Exploring the DNA-recognition potential of homeodomains

The recognition potential of most families of DNA-binding domains (DBDs) remains relatively unexplored. Homeodomains (HDs), like many other families of DBDs, display limited diversity in their preferred recognition sequences. To explore the recognition potential of HDs, we utilized a bacterial selection system to isolate HD variants, from a randomized library, that are compatible with each of the 64 possible 3′ triplet sites (i.e., TAANNN). The majority of these selections yielded sets of HDs with overrepresented residues at specific recognition positions, implying the selection of specific binders. The DNA-binding specificity of 151 representative HD variants was subsequently characterized, identifying HDs that preferentially recognize 44 of these target sites. Many of these variants contain novel combinations of specificity determinants that are uncommon or absent in extant HDs. These novel determinants, when grafted into different HD backbones, produce a corresponding alteration in specificity. This information was used to create more explicit HD recognition models, which can inform the prediction of transcriptional regulatory networks for extant HDs or the engineering of HDs with novel DNA-recognition potential. The diversity of recovered HD recognition sequences raises important questions about the fitness barrier that restricts the evolution of alternate recognition modalities in natural systems

Mechanized Metatheory for the Masses: The \u3cb\u3ePOPLMARK\u3c/b\u3e Challenge

How close are we to a world where every paper on programming languages is accompanied by an electronic appendix with machinechecked proofs? We propose an initial set of benchmarks for measuring progress in this area. Based on the metatheory of System F, a typed lambda-calculus with second-order polymorphism, subtyping, and records, these benchmarks embody many aspects of programming languages that are challenging to formalize: variable binding at both the term and type levels, syntactic forms with variable numbers of components (including binders), and proofs demanding complex induction principles. We hope that these benchmarks will help clarify the current state of the art, provide a basis for comparing competing technologies, and motivate further research

3D Air Quality and the Clean Air Interstate Rule: Lagrangian Sampling of CMAQ Model Results to Aid Regional Accountability Metrics

The Clean Air Interstate Rule (CAIR) is expected to reduce transport of air pollutants (e.g. fine sulfate particles) in nonattainment areas in the Eastern United States. CAIR highlights the need for an integrated air quality observational and modeling system to understand sulfate as it moves in multiple dimensions, both spatially and temporally. Here, we demonstrate how results from an air quality model can be combined with a 3d monitoring network to provide decision makers with a tool to help quantify the impact of CAIR reductions in SO2 emissions on regional transport contributions to sulfate concentrations at surface monitors in the Baltimore, MD area, and help improve decision making for strategic implementation plans (SIPs). We sample results from the Community Multiscale Air Quality (CMAQ) model using ensemble back trajectories computed with the NASA Langley Research Center trajectory model to provide Lagrangian time series and vertical profile information, that can be compared with NASA satellite (MODIS), EPA surface, and lidar measurements. Results are used to assess the regional transport contribution to surface SO4 measurements in the Baltimore MSA, and to characterize the dominant source regions for low, medium, and high SO4 episodes

A Questionnaire on "Diaspora and the Modern"

The twentieth century was deeply grooved with the trodden pathways of mass migrations. These journeys were propelled by violence and historical cataclysm: pogroms and genocides; natural and unnatural famines and disasters; land dispossession, regimes of apartheid and forced labor; revolution, war, and occupation; colonization and decolonization; and the realignments that followed in their wake. The pioneering sociologist W. E. B. Du Bois may have been the first to herald the character of the new century: Already in 1903, in his treatise The Souls of Black Folk, he situated “the color line” as the defining “problem of the twentieth century” in relation to diaspora. Theorists and writers as diverse as Georg Simmel, Paul Gilroy, E?douard Glissant, Kobena Mercer, Tony Judt, Brent Hayes Edwards, Fred Moten, Krista Thompson, Huey Copeland, and Saidiya Hartman have offered frameworks for understanding diaspora as a cultural formation inextricable from modernity itself. As their work suggests, diasporic thinking puts pressure on the ways that we have understood—and often continue to understand—both modernism and the modern. It counters linear narratives of time, geography, and memory; identities defined by national boundaries; the absence of concerns about race and the complicity that modernisms have had with regimes of power; and a vision of the modern severed from heritage or tradition. Yet despite the diasporic displacements that define the modern period, modernist studies within art history have often favored bounded narrative formations still fundamentally shaped by ideas of the individual and the nation-state as well as taxonomic categorizations according to style, movement, medium, and period. In part, these narrative choices both produce and are symptomatic of a deeply siloed field, cleaved into regional micro-domains (Americanists, Mexicanists); medium specialists (photo people and print people); and the imagined ruptures between the mod- ern and the contemporary, the modern and the postmodern, and the Western and the non-Western. Departmental structures, journals, job markets, museums, and galleries are still siloed by race, siphoned into forms of intellectual segregation that are normalized to an extraordinary degree. Art history, in other words, is divided. Given this, what should we do with the modern? The questions are many: How does attention to diasporic thinking shift our understanding of the modern—or does such thinking invalidate its historical and epistemological claims? How do we create space for the unseen and unthought? How do we write history in a mode skeptical of grand narratives that takes account of darkness as well as light? Or, following Fred Moten's explorations regarding a Black avant-garde: How do notions of avant-gardism put pressure on the ways in which we continue to understand modernism? Does the term “modernism” itself have continued viability and usefulness? If so, to what degree is diaspora—the propulsive vectors and cultural effects of multiple mass migrations—integral to it? Or are modernism and the interests of diaspora antithetical frameworks for the history of art, given what the former has historically enabled and repressed? And, finally, what methodological approaches might reveal its structuring forces in our approach to the cultural objects of the modern period? (Leah Dickerman for the Editors.

A multi-institutional study of outcomes in stage I–III uterine carcinosarcoma

To evaluate the use of adjuvant therapy after primary surgery for stage I–III uterine carcinosarcoma (CS)

Landscapes in transition: an analysis of sustainable policy initiatives and emerging corporate commitments in the palm oil industry

The recent Southeast Asian haze crisis has generated intense public scrutiny over the rate, methods and types of landscape change in the tropics. Debate has centred on the environmental impacts of large-scale agricultural expansion, particularly the associated loss of high carbon stock forest and forests of high conservation value. Focusing on palm oil—a versatile food crop and source of bioenergy—this paper analyses national, international and corporate policy initiatives in order to clarify the current and future direction of oil palm expansion in Malaysia and Indonesia. The policies of ‘zero burn’, ‘no deforestation’ and ‘no planting on peatlands’ are given particular emphasis in the paper. The landscape implications of corporate commitments are analysed to determine the amount of land, land types and geographies that could be affected in the future. The paper concludes by identifying key questions related to the further study of sustainable land use policy and practice

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Regional differentiation of felid vertebral column evolution: a study of 3D shape trajectories

Recent advances in geometric morphometrics provide improved techniques for extraction of biological information from shape and have greatly contributed to the study of ecomorphology and morphological evolution. However, the vertebral column remains an under-studied structure due in part to a concentration on skull and limb research, but most importantly because of the difficulties in analysing the shape of a structure composed of multiple articulating discrete units (i.e. vertebrae). Here, we have applied a variety of geometric morphometric analyses to three-dimensional landmarks collected on 19 presacral vertebrae to investigate the influence of potential ecological and functional drivers, such as size, locomotion and prey size specialisation, on regional morphology of the vertebral column in the mammalian family Felidae. In particular, we have here provided a novel application of a method—phenotypic trajectory analysis (PTA)—that allows for shape analysis of a contiguous sequence of vertebrae as functionally linked osteological structures. Our results showed that ecological factors influence the shape of the vertebral column heterogeneously and that distinct vertebral sections may be under different selection pressures. While anterior presacral vertebrae may either have evolved under stronger phylogenetic constraints or are ecologically conservative, posterior presacral vertebrae, specifically in the post-T10 region, show significant differentiation among ecomorphs. Additionally, our PTA results demonstrated that functional vertebral regions differ among felid ecomorphs mainly in the relative covariation of vertebral shape variables (i.e. direction of trajectories, rather than in trajectory size) and, therefore, that ecological divergence among felid species is reflected by morphological changes in vertebral column shape

Removing the invisibility cloak: Using space design to influence patron behavior and increase service desk usage

In small branch libraries, patrons seeking assistance from library staff outside of the dedicated single-service desk often results in large staffing inefficiencies. This paper presents a case study in which the authors applied behavioral psychology models to a branch library’s space arrangement to identify possible factors influencing patron service point choices. A subsequent full space rearrangement was instituted which utilized human behavior research, service desk design principles, and low-cost methods to create a space that reduced barriers and influenced patrons back to the main service desk. The paper reports on the 11-month study that followed and the impact the rearrangement had on patron behavior. Results indicate that simple rearrangement of existing furniture and equipment into new configurations have direct influence on service desk usage and can encourage new patron behaviors. Space and human behavior are inherently connected and library managers should establish goals for how they envision their spaces to be used and arrange them in ways that encourage wanted behaviors.Ye

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology