DECAL: A Reconfigurable Monolithic Active Pixel Sensor for Tracking and Calorimetry in a 180 nm Image Sensor Process.

In this paper, we describe DECAL, a prototype Monolithic Active Pixel Sensor (MAPS) device designed to demonstrate the feasibility of both digital calorimetry and reconfigurability in ASICs for particle physics. The goal of this architecture is to help reduce the development and manufacturing costs of detectors for future colliders by developing a chip that can operate both as a digital silicon calorimeter and a tracking chip. The prototype sensor consists of a matrix of 64 × 64 55 µm pixels, and provides a readout at 40 MHz of the number of particles which have struck the matrix in the preceding 25 ns. It can be configured to report this as a total sum across the sensor (equivalent to the pad of an analogue calorimeter) or the sum per column (equivalent to a traditional strip detector). The design and operation of the sensor are described, and the results of chip characterisation are reported and compared to simulations.

Investigating mangrove-human health relationships: A review of recently reported physiological benefits.

Ecosystems continue to experience degradation worldwide, with diminishing ecosystem services presenting unfavourable outlooks for all aspects of human wellbeing including health. To inform protective policies that safeguard both ecological and health benefits, syntheses of available knowledge are required especially for neglected ecosystems such as mangroves. However, reviews about relationships between mangroves and human health are rare. This review identifies and categorizes evidence reported in the Web of Science database about health impacts of mangrove ecosystem goods and services. 96 papers were retained after application of exclusion criteria and filtration steps to results of database and bibliographical searches. Findings highlight most abundantly that bioactive extracts of mangrove sediment, plant, and plant associates are useful for the treatment of human ailments and infections. Also reported is the heavy and trace metal bioremediation capacity of mangroves ecosystems, with concomitant modulating effects on associated human health risks. Evidence of mangrove influence on human nutrition via fisheries and food production support services, either singularly or in conjunction with linked ecosystems is also offered. Finally, mangrove effects on the prevalence of causative agents, and therefore on the incidence and distribution of infectious diseases, are also presented. Positive influences of mangroves on human health are implied via three of the four routes reported, which diminish with degradation and appreciate with proper ecosystem functioning. The undesirable links lie chiefly with higher infectious disease risk posed by mangroves, which requires further exploration regarding suspected ecological pathways available for limiting said risks. Other gaps identified are sparse information about in-vivo efficacy and safety of mangrove bioactive isolates, specific nutrient content and diversity associated with mangrove-supported food production outcomes, and the geographically limited nature of most findings. Beyond economic value, health benefits of mangroves are significant and outweigh their disservices to humans. To ensure sustainable supply of the full complement of these benefits, they should be considered when designing ecosystems management regimes.

The EpiTect Methyl qPCR Assay as novel age estimation method in forensic biology.

Human aging is associated with epigenetic modification of the genome. DNA methylation at cytosines appears currently as the best characterised modification that occurs during the mammalian lifetime. Such methylation changes at regulatory region can provide insights to track contributor age for criminal investigation. The EpiTect Methyl II PCR system (QIAGEN) was used to compare methylation levels of CpG islands in the promoter regions of a number of age related genes, of which four successfully showed changes across the lifespan (NPTX2, KCNQ1DN, GRIA2 and TRIM58). This technique is based on the detection of remaining input genome after digestion with a methylation-sensitive restriction enzyme. This study examined DNA specimens from 80 female subjects of various ages (18-91 years) obtained from blood, using primers designed to flank the studied gene loci. The data obtained from DNA methylation quantification showed successful discrimination among volunteered ages. Overall, the difference between predicted and real age was about 11 years and absolute mean differences (AMD) was only 7.2 years error. We suggest the EpiTect system can be used as fast and simple innovative tool in future forensic age estimation.

Quantification of global mitochondrial DNA methylation levels and inverse correlation with age at two CpG sites.

Mammalian ageing features biological attrition evident at cellular, genetic and epigenetic levels. Mutation of mitochondrial DNA, and nuclear DNA methylation changes are well established correlates of ageing. The methylation of mitochondrial DNA (mtDNA) is a new and incompletely described phenomenon with unknown biological control and significance. Here we describe the bisulphite sequencing of mtDNA from 82 individuals aged 18-91 years. We detected low and variable levels of mtDNA methylation at 54 of 133 CpG sites interrogated. Regression analysis of methylation levels at two CpG sites (M1215 and M1313) located within the 12S ribosomal RNA gene showed an inverse correlation with subject age suggesting their utility as epigenetic markers of ageing.

Committing to place: the potential of open collaborations for trusted environmental governance.

Conventional modes of environmental governance, which typically exclude those stakeholders that are most directly linked to the specific place, frequently fail to have the desired impact. Using the example of lake water management in Loweswater, a small hamlet within the English Lake District, we consider the ways in which new "collectives" for local, bottom-up governance of water bodies can reframe problems in ways which both bind lay and professional people to place, and also recast the meaning of "solutions" in thought-provoking ways.

Advantage of ForensiX Swabs in Retrieving and Preserving Biological Fluids.

This study compares two novel swabs (forensiX) with a standard cotton swab (EUROTUBE) for the collection of saliva stains on glass slide for STR analysis. ForensiX collection tubes are a standard cotton swab in an "active drying" tube, where swab sample is soon dried by its innovative tube surface of the wall. The other is forensiX Nylon Flocked Swab. The study is two phases: The first "phase" assesses swab types regarding to retrieve ability of saliva. The second "phase" compares the drying ability of each swab to assess how crime samples would fare when left in storage. The main result showed that "active drying" is effective to store swabbed sample. The forensiX swabs generally are effective for higher (twofold to fourfold) DNA yield compared to delta lab swab (around 750 pg and 250 pg from 0.5 µL of saliva), respectively. These findings demonstrate the importance of drying performance in the preservation of DNA and swab selection.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs.

The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.

The discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs.

The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.

Integrating water and agricultural management: collaborative governance for a complex policy problem.

This paper examines governance requirements for integrating water and agricultural management (IWAM). The institutional arrangements for the agriculture and water sectors are complex and multi-dimensional, and integration cannot therefore be achieved through a simplistic 'additive' policy process. Effective integration requires the development of a new collaborative approach to governance that is designed to cope with scale dependencies and interactions, uncertainty and contested knowledge, and interdependency among diverse and unequal interests. When combined with interdisciplinary research, collaborative governance provides a viable normative model because of its emphasis on reciprocity, relationships, learning and creativity. Ultimately, such an approach could lead to the sorts of system adaptations and transformations that are required for IWAM.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.

Antithrombotic potential of GW813893: a novel, orally active, active-site directed factor Xa inhibitor.

BACKGROUND: Factor Xa (FXa) has been a target of considerable interest for drug development efforts aimed at suppressing thrombosis. In this report, a new orally active, small molecule, active-site directed FXa inhibitor, GW813893, has been profiled in a succession of in vitro and in vivo assays involved in its preclinical characterization as a potential antithrombotic therapeutic. METHODS: In vitro profiling of GW813893 consisted of assessing its inhibitory potential against FXa and a broad panel of related and unrelated enzymes and receptors. Additionally, the FXa inhibition potential of GW813893 was assessed in prothrombinase and plasma-based clotting assays. In vivo characterization of GW813893 consisted of thrombosis studies in a rat inferior vena cava model, a rat carotid artery thrombosis model, and a rabbit jugular thrombosis model. Bleeding studies were conducted in a rat tail transection model. Ex vivo determinations of compound effects on FX and clotting activity were also undertaken. RESULTS: GW813893 was more than 90-fold selective over all enzymes tested, and it inhibited FXa and prothrombinase activity with a Ki of 4.0 nM and 9.7 nM, respectively. In vivo, GW813893 concentration-dependently suppressed thrombotic activity in all models tested. The antithrombotic activity correlated with the suppression of plasma-based clotting activity and the inhibition of plasma FX activity (P < 0.02). Over the antithrombotic dose-range, an increased bleeding diathesis was not observed. CONCLUSION: These experiments demonstrate that GW813893 is a potent, selective, orally active inhibitor of FXa. The data suggest that GW813893 has robust antithrombotic potential at doses that have no detectable hemostasis liability. Collectively, the profile suggests that GW813893 has the preclinical pharmacology underpinnings of an oral antithrombotic therapeutic.

Recovery and STR amplification of DNA from RFLP membranes.

Restriction fragment length polymorphism (RFLP) techniques were utilized in the forensic DNA community until the mid 1990s when less labor-intensive polymerase chain reaction short tandem repeat (PCR STR) techniques became available. During the transition from RFLP technology to PCR-based STR platforms, a method for comparing RFLP profiles to STR profiles was not developed. While the preferred approach for applying new technology to old cases would be to analyze the original biological stain, this is not always possible. For unsolved cases that previously underwent RFLP analysis, the only DNA remaining may be restriction cut and bound to nylon membranes. These studies investigate several methods for obtaining STR profiles from membrane bound DNA, including removal of bound DNA with bases, acids, detergents, various chemicals, and conventional cell extraction solutions. Direct multiplex STR amplification of template in the membrane-bound state was also explored. A partial STR profile was obtained from DNA that was recovered from an archived membrane using conventional extraction buffer components, indicating promise for recovering useful STR information from RFLP membranes that have been maintained in long-term frozen storage.

Monolithic Active Pixel Sensors (MAPS) in a Quadruple Well Technology for Nearly 100% Fill Factor and Full CMOS Pixels.

In this paper we present a novel, quadruple well process developed in a modern 0.18 mm CMOS technology called INMAPS. On top of the standard process, we have added a deep P implant that can be used to form a deep P-well and provide screening of N-wells from the P-doped epitaxial layer. This prevents the collection of radiation-induced charge by unrelated N-wells, typically ones where PMOS transistors are integrated. The design of a sensor specifically tailored to a particle physics experiment is presented, where each 50 mm pixel has over 150 PMOS and NMOS transistors. The sensor has been fabricated in the INMAPS process and first experimental evidence of the effectiveness of this process on charge collection is presented, showing a significant improvement in efficiency.

Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.

Selective and dual action orally active inhibitors of thrombin and factor Xa.

The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.

Sulfonamide-related conformational effects and their importance in structure-based design.

Structure-based design (SBD) is a challenging endeavour since even localised SAR can hardly ever be explained by the variation of just one dominating factor. Here, we present a rare example where structural information combined with ab initio calculations clearly indicate that the observed difference in biological activity is dominated by conformational effects. The learnings discussed are successfully put to the test and have the potential to be of general use as a qualitative guide in SBD efforts.

Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.

Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

Evaluation of six presumptive tests for blood, their specificity, sensitivity, and effect on high molecular-weight DNA.

Luminol, leuchomalachite green, phenolphthalein, Hemastix, Hemident, and Bluestar are all used as presumptive tests for blood. In this study, the tests were subjected to dilute blood (from 1:10,000 to 1:10,000,000), many common household substance, and chemicals. Samples were tested for DNA to determine whether the presumptive tests damaged or destroyed DNA. The DNA loci tested were D2S1338 and D19S433. Leuchomalachite green had a sensitivity of 1:10,000, while the remaining tests were able to detect blood to a dilution of 1:100,000. Substances tested include saliva, semen, potato, tomato, tomato sauce, tomato sauce with meat, red onion, red kidney bean, horseradish, 0.1 M ascorbic acid, 5% bleach, 10% cupric sulfate, 10% ferric sulfate, and 10% nickel chloride. Of all the substances tested, not one of the household items reacted with every test; however, the chemicals did. DNA was recovered and amplified from luminol, phenolphthalein, Hemastix, and Bluestar, but not from leuchomalachite green or Hemident.