in prime trials (prime-selection negative priming), in single-prime negative priming, a prime stimulus is presented briefly. To further investigate the nature of single-prime negative priming, its properties were examined. In Experiment 1, the proportion of repetition was varied. The effect of single-prime negative priming was reduced when the proportion of repetition was high. In addition, Experiment 2 showed that high memory load could hamper the single-prime negative priming effect. Overall, the current study indicates controlled processing in single-prime negative priming and similarities between single-prime negative priming and prime-selection negative priming.
Multimodal Measurements of Blood Plasma and Red Blood Cell Volumes during Functional Brain Activation
Authors: Herman Peter , Sanganahalli Basavaraju G , Hyder Fahmeed
Published: September 2008

As an alternative to functional magnetic resonance imaging (fMRI) with blood oxygenation level dependent (BOLD) contrast, cerebral blood volume (CBV)-weighted fMRI with intravascular contrast agents in animal models have become popular. In this study, dynamic measurements of CBV were performed by magnetic resonance imaging (MRI) and laser-Doppler flowmetry (LDF) in α-chloralose anesthetized rats during forepaw stimulation. All recordings were localized to the contralateral primary somatosensory cortex as revealed by BOLD at 11.7 T. Ultra-small superparamagnetic iron oxide (15mg/kg)—a plasma-borne MRI contrast agent with a half-life of several hours in blood circulation—was used to quantify changes in magnetic field inhomogeneity in blood plasma. The LDF backscattered laser light (805 nm), which reflects the amount of red blood cells, was used to measure alterations in the non-plasma compartment. Dynamic and layer-specific comparisons of the two CBV signals during functional hyperemia revealed excellent correlations (> 0.86). These results suggest that CBV measurements from either compartment may be used to reflect dynamic changes in total CBV. Furthermore, by assuming steady-state mass balance and negligible counter flow, these results indicate that volume hematocrit is not appreciably affected during functional activation.
Determination of the Glutamate—Glutamine Cycling Flux Using Two-Compartment Dynamic Metabolic Modeling is Sensitive to Astroglial Dilution
Authors: Shen Jun , Rothman Douglas L , Behar Kevin L , Xu Su
Published: September 2008

Over the last decade 13C magnetic resonance spectroscopy (13C MRS) combined with the infusion of [1-13C]glucose has been used to measure the cerebral rate of the glutamate—glutamine cycle ( Vcyc). However, the effect of the astroglial label dilution pathways on the accuracy and precision of the C MRS measurement of Vcyc has not been evaluated or realized. In this report, we use the numerical Monte Carlo method to study the effect of astroglial dilution on the reliability of extracting Vcyc using the neuronal-astroglial two-compartment metabolic model and [1-13C]glucose infusion. The results show that omission of the astroglial dilution flux leads to a large loss in the sensitivity of the glutamine turnover curve to Vcyc. When the measured isotopic dilution of cerebral glutamine is accounted for in the analysis, the value of Vcyc can be precisely and accurately determined.
Multimodal Magnetic Resonance Imaging for Assessing Evolution of Ischemic Penumbra: A Key Translational Medicine Strategy to Manage the Risk of Developing Novel Therapies for Acute Ischemic Stroke
Authors: Chavez Juan C , Zaleska Margaret M , Wang Xinkang , Wood Andrew , Hurko Orest , Pangalos Menelas N , Feuerstein Giora Z
Published: September 2008

The implicit aim of neuroprotection is to rescue neurons within distressed but still viable tissue, thereby promoting functional recovery upon neuronal salvage. The clinical failure of this approach suggests that previous efforts to develop stroke therapies lacked means to predict success or futility in pre-clinical and early clinical studies. A key translational medicine strategy that can improve predictability relies on imaging methodologies to map the spatiotemporal evolution of the ischemic penumbra. This could serve as a biomarker indicative of neuroprotective potential and could increase likelihood of success in clinical studies by allowing selection of patients who are most likely to respond to therapy.
Normobaric Hyperoxia and Delayed tPA Treatment in a Rat Embolic Stroke Model
Authors: Henninger Nils , Bratane Bernt T , Bastan Birgul , Bouley James , Fisher Marc
Published: September 2008

In a rat embolic stroke (eMCAO) model, the effects of 100% normobaric hyperoxia (NBO) with delayed recombinant tissue plasminogen activator (tPA) administration on ischemic lesion size and safety were assessed by diffusion- and perfusion (PWI)-weighted magnetic resonance imaging. NBO or room air (Air) by a face mask was started at 30 mins posteMCAO and continued for 3.5 h. Tissue plasminogen activator or saline was started at 3 h posteMCAO. Types and location of hemorrhagic transformation were assessed at 24 h and a spectrophotometry hemoglobin assay quantified hemorrhage volume at 10 h. In NBO-treated animals the apparent diffusion coefficient/PWI mismatch persisted during NBO treatment. Relative to Air groups, NBO treatment significantly reduced 24 h infarct volumes by ~30% and ~ 15% with or without delayed tPA, respectively ( P < 0.05). There were significantly more hemorrhagic infarction type 2 hemorrhages in Air/tPA versus Air/saline animals ( P < 0.05). Compared with Air/tPA, the combination of NBO with tPA did not increase hemorrhage volume at 10 h (4.0±2.4 versus 6.6±2.6 μL, P = 0.065) or occurrence of confluent petechial hemorrhages at 24 h ( P > 0.05), respectively. Our results suggest that early NBO treatment in combination with tPA at a later time point may represent a safe and effective strategy for acute stroke treatment.
Homocysteine Reduces Endothelial Progenitor Cells in Stroke Patients through Apoptosis
Authors: Alam Mohammad Murshedul , Mohammad Askar A , Shuaib Umar , Wang Chenxu , Ghani Usman , Schwindt Brenda , Todd Kathryn G , Shuaib Ashfaq
Published: September 2008

Homocysteine (Hcy) is a risk factor for vascular dysfunction. High levels of Hcy may result in vascular injury accelerating atherosclerosis leading to ischemia. After ischemia, endothelial progenitor cells (EPCs) migrate from bone marrow to repair damaged sites either through direct incorporation of EPCs or by repopulating mature endothelial cells. This study looks into the relationship between increased Hcy in patients with cerebrovascular disease (CVD) and EPCs. Some patients with hyperhomocysteinemia were treated with B vitamins to evaluate if the treatment reverses the elevated Hcy and its impact on their EPC levels. EPCs were treated with Hcy to determine the in vitro effects of Hcy. Our clinical findings show that elevated Hcy levels have an inverse relationship with EPC levels and B vitamin intervention can reverse this effect. Our in vitro work shows that Hcy-mediated EPC toxicity is due to apoptosis involving caspase-8, cytochrome c release, and caspase-3 activation. Vitamin B6, and B9 significantly impair Hcy-mediated EPC caspase-3 activation in vitro. Our clinical and in vitro data together indicate that increased Hcy results in a decrease in EPC numbers. This decrease in EPC by Hcy may be occurring through increased apoptosis and B vitamins (B6, B9) intervention can attenuate such effects.
An N-terminally truncated Smad2 protein can partially compensate for loss of full-length Smad2
Authors: Das Debipriya , Randall Rebecca A. , Hill Caroline S.
Published: September 2008

TGFβ (transforming growth factor β) superfamily signalling is critical both for early embryonic development and later for tissue homoeostasis in adult organisms. The use of gene-disruption techniques in mice has been essential to understanding the functional roles of the components of the pathways downstream of TGFβ superfamily ligands, in particular, the receptors and the Smads that transduce signals from the plasma membrane to the nucleus. Smad2 functions downstream of TGFβ, Activin and Nodal, and a number of Smad2 mutant mice have been generated by different laboratories. Although in all cases these Smad2-deficient mice were embryonic lethal, those created by deletion of the first coding exon survived longer than those generated by replacing part of the MH (Mad homology) 1 domain or deleting all or part of the MH2 domain. Moreover, they displayed a less severe phenotype, as they were capable of transiently inducing mesoderm. In the present study, we show that embryonic fibroblasts taken from the Smad2 mutant mice created by deletion of the first coding exon express a small amount of an N-terminally truncated Smad2 protein. We show this protein results from internal initiation at Met241 and encodes the entire MH2 domain and the C-terminal part of the linker. We demonstrate that this protein is incorporated into Smad heteromeric complexes, can interact with DNA-binding transcription factors and thereby can mediate TGFβ-induced transcriptional activation from a number of TGFβ-responsive elements. We propose that this functional truncated Smad2 protein can partially compensate for the loss of full-length Smad2, thereby providing an explanation for the differing phenotypes of Smad2 mutant mice.
Cell surface delivery and structural re-organization by pharmacological chaperones of an oligomerization-defective α1b-adrenoceptor mutant demonstrates membrane targeting of GPCR oligomers
Authors: Canals Meritxell , Lopez-Gimenez Juan F. , Milligan Graeme
Published: September 2008

Many G-protein-coupled receptors, including the α1b-adrenoceptor, form homo-dimers or oligomers. Mutation of hydrophobic residues in transmembrane domains I and IV alters the organization of the α1b-adrenoceptor oligomer, with transmembrane domain IV playing a critical role. These mutations also result in endoplasmic reticulum trapping of the receptor. Following stable expression of this α1b-adrenoceptor mutant, cell surface delivery, receptor function and structural organization were recovered by treatment with a range of α1b-adrenoceptor antagonists that acted at the level of the endoplasmic reticulum. This was accompanied by maturation of the mutant receptor to a terminally N-glycosylated form, and only this mature form was trafficked to the cell surface. Co-expression of the mutant receptor with an otherwise wild-type form of the α1b-adrenoceptor that is unable to bind ligands resulted in this wild-type variant also being retained in the endoplasmic reticulum. Ligand-induced cell surface delivery of the mutant α1b-adrenoceptor now allowed co-recovery to the plasma membrane of the ligand-binding-deficient mutant. These results demonstrate that interactions between α1b-adrenoceptor monomers occur at an early stage in protein synthesis, that ligands of the α1b-adrenoceptor can act as pharmacological chaperones to allow a structurally compromised form of the receptor to pass cellular quality control, that the mutated receptor is not inherently deficient in function and that an oligomeric assembly of ligand-binding-competent and -incompetent forms of the α1b-adrenoceptor can be trafficked to the cell surface by binding of a ligand to only one component of the receptor oligomer.
The crystal structure of rabbit IgG-Fc
Authors: Girardi Enrico , Holdom Mary D. , Davies Anna M. , Sutton Brian J. , Beavil Andrew J.
Published: September 2008

We report the structure of the Fc fragment of rabbit IgG at 1.95 Å (1 Å=0.1 nm) resolution. Rabbit IgG was the molecule for which Porter established the four-chain, Υ-shaped structure of the antibody molecule, and crystals of the Fc (‘Fragment crystallisable’) were first reported almost 50 years ago in this journal [Porter, R. R. (1959) Biochem. J. 73, 119–126]. This high-resolution analysis, apparently of the same crystal form, reveals several features of IgG-Fc structure that have not previously been described. More of the lower hinge region is visible in this structure than in others, demonstrating not only the acute bend in the IgG molecule that this region can mediate, as seen in receptor complexes, but also that this region has a tendency to adopt a bent structure even in the absence of receptor. As observed in other IgG-Fc structures, the Cγ2 domains display greater mobility/disorder within the crystals than the Cγ3 domains; unexpectedly the structure reveals partial cleavage of both Cγ2 intra-domain disulphide bonds, whereas an alternative conformation for one of the cysteine residues in the intact bridge within the more ordered Cγ3 domains is observed. The N-linked oligosaccharide chains at Asn297 are well-defined and reveal two alternative conformations for the galactose units on each of the α(1–6)-linked branches. The presence of this galactose unit is important for stabilizing the structure of the entire branched carbohydrate chain, and its absence correlates with the severity of autoimmune conditions such as rheumatoid arthritis in both human clinical studies and in a rabbit model of the disease. Rabbit IgG, through this high-resolution structure of its Fc region, thus continues to offer new insights into antibody structure.
MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets
Authors: Muslin Anthony J.
Published: September 2008

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.
Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain
Authors: Naylor Andrew S. , Bull Cecilia , Nilsson Marie K. L. , Zhu Changlian , Björk-Eriksson Thomas , Eriksson Peter S. , Blomgren Klas , Kuhn H. Georg
Published: September 2008

Cranial radiation therapy is commonly used in the treatment of childhood cancers. It is associated with cognitive impairments tentatively linked to the hippocampus, a neurogenic region of the brain important in memory function and learning. Hippocampal neurogenesis is positively regulated by voluntary exercise, which is also known to improve hippocampal-dependent cognitive functions. In this work, we irradiated the brains of C57/BL6 mice on postnatal day 9 and evaluated both the acute effects of irradiation and the effects of voluntary running on hippocampal neurogenesis and behavior 3 months after irradiation. Voluntary running significantly restored precursor cell and neurogenesis levels after a clinically relevant, moderate dose of irradiation. We also found that irradiation perturbed the structural integration of immature neurons in the hippocampus and that this was reversed by voluntary exercise. Furthermore, irradiation-induced behavior alterations observed in the open-field test were ameliorated. Together, these results clearly demonstrate the usefulness of physical exercise for functional and structural recovery from radiation-induced injury to the juvenile brain, and they suggest that exercise should be evaluated in rehabilitation therapy of childhood cancer survivors.
FOXO3A genotype is strongly associated with human longevity
Authors: Willcox Bradley J. , Donlon Timothy A. , He Qimei , Chen Randi , Grove John S. , Yano Katsuhiko , Masaki Kamal H. , Willcox D. Craig , Rodriguez Beatriz , Curb J. David
Published: September 2008

Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the
FOXO3A
gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (
P
= 0.00009; adjusted
P
= 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with
FOXO3A
genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the
FOXO3A
GG genotype. Further exploration of the
FOXO3A
gene, human longevity and other aging phenotypes is warranted in other populations.
Macroscopically ordered water in nanopores
Authors: Köfinger Jürgen , Hummer Gerhard , Dellago Christoph
Published: September 2008

Water confined into the interior channels of narrow carbon nanotubes or transmembrane proteins forms collectively oriented molecular wires held together by tight hydrogen bonds. Here, we explore the thermodynamic stability and dipolar orientation of such 1D water chains from nanoscopic to macroscopic dimensions. We show that a dipole lattice model accurately recovers key properties of 1D confined water when compared to atomically detailed simulations. In a major reduction in computational complexity, we represent the dipole model in terms of effective Coulombic charges, which allows us to study pores of macroscopic lengths in equilibrium with a water bath (or vapor). We find that at ambient conditions, the water chains filling the tube are essentially continuous up to macroscopic dimensions. At reduced water vapor pressure, we observe a 1D Ising-like filling/emptying transition without a true phase transition in the thermodynamic limit. In the filled state, the chains of water molecules in the tube remain dipole-ordered up to macroscopic lengths of ≈0.1 mm, and the dipolar order is estimated to persist for times up to ≈0.1 s. The observed dipolar order in continuous water chains is a precondition for the use of nanoconfined 1D water as mediator of fast long-range proton transport, e.g., in fuel cells. For water-filled nanotube bundles and membranes, we expect anti-ferroelectric behavior, resulting in a rich phase diagram similar to that of a 2D Coulomb gas.
Regulation of TATA-binding protein dynamics in living yeast cells
Authors: Sprouse Rebekka O. , Karpova Tatiana S. , Mueller Florian , Dasgupta Arindam , McNally James G. , Auble David T.
Published: September 2008

Although pathways for assembly of RNA polymerase (Pol) II transcription preinitiation complexes (PICs) have been well establishedin vitro, relatively little is known about the dynamic behavior of Pol II general transcription factorsin vivo. In vitro, a subset of Pol II factors facilitates reinitiation by remaining very stably bound to the promoter. This behavior contrasts markedly with the highly dynamic behavior of RNA Pol I transcription complexesin vivo, which undergo cycles of disassembly/reassembly at the promoter for each round of transcription. To determine whether the dynamic behavior of the Pol II machineryin vivois fundamentally different from that of Pol I and whether the static behavior of Pol II factorsin vitrofully recapitulates their behaviorin vivo, we used fluorescence recovery after photobleaching (FRAP). Surprisingly, we found that all or nearly all of the TATA-binding protein (TBP) population is highly mobilein vivo, displaying FRAP recovery rates of <15 s. These high rates require the activity of the TBP-associated factor Mot1, suggesting that TBP/chromatin interactions are destabilized by active cellular processes. Furthermore, the distinguishable FRAP behavior of TBP and TBP-associated factor 1 indicates that there are populations of these molecules that are independent of one another. The distinct FRAP behavior of most Pol II factors that we tested suggests that transcription complexes assemble via stochastic multistep pathways. Our data indicate that active Pol II PICs can be much more dynamic than previously considered.
Prolonged presynaptic posttetanic cyclic GMP signaling in
Drosophila
motoneurons
Authors: Shakiryanova Dinara , Levitan Edwin S.
Published: September 2008

Ca
2+
can stimulate cyclic nucleotide synthesis, but it is not known whether this signaling occurs in nerve terminals in response to activity. Here,
in vivo
imaging of
Drosophila
motoneuron terminals shows that activity rapidly induces a long-lasting signal from a transgenically expressed optical indicator based on the epac1 (exchange protein directly activated by cAMP 1) cAMP-binding domain. The epac1-cAMP sensor (camps) response in synaptic boutons depends on extracellular Ca
2+
and ryanodine receptor-mediated Ca
2+
-induced Ca
2+
release from the endoplasmic reticulum. However, mutations that inhibit
rutabaga
Ca
2+
-stimulated adenylyl cyclase and
dunce
cAMP-specific phosphodiesterase (PDE) have no effect. Instead, the activity-dependent presynaptic epac1-camps signal reflects elevation of cGMP in response to nitric oxide-activated guanylyl cyclase. Posttetanic presynaptic cGMP is long-lived because of limited PDE activity. Thus, nerve terminal biochemical signaling induced by brief bouts of activity temporally summates on a time scale orders of magnitude longer than fast transmission.
Phylogenomic evidence for multiple losses of flight in ratite birds
Authors: Harshman John , Braun Edward L. , Braun Michael J. , Huddleston Christopher J. , Bowie Rauri C. K. , Chojnowski Jena L. , Hackett Shannon J. , Han Kin-Lan , Kimball Rebecca T. , Marks Ben D. , Miglia Kathleen J. , Moore William S. , Reddy Sushma , Sheldon Frederick H. , Steadman David W. , Steppan Scott J. , Witt Christopher C. , Yuri Tamaki
Published: September 2008

Ratites (ostriches, emus, rheas, cassowaries, and kiwis) are large, flightless birds that have long fascinated biologists. Their current distribution on isolated southern land masses is believed to reflect the breakup of the paleocontinent of Gondwana. The prevailing view is that ratites are monophyletic, with the flighted tinamous as their sister group, suggesting a single loss of flight in the common ancestry of ratites. However, phylogenetic analyses of 20 unlinked nuclear genes reveal a genome-wide signal that unequivocally places tinamous within ratites, making ratites polyphyletic and suggesting multiple losses of flight. Phenomena that can mislead phylogenetic analyses, including long branch attraction, base compositional bias, discordance between gene trees and species trees, and sequence alignment errors, have been eliminated as explanations for this result. The most plausible hypothesis requires at least three losses of flight and explains the many morphological and behavioral similarities among ratites by parallel or convergent evolution. Finally, this phylogeny demands fundamental reconsideration of proposals that relate ratite evolution to continental drift.
Sports experience changes the neural processing of action language
Authors: Beilock Sian L. , Lyons Ian M. , Mattarella-Micke Andrew , Nusbaum Howard C. , Small Steven L.
Published: September 2008

Experience alters behavior by producing enduring changes in the neural processes that support performance. For example, performing a specific action improves the execution of that action via changes in associated sensory and motor neural circuitry, and experience using language improves language comprehension by altering the anatomy and physiology of perisylvian neocortical brain regions. Here we provide evidence that specialized (sports) motor experience enhances action-related language understanding by recruitment of left dorsal lateral premotor cortex, a region normally devoted to higher-level action selection and implementation—even when there is no intention to perform a real action. Experience playing and watching sports has enduring effects on language understanding by changing the neural networks that subserve comprehension to incorporate areas active in performing sports skills. Without such experience, sport novices recruit lower-level sensory-motor regions, thought to support the instantiation of movement, during language processing, and activity in primary motor areas does not help comprehension. Thus, the language system is sufficiently plastic and dynamic to encompass expertise-related neural recruitment outside core language networks.
Transplantation of a tyrosine editing domain into a tyrosyl-tRNA synthetase variant enhances its specificity for a tyrosine analog
Authors: Oki Kenji , Sakamoto Kensaku , Kobayashi Takatsugu , Sasaki Hiroshi M. , Yokoyama Shigeyuki
Published: September 2008

To guarantee specific tRNA and amino acid pairing, several aminoacyl-tRNA synthetases correct aminoacylation errors by deacylating or “editing” misaminoacylated tRNA. A previously developed variant of
Escherichia coli
tyrosyl-tRNA synthetase (iodoTyrRS) esterifies or “charges” tRNA
Tyr
with a nonnatural amino acid, 3-iodo-
l
-tyrosine, and with
l
-tyrosine less efficiently. In the present study, the editing domain of phenylalanyl-tRNA synthetase (PheRS) was transplanted into iodoTyrRS to edit tyrosyl-tRNA
Tyr
and thereby improve the overall specificity for 3-iodo-
l
-tyrosine. The β-subunit fragments of the PheRSs from
Pyrococcus horikoshii
and two bacteria were tested for editing activity. The isolated B3/4 editing domain of the archaeal PheRS, which was exogenously added to the tyrosylation reaction with iodoTyrRS, efficiently reduced the production of tyrosyl-tRNA
Tyr
. In addition, the transplantation of this domain into iodoTyrRS at the N terminus prevented tyrosyl-tRNA
Tyr
production most strongly among the tested fragments. We next transplanted this archaeal B3/4 editing domain into iodoTyrRS at several internal positions. Transplantation into the connective polypeptide in the Rossmann-fold domain generated a variant that efficiently charges tRNA
Tyr
with 3-iodo-
l
-tyrosine, but hardly produces tyrosyl-tRNA
Tyr
. This variant, iodoTyrRS-ed, was used, together with an amber suppressor derived from tRNA
Tyr
, in a wheat germ cell-free translation system and incorporated 3-iodo-
l
-tyrosine, but not
l
-tyrosine, in response to the amber codon. Thus, the editing-domain transplantation achieved unambiguous pairing between the tRNA and the nonnatural amino acid in an expanded genetic code.
Cascading failure and robustness in metabolic networks
Authors: Smart Ashley G. , Amaral Luis A. N. , Ottino Julio M.
Published: September 2008

We investigate the relationship between structure and robustness in the metabolic networks of
Escherichia coli
,
Methanosarcina barkeri
,
Staphylococcus aureus
, and
Saccharomyces cerevisiae
, using a cascading failure model based on a topological flux balance criterion. We find that, compared to appropriate null models, the metabolic networks are exceptionally robust. Furthermore, by decomposing each network into rigid clusters and branched metabolites, we demonstrate that the enhanced robustness is related to the organization of branched metabolites, as rigid cluster formations in the metabolic networks appear to be consistent with null model behavior. Finally, we show that cascading in the metabolic networks can be described as a percolation process.
Phylogenetic profiles reveal evolutionary relationships within the “twilight zone” of sequence similarity
Authors: Chang Gue Su , Hong Yoojin , Ko Kyung Dae , Bhardwaj Gaurav , Holmes Edward C. , Patterson Randen L. , van Rossum Damian B.
Published: September 2008

Inferring evolutionary relationships among highly divergent protein sequences is a daunting task. In particular, when pairwise sequence alignments between protein sequences fall <25% identity, the phylogenetic relationships among sequences cannot be estimated with statistical certainty. Here, we show that phylogenetic profiles generated with the Gestalt Domain Detection Algorithm–Basic Local Alignment Tool (GDDA-BLAST) are capable of deriving,
ab initio
, phylogenetic relationships for highly divergent proteins in a quantifiable and robust manner. Notably, the results from our computational case study of the highly divergent family of retroelements accord with previous estimates of their evolutionary relationships. Taken together, these data demonstrate that GDDA-BLAST provides an independent and powerful measure of evolutionary relationships that does not rely on potentially subjective sequence alignment. We demonstrate that evolutionary relationships can be measured with phylogenetic profiles, and therefore propose that these measurements can provide key insights into relationships among distantly related and/or rapidly evolving proteins.
Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways
Authors: Lenz Georg , Wright George W. , Emre N. C. Tolga , Kohlhammer Holger , Dave Sandeep S. , Davis R. Eric , Carty Shannon , Lam Lloyd T. , Shaffer A. L. , Xiao Wenming , Powell John , Rosenwald Andreas , Ott German , Muller-Hermelink Hans Konrad , Gascoyne Randy D. , Connors Joseph M. , Campo Elias , Jaffe Elaine S. , Delabie Jan , Smeland Erlend B. , Rimsza Lisa M. , Fisher Richard I. , Weisenburger Dennis D. , Chan Wing C. , Staudt Louis M.
Published: September 2008

Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (
P
< 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was
SPIB
, which encodes an ETS family transcription factor. Knockdown of
SPIB
by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating
SPIB
as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the
INK4a
/
ARF
tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype.
FOXP1
emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17–92 microRNA cluster and deletion of the tumor suppressor
PTEN
were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.