Toward the Next Generation of Air Quality Monitoring Indicators

This paper introduces an initiative to bridge the state of scientific knowledge on air pollution with the needs of policymakers and stakeholders to design the "next generation" of air quality indicators. As a first step this initiative assesses current monitoring and modeling associated with a number of important pollutants with an eye toward identifying knowledge gaps and scientific needs that are a barrier to reducing air pollution impacts on human and ecosystem health across the globe. Four outdoor air pollutants were considered e particulate matter, ozone, mercury, and Persistent Organic Pollutants (POPs) e because of their clear adverse impacts on human and ecosystem health and because of the availability of baseline data for assessment for each. While other papers appearing in this issue will address each pollutant separately, this paper serves as a summary of the initiative and presents recommendations for needed investments to provide improved measurement, monitoring, and modeling data for policyrelevant indicators. The ultimate goal of this effort is to enable enhanced public policy responses to air pollution by linking improved data and measurement methods to decision-making through the development of indicators that can allow policymakers to better understand the impacts of air pollution and, along with source attribution based on modeling and measurements, facilitate improved policies to solve it. The development of indicators represents a crucial next step in this process

N-terminal Sumoylation of Centromeric Histone H3 Variant Cse4 Regulates Its Proteolysis To Prevent Mislocalization to Non-centromeric Chromatin

Stringent regulation of cellular levels of evolutionarily conserved centromeric histone H3 variant (CENP-A in humans, CID in flies, Cse4 in yeast) prevents its mislocalization to non-centromeric chromatin. Overexpression and mislocalization of CENP-A has been observed in cancers and leads to aneuploidy in yeast, flies, and human cells. Ubiquitin-mediated proteolysis of Cse4 by E3 ligases such as Psh1 and Sumo-Targeted Ubiquitin Ligase (STUbL) Slx5 prevent mislocalization of Cse4. Previously, we identified Siz1 and Siz2 as the major E3 ligases for sumoylation of Cse4. In this study, we have identified lysine 65 (K65) in Cse4 as a site that regulates sumoylation and ubiquitin-mediated proteolysis of Cse4 by Slx5. Strains expressing cse4 K65R exhibit reduced levels of sumoylated and ubiquitinated Cse4 in vivo. Furthermore, co-immunoprecipitation experiments reveal reduced interaction of cse4 K65R with Slx5, leading to increased stability and mislocalization of cse4 K65R under normal physiological conditions. Based on the increased stability of cse4 K65R in psh1 strains but not in slx5 strains, we conclude that Slx5 targets sumoylated Cse4 K65 for ubiquitination-mediated proteolysis independent of Psh1. In summary, we have identified and characterized the physiological role of Cse4 K65 in sumoylation, ubiquitin-mediated proteolysis, and localization of Cse4 for genome stability

SUMO-Targeted Ubiquitin Ligases (STUbLs) Reduce the Toxicity and Abnormal Transcriptional Activity Associated With a Mutant, Aggregation-Prone Fragment of Huntingtin

Cell viability and gene expression profiles are altered in cellular models of neurodegenerative disorders such as Huntington\u27s Disease (HD). Using the yeast model system, we show that the SUMO-targeted ubiquitin ligase (STUbL) Slx5 reduces the toxicity and abnormal transcriptional activity associated with a mutant, aggregation-prone fragment of huntingtin (Htt), the causative agent of HD. We demonstrate that expression of an aggregation-prone Htt construct with 103 glutamine residues (103Q), but not the non-expanded form (25Q), results in severe growth defects in slx5Delta and slx8Delta cells. Since Slx5 is a nuclear protein and because Htt expression affects gene transcription, we assessed the effect of STUbLs on the transcriptional properties of aggregation-prone Htt. Expression of Htt 25Q and 55Q fused to the Gal4 activation domain (AD) resulted in reporter gene auto-activation. Remarkably, the auto-activation of Htt constructs was abolished by expression of Slx5 fused to the Gal4 DNA-binding domain (BD-Slx5). In support of these observations, RNF4, the human ortholog of Slx5, curbs the aberrant transcriptional activity of aggregation-prone Htt in yeast and a variety of cultured human cell lines. Functionally, we find that an extra copy of SLX5 specifically reduces Htt aggregates in the cytosol as well as chromatin-associated Htt aggregates in the nucleus. Finally, using RNA sequencing, we identified and confirmed specific targets of Htt\u27s transcriptional activity that are modulated by Slx5. In summary, this study of STUbLs uncovers a conserved pathway that counteracts the accumulation of aggregating, transcriptionally active Htt (and possibly other poly-glutamine expanded proteins) on chromatin in both yeast and in mammalian cells

Inability of the Rome III Criteria to Distinguish Functional Constipation From Constipation-Subtype Irritable Bowel Syndrome

The Rome III classification system treats functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) as distinct disorders, but this distinction appears artificial, and the same drugs are used to treat both. This study’s hypothesis is that FC and IBS-C defined by Rome III are not distinct entities

Integrating vehicle design and human factors: minimizing elderly driving constraints

With a projected rise in the number of elderly, most of whom have also relied primarily on the private automobile for their mobility, it is likely that future adaptations in vehicle design will be linked in some part to the physical infirmities often faced by the elderly. This paper offers a bridge between medical research on the physical impairments of the elderly and automobile design and driving safety. We describe recent findings on the driving-related physical and cognitive impairments faced by the elderly. We then propose two major types of vehicle design and infrastructure adaptations: (1) modifications for private vehicles, and (2) intelligent technology and support services for private vehicles, which can help to minimize the driving-related effects of these impairments. For example, we present a range of modest vehicle design adaptations for components such as seats and doorways, handles, knobs, and steering wheels, and seat belts. We find that many of these improvements can be made to standard passenger vehicles with little additional design effort, and that the adaptations should also increase overall vehicle marketability. Finally, we argue that while most, if not all, of our proposed adaptations would be made to largely benefit the elderly, they will nevertheless support and improve driving across all age groups

Ten golden rules for optimal antibiotic use in hospital settings: the WARNING call to action

Antibiotics are recognized widely for their benefits when used appropriately. However, they are often used inappropriately despite the importance of responsible use within good clinical practice. Effective antibiotic treatment is an essential component of universal healthcare, and it is a global responsibility to ensure appropriate use. Currently, pharmaceutical companies have little incentive to develop new antibiotics due to scientific, regulatory, and financial barriers, further emphasizing the importance of appropriate antibiotic use. To address this issue, the Global Alliance for Infections in Surgery established an international multidisciplinary task force of 295 experts from 115 countries with different backgrounds. The task force developed a position statement called WARNING (Worldwide Antimicrobial Resistance National/International Network Group) aimed at raising awareness of antimicrobial resistance and improving antibiotic prescribing practices worldwide. The statement outlined is 10 axioms, or “golden rules,” for the appropriate use of antibiotics that all healthcare workers should consistently adhere in clinical practice

The social structure of Islam.

Cambridge536 p.; 22 cm