The Structural Determinants of Insulin-Like Peptide 3 Activity

Insulin-like peptide 3 (INSL3) is a hormone and/or paracrine factor which is a member of the relaxin peptide family. It has key roles as a fertility regulator in both males and females. The receptor for INSL3 is the leucine rich repeat (LRR) containing G-protein coupled receptor 8 (LGR8) which is now known as relaxin family peptide receptor 2 (RXFP2). Receptor activation by INSL3 involves binding to the LRRs in the large ectodomain of RXFP2 by residues within the B-chain of INSL3 as well as an interaction with the transmembrane exoloops of the receptor. Although the binding to the LRRs is well characterized the features of the peptide and receptor involved in the exoloop interaction are currently unknown. This study was designed to determine the key INSL3 determinants for RXFP2 activation. A chimeric peptide approach was first utilized to demonstrate that the A-chain is critical for receptor activation. Replacement of the INSL3 A-chain with that from the related peptides INSL5 and INSL6 resulted in complete loss of activity despite only minor changes in binding affinity. Subsequent replacement of specific A-chain residues with those from the INSL5 peptide highlighted that the N-terminus of the A-chain of INSL3 is critical for its activity. Remarkably, replacement of the entire N-terminus with four or five alanine residues resulted in peptides with near native activity suggesting that specific residues are not necessary for activity. Additionally removal of two amino acids at the C-terminus of the A-chain and mutation of Lys-8 in the B-chain also resulted in minor decreases in peptide activity. Therefore we have demonstrated that the activity of the INSL3 peptide is driven predominantly by residues 5–9 in the A-chain, with minor additional contributions from the two C-terminal A-chain residues and Lys-8 in the B-chain. Using this new knowledge, we were able to produce a truncated INSL3 peptide structure which retained native activity, despite having 14 fewer residues than the parent peptide

Time-Domain Simulation of Mixed Nonlinear Magnetic and Electronic Systems

This paper describes a technique for the simulation of complex magnetic systems intimately connected to any necessary drive electronics. The system is split into two Kirchhoffian domains, one magnetic and one electric. Two-way interaction between the domains is supported by a virtual device called a magneto-electric differential gyrator. Using this technique, arbitrarily complex, non-linear, hysteretic magnetic systems may be simulated in the time domain, coupled to any appropriate non-linear electronics, at a fraction of the cost of a comparable finite element calculation. The capabilities of the system are demonstrated by the simulation of a feedback-controlled current sensing system, and the simulation tracks the measured behaviour of the system well outside its linear region, to the point that the non-linear hysteretic core is being driven into and out of saturation, a consequence of a time delay inherent in the electronics. This is compared with a simulation of the same system using a 'conventional' electronic simulation, and the increased accuracy of this technique clearly demonstrated

Enhancing the value of Facilities Information Management (FIM) through BIM integration

Building Information Modelling (BIM) provides a robust platform for information management in built environment facilities. However, one of the consequences of the limited application of BIM in facilities information management (FIM) is that the potential value gain through the integration of as-built information during the operations management process has had limited exploration in current practice. This paper attempts to explore the potential impact of BIM to enhance the value of Facilities Information Management. A detailed literature review was undertaken to identify BIM application in a construction context, and to develop a framework to investigate the value of information. An interpretative approach was adopted for data collection and analysis. 14 semi-structured interviews were conducted with construction industry professionals to identify how value of FIM can be enhanced through BIM integration. The interview data were analysed using open and selective coding. The findings confirm that information exchange between the construction and facilities management phases of a project are important in terms of efficient and effective maintenance of a facility as well as optimising the design task. With these promising benefits, BIM is an efficient mechanism to facilitate construction information exchange. However, there is an uncertainty over the optimum level of information that ought to be on a BIM model for facilities management purposes. The relationship between different aspects of value is a starting point to filter the required information for each individual project. In contrast, limited awareness of value of information exchange and the potential of BIM enabled FIM during construction is noted. The information exchange considered within this investigation was limited to two key phases of the facility lifecycle, namely construction and facilities management (in-use). The findings bring insight into an unseen aspect of facilities management information needs that should be given priority in upcoming BIM developments. Also, it draws attention to how value is concerned in a daily basis beyond monetary terms. The investigation of value enhancement through BIM integration in particular to facilities information management and ongoing research with new value dimensions

A model of contingency factors affecting contractors' economic organisation of projects

The identification of factors that affect the performance of temporary multidisciplinary organisational teams has been a central aim of managementresearch in the construction industry for over 40 years. This studycontributes to what is known about the formation of a construction projectorganisation by identifying the contingent factors that affect contractor'sgathering and analysis of price information from supply chain organisationsduring the ex ante processes to contract formation.The research methodology adopted a combined approach to data collectionand analysis, and used a theoretical framework adapted from transactioneconomics to identify and explicate a model of contingency factors. Theresearch method for data collection in the dominant quantitative first phaseused a postal survey of 760 estimators working for contracting organisationsin the United Kingdom in December 2003. The resultant data set wasanalysed using descriptive statistics. A multi variable general linear modeland principal component analysis defined the parameters of a model thatinformed the second phase of data collection and analysis. This model wasexplicated using a multiple case study approach that gathered and analysedinterview data from estimators working for organisations that had beenpurposively selected.The findings of this research identified the contingency factors that affectcontractors', seeking, gathering, analysing and synthesising of supply chainprice data, that can be grouped into four categories, which are; externalenvironment, project environment, task environment and inter-organisationalrelations. The research also found that the existence and strength of effect ofthe contingency factors was differentiated by organisational size, andidentified the factors that may be influenced by the intervention of the clientprocurement system, (or the organisation) in the ex ante process of supplychain organisation team development

The empirical analysis of cigarette tax avoidance and illicit trade in Vietnam, 1998-2010.

Illicit trade carries the potential to magnify existing tobacco-related health care costs through increased availability of untaxed and inexpensive cigarettes. What is known with respect to the magnitude of illicit trade for Vietnam is produced primarily by the industry, and methodologies are typically opaque. Independent assessment of the illicit cigarette trade in Vietnam is vital to tobacco control policy. This paper measures the magnitude of illicit cigarette trade for Vietnam between 1998 and 2010 using two methods, discrepancies between legitimate domestic cigarette sales and domestic tobacco consumption estimated from surveys, and trade discrepancies as recorded by Vietnam and trade partners. The results indicate that Vietnam likely experienced net smuggling in during the period studied. With the inclusion of adjustments for survey respondent under-reporting, inward illicit trade likely occurred in three of the four years for which surveys were available. Discrepancies in trade records indicate that the value of smuggled cigarettes into Vietnam ranges from $100 million to$300 million between 2000 and 2010 and that these cigarettes primarily originate in Singapore, Hong Kong, Macao, Malaysia, and Australia. Notable differences in trends over time exist between the two methods, but by comparison, the industry estimates consistently place the magnitude of illicit trade at the upper bounds of what this study shows. The unavailability of annual, survey-based estimates of consumption may obscure the true, annual trend over time. Second, as surveys changed over time, estimates relying on them may be inconsistent with one another. Finally, these two methods measure different components of illicit trade, specifically consumption of illicit cigarettes regardless of origin and smuggling of cigarettes into a particular market. However, absent a gold standard, comparisons of different approaches to illicit trade measurement serve efforts to refine and improve measurement approaches and estimates

Evolution of the relaxin-like peptide family

BACKGROUND: The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 peptides of high structural but low sequence similarity; relaxin-1, 2 and 3, and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, INSL6 remain uncharacterised. The evolution of this family has been contentious; high sequence variability is seen between closely related species, while distantly related species show high similarity; an invertebrate relaxin sequence has been reported, while a relaxin gene has not been found in the avian and ruminant lineages. RESULTS: Sequence similarity searches of genomic and EST data identified homologs of relaxin-like peptides in mammals, and non-mammalian vertebrates such as fish. Phylogenetic analysis was used to resolve the evolution of the family. Searches were unable to identify an invertebrate relaxin-like peptide. The published relaxin cDNA sequence in the tunicate, Ciona intestinalis was not present in the completed C. intestinalis genome. The newly discovered relaxin-3 is likely to be the ancestral relaxin. Multiple relaxin-3-like sequences are present in fugu fish (Takifugu rubripes) and zebrafish (Danio rerio), but these appear to be specific to the fish lineage. Possible relaxin-1 and INSL5 homologs were also identified in fish and frog species, placing their emergence prior to mammalia, earlier than previously believed. Furthermore, estimates of synonymous and nonsynonymous substitution rates (d(N)/d(S)) suggest that the emergence of relaxin-1, INSL4 and INSL6 during mammalia was driven by positive Darwinian selection, hence these peptides are likely to have novel and in the case of relaxin-1, which is still under positive selection in humans and the great apes, possibly still evolving functions. In contrast, relaxin-3 is constrained by strong purifying selection, demonstrating it must have a highly conserved function, supporting its hypothesized important neuropeptide role. CONCLUSIONS: We present a phylogeny describing the evolutionary history of the relaxin-like peptide family and show that positive selection has driven the evolution of the most recent members of the family

Evolution of the relaxin-like peptide family

BACKGROUND: The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 peptides of high structural but low sequence similarity; relaxin-1, 2 and 3, and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, INSL6 remain uncharacterised. The evolution of this family has been contentious; high sequence variability is seen between closely related species, while distantly related species show high similarity; an invertebrate relaxin sequence has been reported, while a relaxin gene has not been found in the avian and ruminant lineages. RESULTS: Sequence similarity searches of genomic and EST data identified homologs of relaxin-like peptides in mammals, and non-mammalian vertebrates such as fish. Phylogenetic analysis was used to resolve the evolution of the family. Searches were unable to identify an invertebrate relaxin-like peptide. The published relaxin cDNA sequence in the tunicate, Ciona intestinalis was not present in the completed C. intestinalis genome. The newly discovered relaxin-3 is likely to be the ancestral relaxin. Multiple relaxin-3-like sequences are present in fugu fish (Takifugu rubripes) and zebrafish (Danio rerio), but these appear to be specific to the fish lineage. Possible relaxin-1 and INSL5 homologs were also identified in fish and frog species, placing their emergence prior to mammalia, earlier than previously believed. Furthermore, estimates of synonymous and nonsynonymous substitution rates (d(N)/d(S)) suggest that the emergence of relaxin-1, INSL4 and INSL6 during mammalia was driven by positive Darwinian selection, hence these peptides are likely to have novel and in the case of relaxin-1, which is still under positive selection in humans and the great apes, possibly still evolving functions. In contrast, relaxin-3 is constrained by strong purifying selection, demonstrating it must have a highly conserved function, supporting its hypothesized important neuropeptide role. CONCLUSIONS: We present a phylogeny describing the evolutionary history of the relaxin-like peptide family and show that positive selection has driven the evolution of the most recent members of the family

Radiocarbon Chronologies and Extinction Dynamics of the Late Quaternary Mammalian Megafauna of the Taimyr Peninsula, Russian Federation

This paper presents 75 new radiocarbon dates based on late Quaternary mammal remains recovered from eastern Taimyr Peninsula and adjacent parts of the northern Siberian lowlands, Russian Federation, including specimens of woolly mammoth (Mammuthus primigenius), steppe bison (Bison priscus), muskox (Ovibos moschatus), moose (Alces alces), reindeer (Rangifer tarandus), horse (Equus caballus) and wolf (Canis lupus). New evidence permits reanalysis of megafaunal extinction dynamics in the Asian high Arctic periphery. Increasingly, radiometric records of individual species show evidence of a gap at or near the Pleistocene/Holocene boundary (PHB). In the past, the PHB gap was regarded as significant only when actually terminal, i.e., when it marked the apparent ‘‘last’’ occurrence of a species (e.g., current ‘‘last’’ occurrence date for woolly mammoth in mainland Eurasia is 9600 yr BP). However, for high Arctic populations of horses and muskoxen the gap marks an interruption rather than extinction, because their radiocarbon records resume, nearly simultaneously, much later in the Holocene. Taphonomic effects, ΔC14 flux, and biased sampling are unlikely explanations for these hiatuses. A possible explanation is that the gap is the signature of an event, of unknown nature, that prompted the nearly simultaneous crash of many megafaunal populations in the high Arctic and possibly elsewhere in Eurasia.

Probabilistic Analysis of Facility Location on Random Shortest Path Metrics

The facility location problem is an NP-hard optimization problem. Therefore, approximation algorithms are often used to solve large instances. Such algorithms often perform much better than worst-case analysis suggests. Therefore, probabilistic analysis is a widely used tool to analyze such algorithms. Most research on probabilistic analysis of NP-hard optimization problems involving metric spaces, such as the facility location problem, has been focused on Euclidean instances, and also instances with independent (random) edge lengths, which are non-metric, have been researched. We would like to extend this knowledge to other, more general, metrics. We investigate the facility location problem using random shortest path metrics. We analyze some probabilistic properties for a simple greedy heuristic which gives a solution to the facility location problem: opening the $\kappa$ cheapest facilities (with $\kappa$ only depending on the facility opening costs). If the facility opening costs are such that $\kappa$ is not too large, then we show that this heuristic is asymptotically optimal. On the other hand, for large values of $\kappa$, the analysis becomes more difficult, and we provide a closed-form expression as upper bound for the expected approximation ratio. In the special case where all facility opening costs are equal this closed-form expression reduces to $O(\sqrt[4]{\ln(n)})$ or $O(1)$ or even $1+o(1)$ if the opening costs are sufficiently small.Comment: A preliminary version accepted to CiE 201