An Online Decision-Theoretic Pipeline for Responder Dispatch

The problem of dispatching emergency responders to service traffic accidents, fire, distress calls and crimes plagues urban areas across the globe. While such problems have been extensively looked at, most approaches are offline. Such methodologies fail to capture the dynamically changing environments under which critical emergency response occurs, and therefore, fail to be implemented in practice. Any holistic approach towards creating a pipeline for effective emergency response must also look at other challenges that it subsumes - predicting when and where incidents happen and understanding the changing environmental dynamics. We describe a system that collectively deals with all these problems in an online manner, meaning that the models get updated with streaming data sources. We highlight why such an approach is crucial to the effectiveness of emergency response, and present an algorithmic framework that can compute promising actions for a given decision-theoretic model for responder dispatch. We argue that carefully crafted heuristic measures can balance the trade-off between computational time and the quality of solutions achieved and highlight why such an approach is more scalable and tractable than traditional approaches. We also present an online mechanism for incident prediction, as well as an approach based on recurrent neural networks for learning and predicting environmental features that affect responder dispatch. We compare our methodology with prior state-of-the-art and existing dispatch strategies in the field, which show that our approach results in a reduction in response time with a drastic reduction in computational time.Comment: Appeared in ICCPS 201

Does microbicide use in consumer products promote antimicrobial resistance? A critical review and recommendations for a cohesive approach to risk assessment

The increasing use of microbicides in consumer products is raising concerns related to enhanced microbicide resistance in bacteria and potential cross resistance to antibiotics. The recently published documents on this topic from the European Commission have spawned much interest to better understand the true extent of the putative links for the benefit of the manufacturers, regulators, and consumers alike. This white paper is based on a 2-day workshop (SEAC-Unilever, Bedford, United Kingdom; June 2012) in the fields of microbicide usage and resistance. It identifies gaps in our knowledge and also makes specific recommendations for harmonization of key terms and refinement/standardization of methods for testing microbicide resistance to better assess the impact and possible links with cross resistance to antibiotics. It also calls for a better cohesion in research in this field. Such information is crucial to developing any risk assessment framework on microbicide use notably in consumer products. The article also identifies key research questions where there are inadequate data, which, if addressed, could promote improved knowledge and understanding to assess any related risks for consumer and environmental safety

Microstructures in Metasedimentary Rocks from the Neoproterozoic Bonahaven Formation, Scotland: Microconcretions, Impact Spherules, or Microfossils?

Microscopic spherules in relatively undeformed mudstones of the Neoproterozoic Bonahaven Formation, Islay, Scotland, are differentiated from their matrix by a sharp micron-scale, smoothly rounded boundary. These elongate spherules were earlier interpreted as hollow bodies filled penecontemporaneously by glauconite and subsequently metamorphosed to phengite, but their origin remains a matter of debate. Spherules observed in thin section are predominantly rounded (∼74%) but can exhibit a flat edge or protrusion at one end. In 11% of a sample population, two or more spherules are conjoined. X-ray diffraction indicates that spherule-bearing mudstones consist mainly of muscovite, with variable amounts of kaolin-group minerals and minor iron-chlorites. A range of physical origins for the spherules – including microconcretions or metamorphic microstructures; deposition from the sky as micrometeorites, microtektites/microkrystites, or accretionary volcanic ash particles; and detrital grains – is considered but rejected on distributional, morphological, and mineralogical evidence. Biological origins are considered most likely, especially protistan tests similar to the vase-shaped microfossils found in somewhat older Neoproterozoic rocks. If correct, this provides the first report of eukaryotic life in the Dalradian succession that passes critical tests for biogenicity and new evidence for testate microfossils in post-Sturtian but pre-Marinoan aged rocks.Earth and Planetary SciencesOrganismic and Evolutionary Biolog

Biologically Induced Initiation of Neoproterozoic Snowball-Earth Events

The glaciations of the Neoproterozoic Era (1,000 to 542 MyBP) were preceded by dramatically light C isotopic excursions preserved in preglacial deposits. Standard explanations of these excursions involve remineralization of isotopically light organic matter and imply strong enhancement of atmospheric $CO_2$ greenhouse gas concentration, apparently inconsistent with the glaciations that followed. We examine a scenario in which the isotopic signal, as well as the global glaciation, result from enhanced export of organic matter from the upper ocean into anoxic subsurface waters and sediments. The organic matter undergoes anoxic remineralization at depth via either sulfate- or iron-reducing bacteria. In both cases, this can lead to changes in carbonate alkalinity and dissolved inorganic pool that efficiently lower the atmospheric $CO_2$ concentration, possibly plunging Earth into an ice age. This scenario predicts enhanced deposition of calcium carbonate, the formation of siderite, and an increase in ocean pH, all of which are consistent with recent observations. Late Neoproterozoic diversification of marine eukaryotes may have facilitated the episodic enhancement of export of organic matter from the upper ocean, by causing a greater proportion of organic matter to be partitioned as particulate aggregates that can sink more efficiently, via increased cell size, biomineralization or increased C∶N of eukaryotic phytoplankton. The scenario explains isotopic excursions that are correlated or uncorrelated with snowball initiation, and suggests that increasing atmospheric oxygen concentrations and a progressive oxygenation of the subsurface ocean helped to prevent snowball glaciation on the Phanerozoic Earth.Earth and Planetary Science

A Basin Redox Transect at the Dawn of Animal Life

Multiple eukaryotic clades make their first appearance in the fossil record between ~810 and 715 Ma. Molecular clock studies suggest that the origin of animal multicellularity may have been part of this broader eukaryotic radiation. Animals require oxygen to fuel their metabolism, and low oxygen levels have been hypothesized to account for the temporal lag between metazoan origins and the Cambrian radiation of large, ecologically diverse animals. Here, paleoredox conditions were investigated in the Fifteenmile Group, Ogilvie Mountains, Yukon, Canada, which hosts an 811 Ma ash horizon and spans the temporal window that captures the inferred origin and early evolution of animals. Iron-based redox proxies, redox-sensitive trace elements, organic carbon percentages and pyrite sulfur isotopes were analyzed in seven stratigraphic sections along two parallel basin transects. These data suggest that for this basin, oxygenated shelf waters overlay generally anoxic deeper waters. The anoxic water column was dominantly ferruginous, but brief periods of euxinia likely occurred. These oscillations coincide with changes in total organic carbon, suggesting euxinia was primarily driven by increased organic carbon loading. Overall, these data are consistent with proposed quantitative constraints on Proterozoic atmospheric oxygen being greater than 1% of modern levels, but less than present levels. Comparing these oxygen levels against the likely oxygen requirements of the earliest animals, both theoretical considerations and the ecology of modern oxygen-deficient settings suggest that the inferred oxygen levels in the mixed layer would not have been prohibitive to the presence of sponges, eumetazoans or bilaterians. Thus the evolution of the earliest animals was probably not limited by the low absolute oxygen levels that may have characterized Neoproterozoic oceans, although these inferred levels would constrain animals to very small sizes and low metabolic rates.Earth and Planetary SciencesOrganismic and Evolutionary Biolog

An evaluation of the complement-regulating activities of human complement factor H (FH) variants associated with age-related macular degeneration

PURPOSE: Factor H (FH, encoded by CFH) prevents activation of the complement system's alternative pathway (AP) on host tissues. FH impedes C3 convertase (C3bBb) formation, accelerates C3bBb decay, and is a cofactor for factor I (FI)–catalyzed C3b cleavage. Numerous CFH variants are associated with age-related macular degeneration (AMD), but their functional consequences frequently remain undetermined. Here, we conduct functional comparisons between a control version of FH (not AMD linked) and 21 AMD-linked FH variants. METHODS: Recombinantly produced, untagged, full-length FH versions were assayed for binding to C3b and decay acceleration of C3bBb using surface-plasmon resonance, FI-cofactor activity using a fluorescent probe of C3b integrity, suppression of C5b-9 assembly on an AP-activating surface, and inhibition of human AP-mediated lysis of sheep erythrocytes. RESULTS: All versions were successfully purified despite below-average yields for Arg2Thr, Arg53Cys, Arg175Pro, Arg175Gln, Ile221Val, Tyr402His, Pro503Ala, Arg567Gly, Gly1194Asp, and Arg1210Cys. Compared to control FH, Arg2Thr, Leu3Val, Ser58Ala, Asp90Gly, Asp130Asn, Gln400Lys, Tyr402His, Gly650Val, Ser890Ile, and Thr965Met showed minimal functional differences. Arg1210C, Arg53His, Arg175Gln, Gly1194Asp, Pro503Ala, Arg53Cys, Arg576Gly, and Arg175Pro (in order of decreasing efficacy) underperformed, while Ile221Val, Arg303Gln, and Arg303Trp were “marginal.” We newly identified variants toward the center of the molecule, Pro503Ala and Arg567Gly, as potentially pathogenic. CONCLUSIONS: Our approach could be extended to other variants of uncertain significance and to assays for noncanonical FH activities, aiming to facilitate selection of cohorts most likely to benefit from therapeutic FH. This is timely as recombinant therapeutic FH is in development for intravitreal treatment of AMD in patients with reduced FH functionality

Molecular Investigations of PenA-mediated β-lactam Resistance in Burkholderia pseudomallei

Burkholderia pseudomallei is the etiological agent of melioidosis. Because of the bacterium’s intrinsic resistance and propensity to establish latent infections, melioidosis therapy is complicated and prolonged. Newer generation β-lactams, specifically ceftazidime, are used for acute phase therapy, but resistance to this cephalosporin has been observed. The chromosomally encoded penA gene encodes a putative twin arginine translocase (TAT)-secreted β-lactamase, and penA mutations have been implicated in ceftazidime resistance in clinical isolates. However, the role of PenA in resistance has not yet been systematically studied in isogenetic B. pseudomallei mutant backgrounds. We investigated the effects of penA deletion, point mutations, and up-regulation, as well as tat operon deletion and PenA TAT-signal sequence mutations. These experiments were made possible by employing a B. pseudomallei strain that is excluded from Select Agent regulations. Deletion of penA significantly (>4-fold) reduced the susceptibility to six of the nine β-lactams tested and ≥16-fold for ampicillin, amoxicillin, and carbenicillin. Overexpression of penA by single-copy, chromosomal expression of the gene under control of the inducible Ptac promoter, increased resistance levels for all β-lactams tested 2- to 10-fold. Recreation of the C69Y and P167S PenA amino acid substitutions previously observed in resistant clinical isolates increased resistance to ceftazidime by ≥85- and 5- to 8-fold, respectively. Similarly, a S72F substitution resulted in a 4-fold increase in resistance to amoxicillin and clavulanic acid. Susceptibility assays with PenA TAT-signal sequence and ΔtatABC mutants, as well as Western blot analysis, confirmed that PenA is a TAT secreted enzyme and not periplasmic but associated with the spheroplastic cell fraction. Lastly, we determined that two LysR-family regulators encoded by genes adjacent to penA do not play a role in transcriptional regulation of penA expression

Structural basis for complement factor H-linked age-related macular degeneration

This is the final version of the article. Available from the publisher via the DOI in this record.Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to approximately 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance-monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG-FH complex.B. Prosser is funded by the Wellcome Trust Structural Biology Training Program (075415/Z/04/Z). S. Johnson and P. Roversi were funded by grants to S.M. Lea from the Medical Research Council (MRC) of the United Kingdom (grants G0400389 and G0400775). D. Uhrin and P.N. Barlow were funded by the Wellcome Trust (078780/ Z/05/Z). S.J. Clark was funded by an MRC Doctoral Training Account (G78/7925), and R.B. Sim and A.J. Day were funded by MRC core funding to the MRC Immunochemistry Unit