Synthetic Heparan Sulfate Oligosaccharides Inhibit Endothelial Cell Functions Essential for Angiogenesis

Heparan sulfate (HS) is an important regulator of the assembly and activity of various angiogenic signalling complexes. However, the significance of precisely defined HS structures in regulating cytokine-dependent angiogenic cellular functions and signalling through receptors regulating angiogenic responses remains unclear. Understanding such structure-activity relationships is important for the rational design of HS fragments that inhibit HS-dependent angiogenic signalling complexes.We synthesized a series of HS oligosaccharides ranging from 7 to 12 saccharide residues that contained a repeating disaccharide unit consisting of iduronate 2-O-sulfate linked to glucosamine with or without N-sulfate. The ability of oligosaccharides to compete with HS for FGF2 and VEGF165 binding significantly increased with oligosaccharide length and sulfation. Correspondingly, the inhibitory potential of oligosaccharides against FGF2- and VEGF165-induced endothelial cell responses was greater in longer oligosaccharide species that were comprised of disaccharides bearing both 2-O- and N-sulfation (2SNS). FGF2- and VEGF165-induced endothelial cell migration were inhibited by longer 2SNS oligosaccharide species with 2SNS dodecasaccharide activity being comparable to that of receptor tyrosine kinase inhibitors targeting FGFR or VEGFR-2. Moreover, the 2SNS dodecasaccharide ablated FGF2- or VEGF165-induced phosphorylation of FAK and assembly of F-actin in peripheral lamellipodia-like structures. In contrast, FGF2-induced endothelial cell proliferation was only moderately inhibited by longer 2SNS oligosaccharides. Inhibition of FGF2- and VEGF165-dependent endothelial tube formation strongly correlated with oligosaccharide length and sulfation with 10-mer and 12-mer 2SNS oligosaccharides being the most potent species. FGF2- and VEGF165-induced activation of MAPK pathway was inhibited by biologically active oligosaccharides correlating with the specific phosphorylation events in FRS2 and VEGFR-2, respectively.These results demonstrate structure-function relationships for synthetic HS saccharides that suppress endothelial cell migration, tube formation and signalling induced by key angiogenic cytokines

The impacts of changing transport and precipitation on pollutant distributions in a future climate

Air pollution (ozone and particulate matter in surface air) is strongly linked to synoptic weather and thus is likely sensitive to climate change. In order to isolate the responses of air pollutant transport and wet removal to a warming climate, we examine a simple carbon monoxide–like (CO) tracer (COt) and a soluble version (SAt), both with the 2001 CO emissions, in simulations with the Geophysical Fluid Dynamics Laboratory chemistry-climate model (AM3) for present (1981–2000) and future (2081–2100) climates. In 2081–2100, projected reductions in lower-tropospheric ventilation and wet deposition exacerbate surface air pollution as evidenced by higher surface COt and SAt concentrations. However, the average horizontal general circulation patterns in 2081–2100 are similar to 1981–2000, so the spatial distribution of COt changes little. Precipitation is an important factor controlling soluble pollutant wet removal, but the total global precipitation change alone does not necessarily indicate the sign of the soluble pollutant response to climate change. Over certain latitudinal bands, however, the annual wet deposition change can be explained mainly by the simulated changes in large-scale (LS) precipitation. In regions such as North America, differences in the seasonality of LS precipitation and tracer burdens contribute to an apparent inconsistency of changes in annual wet deposition versus annual precipitation. As a step toward an ultimate goal of developing a simple index that can be applied to infer changes in soluble pollutants directly from changes in precipitation fields as projected by physical climate models, we explore here a “Diagnosed Precipitation Impact” (DPI) index. This index captures the sign and magnitude (within 50%) of the relative annual mean changes in the global wet deposition of the soluble pollutant. DPI can only be usefully applied in climate models in which LS precipitation dominates wet deposition and horizontal transport patterns change little as climate warms. Our findings support the need for tighter emission regulations, for both soluble and insoluble pollutants, to obtain a desired level of air quality as climate warms

The listening talker: A review of human and algorithmic context-induced modifications of speech

International audienceSpeech output technology is finding widespread application, including in scenarios where intelligibility might be compromised - at least for some listeners - by adverse conditions. Unlike most current algorithms, talkers continually adapt their speech patterns as a response to the immediate context of spoken communication, where the type of interlocutor and the environment are the dominant situational factors influencing speech production. Observations of talker behaviour can motivate the design of more robust speech output algorithms. Starting with a listener-oriented categorisation of possible goals for speech modification, this review article summarises the extensive set of behavioural findings related to human speech modification, identifies which factors appear to be beneficial, and goes on to examine previous computational attempts to improve intelligibility in noise. The review concludes by tabulating 46 speech modifications, many of which have yet to be perceptually or algorithmically evaluated. Consequently, the review provides a roadmap for future work in improving the robustness of speech output

Importance of carbon-nitrogen interactions and ozone on ecosystem hydrology during the 21st century

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 114 (2009): G01020, doi:10.1029/2008JG000826.There is evidence that increasing CO2 concentrations have reduced evapotranspiration and increased runoff through reductions in stomatal conductance during the twentieth century. While this process will continue to counteract increased evapotranspiration associated with future warming, it is highly dependent upon concurrent changes in photosynthesis, especially due to CO2 fertilization, nitrogen limitation, and ozone exposure. A new version of the Terrestrial Ecosystem Model (TEM-Hydro) was developed to examine the effects of carbon and nitrogen on the water cycle. We used two climate models (NCAR CCSM3 and DOE PCM) and two emissions scenarios (SRES B1 and A2) to examine the effects of climate, elevated CO2, nitrogen limitation, and ozone exposure on the hydrological cycle in the eastern United States. While the direction of future runoff changes is largely dependent upon predicted precipitation changes, the effects of elevated CO2 on ecosystem function (stomatal closure and CO2 fertilization) increase runoff by 3–7%, as compared to the effects of climate alone. Consideration of nitrogen limitation and ozone damage on photosynthesis increases runoff by a further 6–11%. Failure to consider the effects of the interactions among nitrogen, ozone, and elevated CO2 may lead to significant regional underestimates of future runoff.This study was funded by the Interdisciplinary Science Program of the U.S. National Aeronautics and Space Administration (NNG04GJ80G, NNG04GM39G), the Dynamic Global Economic Modeling of Greenhouse Gas Emissions and Mitigation from Land-Use Activities of the U.S. Environmental Protection Agency (XA-83240101), and the Nonlinear Response to Global Change in Linked Aquatic and Terrestrial Ecosystems of the U.S. EPA (XA-83326101)

Working with Language: A Refocused Research Agenda for Cultural Leadership Studies

© 2016 British Academy of Management and John Wiley & Sons Ltd This paper critically reviews existing contributions from the field of cultural leadership studies with a view to highlighting the conceptual and methodological limitations of the dominant etic, cross-cultural approach in leadership studies and illuminating implications of the relative dominance and unreflective use of the English language as the academic and business lingua franca within this field. It subsequently outlines the negative implications of overlooking cultural and linguistic multiplicity for an understanding of culturally sensitive leadership practices. In drawing on lessons from this critical review and the emergent fields of emic, non-positivist cultural leadership studies, this analysis argues that the field of cultural leadership studies requires an alternative research agenda focused on language multiplicity, which enables the field to move towards emic, qualitative research that helps to empower individual cultural voices and explore cultural intra- and interrelationships, tensions and paradoxes embedded in leadership processes. The paper concludes by offering suggestions on methodological approaches for emic cultural leadership studies that are centred on the exploration of language as a cultural voice

Final devoicing and vowel lengthening in Friulian: A representational approach

This paper proposes an account of final devoicing in Friulian which relies on contrastive feature specification and feature geometry to explicate the connection between final devoicing and vowel lengthening. It is proposed that obstruents which are the outcome of final devoicing are phonologically distinct from true voiceless obstruents, being completely unspecified for laryngeal features. It is argued that the representational deficiency of such delaryngealized obstruents is directly connected to their inability to license a mora, which opens the way to vowel lengthening. More generally, the paper shows how feature geometrymay be adapted to capture the effects of contrastive specification and express markedness relations, and proposes a novel approach to hierarchies involving the sonority of coda segments

Histological analysis of surgical lumbar intervertebral disc tissue provides evidence for an association between disc degeneration and increased body mass index

<p>Abstract</p> <p>Background</p> <p>Although histopathological grading systems for disc degeneration are frequently used in research, they are not yet integrated into daily care routine pathology of surgical samples. Therefore, data on histopathological changes in surgically excised disc material and their correlation to clinical parameters such as age, gender or body mass index (BMI) is limited to date. The current study was designed to correlate major physico-clinical parameters from a population of orthopaedic spine center patients (gender, age and BMI) with a quantitative histologic degeneration score (HDS).</p> <p>Methods</p> <p>Excised lumbar disc material from 854 patients (529 men/325 women/mean age 56 (15-96) yrs.) was graded based on a previously validated histologic degeneration score (HDS) in a cohort of surgical disc samples that had been obtained for the treatment of either disc herniation or discogenic back pain. Cases with obvious inflammation, tumor formation or congenital disc pathology were excluded. The degree of histological changes was correlated with sex, age and BMI.</p> <p>Results</p> <p>The HDS (0-15 points) showed significantly higher values in the nucleus pulposus (NP) than in the annulus fibrosus (AF) (Mean: NP 11.45/AF 7.87), with a significantly higher frequency of histomorphological alterations in men in comparison to women. Furthermore, the HDS revealed a positive significant correlation between the BMI and the extent of histological changes. No statistical age relation of the degenerative lesions was seen.</p> <p>Conclusions</p> <p>This study demonstrated that histological disc alterations in surgical specimens can be graded in a reliable manner based on a quantitative histologic degeneration score (HDS). Increased BMI was identified as a positive risk factor for the development of symptomatic, clinically significant disc degeneration.</p

Guidelines for Family-Centered Care in the Neonatal, Pediatric, and Adult ICU.

OBJECTIVE: To provide clinicians with evidence-based strategies to optimize the support of the family of critically ill patients in the ICU. METHODS: We used the Council of Medical Specialty Societies principles for the development of clinical guidelines as the framework for guideline development. We assembled an international multidisciplinary team of 29 members with expertise in guideline development, evidence analysis, and family-centered care to revise the 2007 Clinical Practice Guidelines for support of the family in the patient-centered ICU. We conducted a scoping review of qualitative research that explored family-centered care in the ICU. Thematic analyses were conducted to support Population, Intervention, Comparison, Outcome question development. Patients and families validated the importance of interventions and outcomes. We then conducted a systematic review using the Grading of Recommendations, Assessment, Development and Evaluations methodology to make recommendations for practice. Recommendations were subjected to electronic voting with pre-established voting thresholds. No industry funding was associated with the guideline development. RESULTS: The scoping review yielded 683 qualitative studies; 228 were used for thematic analysis and Population, Intervention, Comparison, Outcome question development. The systematic review search yielded 4,158 reports after deduplication and 76 additional studies were added from alerts and hand searches; 238 studies met inclusion criteria. We made 23 recommendations from moderate, low, and very low level of evidence on the topics of: communication with family members, family presence, family support, consultations and ICU team members, and operational and environmental issues. We provide recommendations for future research and work-tools to support translation of the recommendations into practice. CONCLUSIONS: These guidelines identify the evidence base for best practices for family-centered care in the ICU. All recommendations were weak, highlighting the relative nascency of this field of research and the importance of future research to identify the most effective interventions to improve this important aspect of ICU care

Who benefits from environmental policy? An environmental justice analysis of air quality change in Britain, 2001-2011

Air quality in Great Britain has improved in recent years, but not enough to prevent the European Commission (EC) taking legal action for non-compliance with limit values. Air quality is a national public health concern, with disease burden associated with current air quality estimated at 29 000 premature deaths per year due to fine particulates, with a further burden due to NO2. National small-area analyses showed that in 2001 poor air quality was much more prevalent in socioeconomically deprived areas. We extend this social distribution of air quality analysis to consider how the distribution changed over the following decade (2001-2011), a period when significant efforts to meet EC air quality directive limits have been made, and air quality has improved. We find air quality improvement is greatest in the least deprived areas, whilst the most deprived areas bear a disproportionate and rising share of declining air quality including non-compliance with air quality standards. We discuss the implications for health inequalities, progress towards environmental justice, and compatibility of social justice and environmental sustainability objectives

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701