bluuebunny/crossref_metadata_2025 huggingface dataset:
The Market Approach to the Rise of the Geluk School, 1419–1642
Authors: McCleary Rachel M. , van der Kuijp Leonard W. J.
Published: March 2010

Religious pluralism characterized Tibetan Buddhism by the eleventh or twelfth century, allowing for the development of many schools and sects with little differentiation in religious products. The early Ming dynasty (1368–1424) saw a significant shift in policy on Tibetan affairs compared to the Mongolian Yuan dynasty (1271–1368). Relative disengagement from Tibet translated into a liberalization of local politics, resulting in a shift from secular politics and clan wealth to ecclesiastical monastic institutions. The Geluk sect formed during this period, introducing superior technology in its organizational characteristics—celibacy, ordained abbots, casuistical adherence, scholastic training, and doctrinal orthodoxy—that distinguished it from other schools and sects. With the loss of its major Tibetan patron, the Gelukpa faced a serious challenge from its fiercest competitor, the Karmapa, and raised the stakes by introducing the incarnate position of the Dalai Lama and his labrang (financial estate). This allowed the Gelukpa to directly compete with the Karmapa for wealthy patrons. By forming an alliance with the Mongols, the Gelukpa were willing to counter violence with violence to become the monopoly religion.
The Begims of the Mystic Feast: Turco-Mongol Tradition in the Mughal Harem
Authors: Balabanlilar Lisa
Published: March 2010

The founders of India's Mughal Empire were the last surviving remnants of the Timurid-Mongol ruling elite, descendants of Timur and Chingis Khan, for whom the traditions and institutions of Central Asia were universally recognized and potent symbols of cultural prowess and legitimacy. These ideas and understandings were not abandoned in the dynasty's displacement and reestablishment in India. Among them remained a distinctly Timurid understanding of the rights and roles of elite women—not only with regard to their artistic production or patronage but also, in marked contrast to their contemporaries the Ottomans and Safavids, the power offered to young, even childless, royal women and their active participation in dynastic survival and political success. In generations of Mughal rule on the Subcontinent, the comfortable cultural accommodation of independent elite women was a vital component of the Timurid cultural and social legacy, inherited and carefully maintained at the royal courts of India.
Experience report: Functional programming in C-Rules
Authors: WAZNY JEREMY
Published: March 2010

C-Rules is a business rules management system developed by Constraint Technologies International (www.constrainttechnologies.com) that is designed for use in transport, travel and logistics problems. Individual businesses within these industries often need to solve the same kinds of problems related to scheduling of operations, resource allocation, staff rostering and so on, but each organisation has its own rules and procedures. Furthermore, these problems tend to be combinatorially challenging: before a final solution is chosen, many potential choices need to be generated, evaluated and compared. In C-Rules, users define rules that describe various aspects of a problem. These rules can be invoked from an application, which is typically either an optimising solver or an interactive planning tool. Rules can be used to encode evaluation criteria, such as the legality or cost of a proposed solution, or values like configuration parameters that may be used by the host application to tune or direct its progress. At its core, C-Rules provides a functional expression language that affords users power and flexibility when formulating rules. In this paper we will describe our experiences of using functional programming both at the end-user level and at the implementation level. We highlight some of the benefits of basing our rule system on features such as higher-order functions, referential transparency and static, polymorphic typing. We also outline some of our experiences in using Haskell to build an efficient compiler for the core language.
The impact of brain size on pilot performance varies with aviation training and years of education
Authors: ADAMSON MAHEEN M. , SAMARINA VIKTORIYA , XIANGYAN XU , HUYNH VIRGINIA , KENNEDY QUINN , WEINER MICHAEL , YESAVAGE JEROME , TAYLOR JOY L.
Published: March 2010

Previous studies have consistently reported age-related changes in cognitive abilities and brain structure. Previous studies also suggest compensatory roles for specialized training, skill, and years of education in the age-related decline of cognitive function. The Stanford/VA Aviation Study examines the influence of specialized training and skill level (expertise) on age-related changes in cognition and brain structure. This preliminary report examines the effect of aviation expertise, years of education, age, and brain size on flight simulator performance in pilots aged 45–68 years. Fifty-one pilots were studied with structural magnetic resonance imaging, flight simulator, and processing speed tasks. There were significant main effects of age (p < .01) and expertise (p < .01), but not of whole brain size (p > .1) or education (p > .1), on flight simulator performance. However, even though age and brain size were correlated (r = −0.41), age differences in flight simulator performance were not explained by brain size. Both aviation expertise and education were involved in an interaction with brain size in predicting flight simulator performance (p < .05). These results point to the importance of examining measures of expertise and their interactions to assess age-related cognitive changes. (JINS, 2010, 16, 412–423.)
Imaging and characterization of solute transport during two tracer tests in a shallow aquifer using electrical resistivity tomography and multilevel groundwater samplers
Authors: Müller Kerstin , Vanderborght Jan , Englert Andreas , Kemna Andreas , Huisman Johan A. , Rings Joerg , Vereecken Harry
Published: March 2010

The relevance of aquifer heterogeneity for flow and transport is recognized broadly; however, its characterization is hampered by the inaccessibility of the subsurface. Time‐lapse electrical resistivity tomography (ERT) offers the possibility of imaging noninvasively subsurface transport. We present results of two tracer tests that were carried out successively in a shallow aquifer at the Krauthausen test site (Germany). The breakthroughs of an electrically conductive and a resistive tracer were monitored with ERT and local multilevel groundwater samplers (MLS) along two cross sections perpendicular to the mean flow direction. Sinking of the conductive salt tracer due to density effects was observed with ERT. We applied a stream tube model to characterize the spatially variable transport. ERT‐derived stream tube parameters showed similar patterns for the two tracer experiments, reflecting the effect of aquifer heterogeneity on transport. MLS data did not show similar spatial patterns, which indicates that these measurements may be prone to subtle changes of the flow field in the small sampling volume and mixing within screened wells. Between 50% and 10% of the tracer was recovered in the ERT‐derived breakthrough curves. Compared with transport simulations in a homogeneous aquifer, ERT‐derived time‐integrated changes in electrical conductivity were locally larger but focused in a smaller area. MLS data indicated that in this area, ERT did not underestimate the tracer recovery. The relatively low tracer recovery was attributed to undetected tracer breakthrough in regions with low ERT sensitivity and in regions where the length of the tracer plume and the electrical conductivity contrast were small.
Pan‐Arctic sunphotometry during the ARCTAS‐A campaign of April 2008
Authors: Saha A. , O'Neill N. T. , Eloranta E. , Stone R. S. , Eck T. F. , Zidane S. , Daou D. , Lupu A. , Lesins G. , Shiobara M. , McArthur L. J. B.
Published: March 2010

Aerosol optical depth (AOD) measurements were acquired at six Arctic sunphotometer sites during the ARCTAS‐A (April, 2008) campaign. Numerous smoke events were identified and related to extensive forest and agricultural fires in eastern Russia and northern Kazakhstan/southwestern Russia respectively. An analysis of the fine (sub‐micron) optical depths from the six stations indicated the presence of underlying low frequency trends which were coherent with general meteorological considerations, source information, model estimates and remote sensing information. Low frequency (diurnal) coarse‐mode optical depth events were observed at a number of the stations; these singular events are likely due to ice particles whose nucleation may have been associated with the presence of smoke, or possibly dust.
Modality of semiannual to multidecadal oscillations in global sea surface temperature variability
Authors: Chen Ge , Shao Baomin , Han Yong , Ma Jun , Chapron Bertrand
Published: March 2010

Repeating the history of study on El Niño‐Southern Oscillation (ENSO) in the 1980s, interdecadal oscillation (IDO) in climate variability is currently an area of active research and debate, following the recognition of its emerging significance in nature and science. In this work, a two‐dimensional propagating modal extraction technique is applied to a reconstructed global monthly sea surface temperature (SST) data set spanning 1854 through 2007, to examine the spatiotemporal structure of SST variability with an emphasis on the fine modal pattern of IDOs. In the time domain, it is revealed that a canonical modal spectrum of decadal‐to‐centennial SST variability constitutes four most distinct oscillations with periodicities at 9.0, 13.0, 21.2, and 62.2 years, which are naturally defined as primary modes and are, respectively, termed as the subdecadal mode, the quasidecadal mode, the interdecadal mode, and the multidecadal mode (modes S, Q, I, and M). They join the energetic annual mode (mode A) and two major ENSO modes at 3.7 and 5.8 years (modes B and C), as well as a dozen of secondary modes ranging from semiannual to multidecadal, in determining the key pattern of SST‐related climate variability. In the space domain, seven modally dynamic areas, analogous to the Niño regions for ENSO, are clearly identified and are named as IDO zones. Contrary to ENSO, dominant IDO zones are most visible in the extratropical oceans, especially in the North Atlantic/North Pacific sectors, while secondary signatures are observed in the tropical oceans. The array of (four) primary modes with respect to (seven) major zones yields a sophisticated yet canonical pattern of IDOs, leading to a basic conclusion that multimodality (for a given region) and multiregionality (for a given mode) are fundamental features of the IDO system.
Forecasting Hurricane Impact on Coastal Topography
Authors: Plant Nathaniel G. , Stockdon Hilary F. , Sallenger Asbury H. , Turco Michael J. , East Jeffery W. , Taylor Arthur A. , Shaffer Wilson A.
Published: March 2010

Extreme storms can have a profound impact on coastal topography and thus on ecosystems and human‐built structures within coastal regions. For instance, landfalls of several recent major hurricanes have caused significant changes to the U.S. coastline, particularly along the Gulf of Mexico. Some of these hurricanes (e.g., Ivan in 2004, Katrina and Rita in 2005, and Gustav and Ike in 2008) led to shoreline position changes of about 100 meters. Sand dunes, which protect the coast from waves and surge, eroded, losing several meters of elevation in the course of a single storm. Observations during these events raise the question of how storm‐related changes affect the future vulnerability of a coast.
Obama Administration Proposes Increases for NASA and Energy Department Budgets
Authors: Showstack Randy
Published: March 2010

Obama Administration Proposes Increases for NASA and Energy Department Budgets

NASA's FY 2011 budget would increase to US$19 billion, up 1.5% from $18.7 billion. In addition, the budget would set the agency on a trajectory to increase by about $6 billion between FY 2011 and FY 2015. Within the overall budget, the Science account would increase to $5 billion (up from $4.5 billion), with Earth Science receiving $1.8 billion (up a whopping 29% from $1.4 billion) in FY 2011 and approximately an additional $1.8 billion between FY 2011 and FY 2014. Planetary Science would get $1.49 billion (up from $1.34 billion), Heliophysics would increase slightly to $642 million from $627 million, and Astrophysics would dip to $1.08 billion from $1.1 billion.
One in Five AGU Members Votes for Governance Changes
Authors: Galvin Cyril
Published: March 2010

At the top of the front page of the 24 November 2009 issue of Eos is a red headline that reads, “Overwhelming Approval for AGU Governance Change.” Three pages farther, the AGU president opens his discussion with, “Over the past month, AGU members have made their voices heard, overwhelmingly supporting the Council‐endorsed governance changes….”

The plain English meaning of those words in Eos—contrasted against the data provided—suggests that a more accurate statement of the facts would say, “Despite an energetic program of e‐mail and print advertisement, fewer than one out of five AGU members voted for the governance changes.”
Reply to “One in Five AGU Members Votes for Governance Changes”
Authors: Van Hook Robert T.
Published: March 2010

Of the 56,670 AGU members eligible to vote for the recent governance changes, 11,614 cast usable ballots. This is a 20.5% participation rate; Cyril Galvin is correct in saying that one out of five AGU members voted. It is also correct to say that the recent vote on governance changes had a record turnout.

The total number of ballots cast in the governance vote—and the percentage of members voting—exceeds that of the previous four elections. For the officers elected to serve terms in 2008–2010, about 9700 ballots were cast (19.1%); for 2006–2008, about 8400 ballots were cast (19.0%). The elections held for terms in 2004–2006 and in 2002–2004 each had much lower turnouts of roughly 6600 (around 16.5%).
Women and telomeres
Authors: Wolinsky Howard
Published: March 2010

Last year, two eminent female scientists and mothers shared the Nobel Prize for Physiology. Howard Wolinsky explores how their field of telomerase research was shaped and what hope this award to two working mothers offers for other female scientists.
miR‐146a in PBMCs modulates Th1 function in patients with acute coronary syndrome
Authors: Guo Min , Mao Xiaobo , Ji Qingwei , Lang Mingjian , Li Songnan , Peng Yudong , Zhou Wei , Xiong Bo , Zeng Qiutang
Published: March 2010

The upregulation of Th1 cells has been suggested to have an essential function in the development of atherosclerosis (AS). Recent studies indicate that miR‐146a is a microRNA specifically and highly expressed in Th1‐driven autoimmune disease. The aim of the study was to investigate the possible mechanisms of the miR‐146a in the onset of acute coronary syndrome (ACS). The results showed that the expression of miR‐146a in peripheral blood mononuclear cells (PBMCs) was significantly increased in patients with ACS. We showed that overexpression of miR‐146a in PBMCs could significantly upregulate the function of Th1 cells. Furthermore, we showed that miR‐146a treatment could modulate the Th1 differentiation through posttranscriptional enhancing the T‐bet pathway in PBMCs. In addition, this study also provided evidence that miR‐146a treatment in vitro could induce the protein expression of TNF‐α, MCP‐1, NF‐κB p65, which are key pro‐inflammatory cytokines and critical transcription factor in AS. In contrast, miR‐146a inhibitor could attenuate these phenomena significantly. The results support the concept that miR‐146a may be a novel regulatory factor in Th1 differentiation and a new therapeutic target for AS and ACS.
Cross‐presentation of HCMV chimeric protein enables generation and measurement of polyclonal T cells
Authors: Nguyen Thi H O , Sullivan Lucy C , Kotsimbos Tom C , Schwarer Anthony P , Mifsud Nicole A
Published: March 2010

CD8+ T cell immunity has a critical function in controlling human cytomegalovirus (HCMV) infection. In immunocompromized individuals, HCMV reactivation or disease can lead to increased morbidity and mortality, particularly in transplant recipients. In this setting, adoptive transfer of HCMV‐specific CD8+ T cells is a promising vaccine strategy to restore viral immunity, with most clinical approaches focussing on the use of peptides for the generation of single epitope‐specific CD8+ T cells. We show that using an IE1‐pp65 chimeric protein as the antigen source promotes effective cross‐presentation, by monocyte‐derived dendritic cells (MoDCs), to generate polyclonal CD8+ T cell epitopes. By exploring human leukocyte antigen (HLA)‐restricted immunodominance hierarchies both within and across two immunodominant proteins, we show that HLA‐B7 epitopes elicit higher CD8+ T cell responses compared with HLA‐A1, ‐A2 or ‐B8. This study provides important evidence highlighting both the efficacy of the IE1‐pp65 chimeric protein and the importance of immunodominance in designing future therapeutic vaccines.
Mechanism and Synthesis
Authors:   The Open University
Published: March 2010

This book pursues possible strategies for synthesising mainly organic compounds, particularly those of interest to the health sector and related industries. Topics covered include addition reactions of aldehydes and ketones; the use of organometallic reagents to form carbon-carbon bonds (eg Grignard reagents); and radical reactions, including selectivity and chain reactions. Retrosynthetic analysis is introduced as a strategy for developing syntheses, along with biochemical pathways. Mechanism and Synthesis concludes with a Case Study on polymers, which demonstrates how chain reactions can be used to build up useful materials with specific properties, such as contact lenses. The Molecular World series provides an integrated introduction to all branches of chemistry for both students wishing to specialise and those wishing to gain a broad understanding of chemistry and its relevance to the everyday world and to other areas of science. The books, with their Case Studies and accompanying multi-media interactive CD-ROMs, will also provide valuable resource material for teachers and lecturers. (The CD-ROMs are designed for use on a PC running Windows 95, 98, ME or 2000.)
How (Not) to be Governed: Foucault, Critique, and the Political
Authors: Cadman Louisa
Published: March 2010

In this paper I offer an interpretation of Foucault's 1978 and 1979 lectures at the Collège de France: Security, Territory, Population and The Birth of Biopolitics. Through doing so, I suspend the mainstay of social scientific research that falls within the field of governmentality studies and turn instead to the historico-critical basis for Foucault's researches. Embracing notions of governmental ‘counter-conducts' and the ‘critical attitude’, I show how a positive desubjugating form of critique, which temporarily suspends the power of governmental norms, is wholly immanent to the formation and development of modern political governmentality. Furthermore, the ethos of this critique is key to understanding Foucault's genealogical method and his conception of the political. To advance these claims, throughout this paper I draw on the example of rights. I move away from the normative approach to rights in an era of (liberal) political governmentality towards a more performative understanding—what Foucault terms the ‘right to question’ governmental regimes of truth. I finish by describing Foucault's own questioning of governmental regimes and offer a rereading of his defence of the Vietnamese boat people in the early 1980s.
“A Beautiful Soaking Rain”: Environmental Value and Water beyond Eurocentrism
Authors: Gibbs Leah M
Published: March 2010

Current approaches to valuing nature within environmental and natural resource management are based on and limited by Eurocentric knowledge and experience of northern temperate nature. Methods based on separation and domination marginalise other ways of knowing nature and thinking about value. The aims of this paper are to unsettle current ways of thinking about water values; to decentre Eurocentric thinking about water management; and to present a different way of thinking about values associated with water, based on an empirical study of the Lake Eyre Basin in central Australia. The paper takes a multidisciplinary approach, drawing on multiple knowledges of Australian water, including indigenous, local settler, and scientific knowledge, and on lessons from Australian Aboriginal people and the academic discourse of Aboriginal Studies. In particular, it considers how a focus on variability—a concept emerging from the Australian landscape (rather than from northern temperate landscapes)—might foster different thinking about water and value. Variability takes as a starting point the diversity, change, and complexity of water and values, as opposed to separation and domination. This focus highlights two points currently marginalised in dominant practice of environmental valuation: that the variability of Australian water regimes is valued, and that values themselves are characterised by variability.
Spelling and Reading: Using Visual Sensitivity to Explore Shared or Separate Orthographic Representations
Authors: Pammer Kristen , Connell Ellen , Kevan Alison
Published: March 2010

Do we use the same neurocognitive mechanisms to spell that we do to read? There is a considerable number of conflicting findings, such that evidence has been provided to support common mechanisms for reading and spelling, while other research supports the proposal that reading and spelling utilise unique neurocognitive resources. Sensitivity to visual spatial-frequency doubling (FD) has been demonstrated to correlate with and specifically predict orthographic processing when reading; therefore, if spelling and reading share some elements of orthographic representation, sensitivity to FD should similarly correlate with, and predict, spelling ability by virtue of this shared association. A double dissociation between reading and spelling was found such that sensitivity to the FD task, as mediated by the visual dorsal stream, predicted reading ability but not spelling, while the visual control task predicted spelling but not reading ability, in poor readers/spellers. The results support a dual-orthographic model with separate orthographic representations for reading and spelling.
A Sweet Sound? Food Names Reveal Implicit Associations between Taste and Pitch
Authors: Crisinel Anne-Sylvie , Spence Charles
Published: March 2010

Sounds (high- and low-pitched) have been shown to be implicitly associated with basic tastes (sour and bitter—see Crisinel and Spence, 2009 Neuroscience Letters464 39–42). In the present study, a version of the implicit association test was used to assess the strength of the association between high-pitched sounds and names of sweet-tasting foodstuffs, and between low-pitched sounds and names of salty-tasting foodstuffs (experiment 1). A similar task, the go/no-go association task was then used to evaluate the relative strengths of these associations (experiment 2). Analysis of the sensitivity of participants' responses suggested that both sour- and sweet-tasting (names of) food items were associated with high-pitched sounds. This result highlights the existence of robust cross-modal associations between certain sounds and basic tastes.
Ecosystem service bundles for analyzing tradeoffs in diverse landscapes
Authors: Raudsepp-Hearne C. , Peterson G. D. , Bennett E. M.
Published: March 2010

A key challenge of ecosystem management is determining how to manage multiple ecosystem services across landscapes. Enhancing important provisioning ecosystem services, such as food and timber, often leads to tradeoffs between regulating and cultural ecosystem services, such as nutrient cycling, flood protection, and tourism. We developed a framework for analyzing the provision of multiple ecosystem services across landscapes and present an empirical demonstration of ecosystem service bundles, sets of services that appear together repeatedly. Ecosystem service bundles were identified by analyzing the spatial patterns of 12 ecosystem services in a mixed-use landscape consisting of 137 municipalities in Quebec, Canada. We identified six types of ecosystem service bundles and were able to link these bundles to areas on the landscape characterized by distinct social–ecological dynamics. Our results show landscape-scale tradeoffs between provisioning and almost all regulating and cultural ecosystem services, and they show that a greater diversity of ecosystem services is positively correlated with the provision of regulating ecosystem services. Ecosystem service-bundle analysis can identify areas on a landscape where ecosystem management has produced exceptionally desirable or undesirable sets of ecosystem services.
In vivo gene delivery by cationic tetraamino fullerene
Authors: Maeda-Mamiya Rui , Noiri Eisei , Isobe Hiroyuki , Nakanishi Waka , Okamoto Koji , Doi Kent , Sugaya Takeshi , Izumi Tetsuro , Homma Tatsuya , Nakamura Eiichi
Published: March 2010

Application of nanotechnology to medical biology has brought remarkable success. Water-soluble fullerenes are molecules with great potential for biological use because they can endow unique characteristics of amphipathic property and form a self-assembled structure by chemical modification. Effective gene delivery in vitro with tetra(piperazino)fullerene epoxide (TPFE) and its superiority to Lipofectin have been described in a previous report. For this study, we evaluated the efficacy of in vivo gene delivery by TPFE. Delivery of enhanced green fluorescent protein gene (EGFP) by TPFE on pregnant female ICR mice showed distinct organ selectivity compared with Lipofectin; moreover, higher gene expression by TPFE was found in liver and spleen, but not in the lung. No acute toxicity of TPFE was found for the liver and kidney, although Lipofectin significantly increased liver enzymes and blood urea nitrogen. In fetal tissues, neither TPFE nor Lipofectin induced EGFP gene expression. Delivery of insulin 2 gene to female C57/BL6 mice increased plasma insulin levels and reduced blood glucose concentrations, indicating the potential of TPFE-based gene delivery for clinical application. In conclusion, this study demonstrated effective gene delivery in vivo for the first time using a water-soluble fullerene.
Leptin therapy in insulin-deficient type I diabetes
Authors: Wang May-yun , Chen Lijun , Clark Gregory O. , Lee Young , Stevens Robert D. , Ilkayeva Olga R. , Wenner Brett R. , Bain James R. , Charron Maureen J. , Newgard Christopher B. , Unger Roger H.
Published: March 2010

In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes.
Picomole-scale characterization of protein stability and function by quantitative cysteine reactivity
Authors: Isom Daniel G. , Vardy Eyal , Oas Terrence G. , Hellinga Homme W.
Published: March 2010

The Gibbs free energy difference between native and unfolded states (“stability”) is one of the fundamental characteristics of a protein. By exploiting the thermodynamic linkage between ligand binding and stability, interactions of a protein with small molecules, nucleic acids, or other proteins can be detected and quantified. Determination of protein stability can therefore provide a universal monitor of biochemical function. Yet, the use of stability measurements as a functional probe is underutilized, because such experiments traditionally require large amounts of protein and special instrumentation. Here we present the quantitative cysteine reactivity (QCR) technique to determine protein stabilities rapidly and accurately using only picomole quantities of material and readily accessible laboratory equipment. We demonstrate that QCR-derived stabilities can be used to measure ligand binding over a wide range of ligand concentrations and affinities. We anticipate that this technique will have broad applications in high-throughput protein engineering experiments and functional genomics.
Interaction of natural survival instincts and internalized social norms exploring the
Titanic
and
Lusitania
disasters
Authors: Frey Bruno S. , Savage David A. , Torgler Benno
Published: March 2010

To understand human behavior, it is important to know under what conditions people deviate from selfish rationality. This study explores the interaction of natural survival instincts and internalized social norms using data on the sinking of the
Titanic
and the
Lusitania
. We show that time pressure appears to be crucial when explaining behavior under extreme conditions of life and death. Even though the two vessels and the composition of their passengers were quite similar, the behavior of the individuals on board was dramatically different. On the
Lusitania
, selfish behavior dominated (which corresponds to the classical homo economicus); on the
Titanic
, social norms and social status (class) dominated, which contradicts standard economics. This difference could be attributed to the fact that the
Lusitania
sank in 18 min, creating a situation in which the short-run flight impulse dominated behavior. On the slowly sinking
Titanic
(2 h, 40 min), there was time for socially determined behavioral patterns to reemerge. Maritime disasters are traditionally not analyzed in a comparative manner with advanced statistical (econometric) techniques using individual data of the passengers and crew. Knowing human behavior under extreme conditions provides insight into how widely human behavior can vary, depending on differing external conditions.
Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease
Authors: Vallet Sonia , Mukherjee Siddhartha , Vaghela Nileshwari , Hideshima Teru , Fulciniti Mariateresa , Pozzi Samantha , Santo Loredana , Cirstea Diana , Patel Kishan , Sohani Aliyah R. , Guimaraes Alex , Xie Wanling , Chauhan Dharminder , Schoonmaker Jesse A. , Attar Eyal , Churchill Michael , Weller Edie , Munshi Nikhil , Seehra Jasbir S. , Weissleder Ralph , Anderson Kenneth C. , Scadden David T. , Raje Noopur
Published: March 2010

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-β family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox–5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.
Strong intranucleoid interactions organize the
Escherichia coli
chromosome into a nucleoid filament
Authors: Wiggins Paul A. , Cheveralls Keith C. , Martin Joshua S. , Lintner Robert , Kondev Jané
Published: March 2010

The stochasticity of chromosome organization was investigated by fluorescently labeling genetic loci in live
Escherichia coli
cells. In spite of the common assumption that the chromosome is well modeled by an unstructured polymer, measurements of the locus distributions reveal that the
E. coli
chromosome is precisely organized into a nucleoid filament with a linear order. Loci in the body of the nucleoid show a precision of positioning within the cell of better than 10% of the cell length. The precision of interlocus distance of genomically-proximate loci was better than 4% of the cell length. The measured dependence of the precision of interlocus distance on genomic distance singles out intranucleoid interactions as the mechanism responsible for chromosome organization. From the magnitude of the variance, we infer the existence of an as-yet uncharacterized higher-order DNA organization in bacteria. We demonstrate that both the stochastic and average structure of the nucleoid is captured by a fluctuating elastic filament model.
Fermentable sugars by chemical hydrolysis of biomass
Authors: Binder Joseph B. , Raines Ronald T.
Published: March 2010

Abundant plant biomass has the potential to become a sustainable source of fuels and chemicals. Realizing this potential requires the economical conversion of recalcitrant lignocellulose into useful intermediates, such as sugars. We report a high-yielding chemical process for the hydrolysis of biomass into monosaccharides. Adding water gradually to a chloride ionic liquid-containing catalytic acid leads to a nearly 90% yield of glucose from cellulose and 70–80% yield of sugars from untreated corn stover. Ion-exclusion chromatography allows recovery of the ionic liquid and delivers sugar feedstocks that support the vigorous growth of ethanologenic microbes. This simple chemical process, which requires neither an edible plant nor a cellulase, could enable crude biomass to be the sole source of carbon for a scalable biorefinery.
Allosteric modulation of Ras positions Q61 for a direct role in catalysis
Authors: Buhrman Greg , Holzapfel Genevieve , Fetics Susan , Mattos Carla
Published: March 2010

Ras and its effector Raf are key mediators of the Ras/Raf/MEK/ERK signal transduction pathway. Mutants of residue Q61 impair the GTPase activity of Ras and are found prominently in human cancers. Yet the mechanism through which Q61 contributes to catalysis has been elusive. It is thought to position the catalytic water molecule for nucleophilic attack on the γ-phosphate of GTP. However, we previously solved the structure of Ras from crystals with symmetry of the space group R32 in which switch II is disordered and found that the catalytic water molecule is present. Here we present a structure of wild-type Ras with calcium acetate from the crystallization mother liquor bound at a site remote from the active site and likely near the membrane. This results in a shift in helix 3/loop 7 and a network of H-bonding interactions that propagates across the molecule, culminating in the ordering of switch II and placement of Q61 in the active site in a previously unobserved conformation. This structure suggests a direct catalytic role for Q61 where it interacts with a water molecule that bridges one of the γ-phosphate oxygen atoms to the hydroxyl group of Y32 to stabilize the transition state of the hydrolysis reaction. We propose that Raf together with the binding of Ca
2+
and a negatively charged group mimicked in our structure by the acetate molecule induces the ordering of switch I and switch II to complete the active site of Ras.
Allele-specific tumor spectrum in
Pten
knockin mice
Authors: Wang Hui , Karikomi Matt , Naidu Shan , Rajmohan Ravi , Caserta Enrico , Chen Hui-Zi , Rawahneh Maysoon , Moffitt Julie , Stephens Julie A. , Fernandez Soledad A. , Weinstein Michael , Wang Danxin , Sadee Wolfgang , La Perle Krista , Stromberg Paul , Rosol Thomas J. , Eng Charis , Ostrowski Michael C. , Leone Gustavo
Published: March 2010

Germline mutations in the tumor suppressor gene
PTEN
(phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan–Riley–Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of
PTEN
identified in patients with Cowden syndrome and show that the nonsense

Pten
∆4–5

and missense

Pten
C124R

and

Pten
G129E

alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for

Pten
∆4–5

, hypomorphic function for

Pten
C124R

, and gain of function for

Pten
G129E

. These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in
PTEN
that alter protein function through distinct mechanisms.
Distal axonopathy with structural persistence in glaucomatous neurodegeneration
Authors: Crish Samuel D. , Sappington Rebecca M. , Inman Denise M. , Horner Philip J. , Calkins David J.
Published: March 2010

An early hallmark of neuronal degeneration is distal transport loss and axon pathology. Glaucoma involves the degeneration of retinal ganglion cell (RGC) neurons and their axons in the optic nerve. Here we show that, like other neurodegenerations, distal axon injury appears early in mouse glaucoma. Where RGC axons terminate in the superior colliculus, reduction of active transport follows a retinotopic pattern resembling glaucomatous vision loss. Like glaucoma, susceptibility to transport deficits increases with age and is not necessarily associated with elevated ocular pressure. Transport deficits progress distal-to-proximal, appearing in the colliculus first followed by more proximal secondary targets and then the optic tract. Transport persists through the optic nerve head before finally failing in the retina. Although axon degeneration also progresses distal-to-proximal, myelinated RGC axons and their presynaptic terminals persist in the colliculus well after transport fails. Thus, distal transport loss is predegenerative and may represent a therapeutic target.
Origins of catalysis by computationally designed retroaldolase enzymes
Authors: Lassila Jonathan K. , Baker David , Herschlag Daniel
Published: March 2010

We have investigated recently reported computationally designed retroaldolase enzymes with the goal of understanding the extent and the origins of their catalytic power. Direct comparison of the designed enzymes to primary amine catalysts in solution revealed a rate acceleration of 10
5
-fold for the most active of the designed retroaldolases. Through pH-rate studies of the designed retroaldolases and evaluation of a Brønsted correlation for a series of amine catalysts, we found that lysine p
K

a

values are shifted by 3–4 units in the enzymes but that the catalytic contributions from the shifted p
K

a

values are estimated to be modest, about 10-fold. For the most active of the reported enzymes, we evaluated the catalytic contribution of two other design components: a motif intended to stabilize a bound water molecule and hydrophobic substrate binding interactions. Mutational analysis suggested that the bound water motif does not contribute to the rate acceleration. Comparison of the rate acceleration of the designed substrate relative to a minimal substrate suggested that hydrophobic substrate binding interactions contribute around 10
3
-fold to the enzymatic rate acceleration. Altogether, these results suggest that substrate binding interactions and shifting the p
K

a

of the catalytic lysine can account for much of the enzyme’s rate acceleration. Additional observations suggest that these interactions are limited in the specificity of placement of substrate and active site catalytic groups. Thus, future design efforts may benefit from a focus on achieving precision in binding interactions and placement of catalytic groups.
Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors
Authors: Groom Harriet C. T. , Yap Melvyn W. , Galão Rui Pedro , Neil Stuart J. D. , Bishop Kate N.
Published: March 2010

Xenotropic murine leukemia virus-related virus (XMRV) is a recently discovered gammaretrovirus that has been linked to prostate cancer and chronic fatigue syndrome. This virus is therefore an important potential human pathogen and, as such, it is essential to understand its host cell tropism. Intriguingly, infectious virus has been recovered from patient-derived peripheral blood mononuclear cells. These cells express several antiviral restriction factors that are capable of inhibiting the replication of a wide range of retroviruses, including other gamma retroviruses. This raises the possibility that, similar to HIV, XMRV may have acquired resistance to restriction. We therefore investigated the susceptibility of XMRV to a panel of different restriction factors. We found that both human APOBEC3 and tetherin proteins are able to block XMRV replication. Expression of human TRIM5α, however, had no effect on viral infectivity. There was no evidence that XMRV expressed countermeasures to overcome restriction. In addition, the virus was inhibited by factors from nonhuman species, including mouse Apobec3, tetherin, and Fv1 proteins. These results have important implications for predicting the natural target cells for XMRV replication, for relating infection to viral pathogenicity and pathology, and for the design of model systems with which to study XMRV-related diseases.
Macroecological signals of species interactions in the Danish avifauna
Authors: Gotelli Nicholas J. , Graves Gary R. , Rahbek Carsten
Published: March 2010

The role of intraspecific and interspecific interactions in structuring biotic communities at fine spatial scales is well documented, but the signature of species interactions at coarser spatial scales is unclear. We present evidence that species interactions may be a significant factor in mediating the regional assembly of the Danish avifauna. Because >95% of breeding species (
n
= 197) are migratory, we hypothesized that dispersal limitation would not be important and that breeding distributions would largely reflect resource availability and autecological habitat preferences. Instead, we detected a striking pattern of spatial segregation between ecologically similar species at two spatial scales with a suite of null models that factored in the spatial distribution of habitats in Denmark as well as population size and biomass of each species. Habitat utilization analyses indicated that community-wide patterns of spatial segregation could not be attributed to the patchy distribution of habitat or to gross differences in habitat utilization among ecologically similar species. We hypothesize that, when habitat patch size is limited, conspecific attraction in concert with interspecific territoriality may result in spatially segregated distributions of ecologically similar species at larger spatial scales. In the Danish avifauna, the effects of species interactions on community assembly appear pervasive and can be discerned at grain sizes up to four orders of magnitude larger than those of individual territories. These results suggest that species interactions should be incorporated into species distribution modeling algorithms designed to predict species occupancy patterns based on environmental variables.
Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases
Authors: Nick McElhinny Stephanie A. , Watts Brian E. , Kumar Dinesh , Watt Danielle L. , Lundström Else-Britt , Burgers Peter M. J. , Johansson Erik , Chabes Andrei , Kunkel Thomas A.
Published: March 2010

Measurements of nucleoside triphosphate levels in
Saccharomyces cerevisiae
reveal that the four rNTPs are in 36- to 190-fold molar excess over their corresponding dNTPs. During DNA synthesis in vitro using the physiological nucleoside triphosphate concentrations, yeast DNA polymerase
ε
, which is implicated in leading strand replication, incorporates one rNMP for every 1,250 dNMPs. Pol
δ
and Pol α, which conduct lagging strand replication, incorporate one rNMP for every 5,000 or 625 dNMPs, respectively. Discrimination against rNMP incorporation varies widely, in some cases by more than 100-fold, depending on the identity of the base and the template sequence context in which it is located. Given estimates of the amount of replication catalyzed by Pols α,
δ
, and
ε
, the results are consistent with the possibility that more than 10,000 rNMPs may be incorporated into the nuclear genome during each round of replication in yeast. Thus, rNMPs may be the most common noncanonical nucleotides introduced into the eukaryotic genome. Potential beneficial and negative consequences of abundant ribonucleotide incorporation into DNA are discussed, including the possibility that unrepaired rNMPs in DNA could be problematic because yeast DNA polymerase
ε
has difficulty bypassing a single rNMP present within a DNA template.
In vivo vomeronasal stimulation reveals sensory encoding of conspecific and allospecific cues by the mouse accessory olfactory bulb
Authors: Ben-Shaul Y. , Katz L. C. , Mooney R. , Dulac C.
Published: March 2010

The rodent vomeronasal system plays a critical role in mediating pheromone-evoked social and sexual behaviors. Recent studies of the anatomical and molecular architecture of the vomeronasal organ (VNO) and of its synaptic target, the accessory olfactory bulb (AOB), have suggested that unique features underlie vomeronasal sensory processing. However, the neuronal representation of pheromonal information leading to specific behavioral and endocrine responses has remained largely unexplored due to the experimental difficulty of precise stimulus delivery to the VNO. To determine the basic rules of information processing in the vomeronasal system, we developed a unique preparation that allows controlled and repeated stimulus delivery to the VNO and combined this approach with multisite recordings of neuronal activity in the AOB. We found that urine, a well-characterized pheromone source in mammals, as well as saliva, activates AOB neurons in a manner that reliably encodes the donor animal’s sexual and genetic status. We also identified a significant fraction of AOB neurons that respond robustly and selectively to predator cues, suggesting an expanded role for the vomeronasal system in both conspecific and interspecific recognition. Further analysis reveals that mixed stimuli from distinct sources evoke synergistic responses in AOB neurons, thereby supporting the notion of integrative processing of chemosensory information.