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The human immunodeficiency virus 1 (HIV-1) capsid serves as a binding platform for proteins and small molecules from the host cell that regulate various steps in the virus life cycle. However, there are currently no quantitative methods that use assembled capsid lattices for measuring host-pathogen interaction dynamics. Here we developed a single molecule fluorescence biosensor using self-assembled capsid tubes as biorecognition elements and imaged capsid binders using total internal reflection fluorescence microscopy in a microfluidic setup. The method is highly sensitive in its ability to observe and quantify binding, obtain dissociation constants, extract kinetics with an extended application of using more complex analytes that can accelerate characterisation of novel capsid binders.

Dismount skin detection from an aerial platform has posed challenges compared to ground-based platforms. A small, area scanning multispectral imager was constructed and tested on a Small Unmanned Aerial System (SUAS). Computer vision registration, stereo camera calibration, and geolocation from autopilot telemetry were utilized to design a dismount detection platform. The test expedient prototype was 2kg and exhibited skin detection performance similar to a larger line scan hyperspectral imager (HSI). Outdoor tests with a line scan HSI and the prototype resulted in an average 5.112% difference in Receiver Operating Characteristic (ROC) Area Under Curve (AUC). This research indicated that SUAS-based Spectral Imagers are capable tools in dismount detection protocols.

This paper explores the practical usage of model-based systems engineering (MBSE) to compare the ability of both traditional and CubeSat remote sensing architectures to fulfill a set of mission requirements. Mission requirements originating from a hurricane disaster response scenario are developed to derive a set of system requirements. These system requirements are used to develop notional traditional and CubeSat architecture models. The technical performance of these architectures is analyzed using Systems Toolkit (STK); the results are compared against measures of effectiveness (MOEs) derived from the disaster response scenario. The performance comparison between the traditional and CubeSat architectures is intended to inform future discussions relating to the benefits and limitations of using CubeSats to conduct operational missions.

There is an ongoing demand for organizations to become more agile in order to prosper amongst their competitors. Many military organizations have declared a renewed focus towards organizational agility. The goal of this research is to isolate the variables needed to measure organizational agility (OA) in military organizations, allowing for the future development of a suitable method to measure OA without the need to interact with outside organizations. This article begins by providing a suitable and formal definition of organizational agility by exploring and analyzing relevant scholarly literature on the subject. Related terms, such as organizational resiliency, flexibility, robustness, versatility, and adaptability are also explored to examine their definition boundaries and any overlapping areas. Existing methods to measure organizational agility are examined and summarized, and the current limitations to their application are highlighted. Previous studies to find characteristics associated with organizational agility were also examined, and an initial set of 88 organizational agility characteristics was built. Since these included possible redundant or overlapping characteristics, the Q-sort method was employed to discover, analyze, and eliminate redundant items from the dataset, ultimately resulting in 64 unique characteristics. The result is a suitable definition for organization agility applicable to military organizations and a list of potential associated characteristics that summarizes related research to date. This groundwork establishes the foundation to conduct a multi-organization study to further refine the characteristic list and ultimately develop a method to measure organizational agility.

The HIV capsid is semipermeable and covered in electropositive pores that are essential for viral DNA synthesis and infection. Here, we show that these pores bind the abundant cellular polyanion IP6, transforming viral stability from minutes to hours and allowing newly synthesised DNA to accumulate inside the capsid. An arginine ring within the pore coordinates IP6, which strengthens capsid hexamers by almost 10°C. Single molecule measurements demonstrate that this renders native HIV capsids highly stable and protected from spontaneous collapse. Moreover, encapsidated reverse transcription assays reveal that, once stabilised by IP6, the accumulation of new viral DNA inside the capsid increases >100 fold. Remarkably, isotopic labelling of inositol in virus-producing cells reveals that HIV selectively packages over 300 IP6 molecules per infectious virion. We propose that HIV recruits IP6 to regulate capsid stability and uncoating, analogous to picornavirus pocket factors. HIV-1/IP6/capsid/co-factor/reverse transcription., eLife digest Viruses like HIV invade cells and replicate their genome to create new viruses. To hide from components of our immune system that are active inside the cell, HIV uses a protein shell called a capsid, which protects its genome from detection and destruction. However, the capsid faces an engineering challenge beyond those faced by even the most complex man-made structures. This is because the capsid must be strong enough to survive for hours inside the cell but not so strong that it cannot quickly open when the virus needs to release its genome. How this process, called ‘uncoating’, is achieved is one of the great unanswered questions in HIV biology. In 2016, researchers made the unexpected discovery that the HIV capsid is decorated with hundreds of pores: one at the center of every subunit from which it is built. Each pore contains a ring of six positively charged amino acids that should destabilize the capsid and cause it to break apart. Yet similar pores are found on a diverse range of viruses. Mallery et al. – who include several of the researchers involved in the 2016 work – set out to investigate why the HIV capsid contains the positively charged pores. Initial experiments revealed that a molecule called IP6, which is abundant in cells, can bind to the HIV capsid. To do so, six negatively charged phosphate groups in IP6 match up with the six positively charged residues in the pore. In a related study, Márquez et al. developed a new method that allows the fate of individual capsids to be visualized through time. Here, Mallery et al. use the method to show that IP6 increases how long the capsid remains intact from several minutes to over 10 hours. This allows HIV to copy its genome inside the capsid, meaning it remains protected while the virus prepares to produce new viruses. Mallery et al. also show that HIV packages more than 300 IP6 molecules into itself when it replicates. Other viruses called picornaviruses use small molecules called pocket factors to stabilize the capsid and to trigger uncoating. Mallery et al. propose that IP6 is an HIV pocket factor. Just as studies of pocket factors have stimulated the development of anti-picornavirus drugs, understanding the role of IP6 may help to develop new treatments for HIV.

Human immunodeficiency virus (HIV) is one of the most studied of all human pathogens. One strain—HIV-1 group M—is responsible for a global pandemic that has infected >60 million people and killed >20 million. Understanding the stages of HIV infection has led to highly effective therapeutics in the form of antiviral drugs that target the viral enzymes reverse transcriptase, integrase, and protease as well as biotechnological developments in the form of retroviral and lentiviral vectors for the transduction of cells in tissue culture and, potentially, gene therapy. However, despite considerable research focus in this area, there is much we still do not understand about the HIV replicative cycle, particularly the first steps that are crucial to establishing a productive infection. One especially enigmatic player has been the HIV capsid. In this review, we discuss three aspects of the HIV capsid: its function as a structural shell, its role in mediating host interactions, and its vulnerability to antiviral activity.

Viruses need to enter their host’s cells in order to replicate their genetic material and produce more copies of the virus. A protein shell called a capsid protects the virus during this journey. But the structure of the capsid presents a mystery. How can this protein shell be strong enough to remain intact as it enters a host cell, and yet quickly open up to release the viral genome after replication? Unlike the capsids of many other viruses, those of HIV have irregular structures that rapidly fall apart once removed from the virus. This has thwarted attempts to study intact HIV capsids in order to understand how they work. However, we do know that HIV hijacks a range of molecules produced by the invaded host cell. Dissecting their effects on the capsid is key to understanding how the capsid disassembles. Marquez et al. have now developed a method that can visualize individual HIV capsids – and how they disassemble – in real time using single-molecule microscopy. This revealed that capsids differ widely in their stability. The shell remains closed for a variable period of time and then collapses catastrophically as soon as it loses its first subunit. Using the new technique, Marquez et al. also found that a small molecule drug called PF74 causes the capsid to crack open rapidly, but the remaining shell is then stabilized against further disassembly. These observations reconcile seemingly contradictory observations made by different research groups about how this drug affects the stability of the capsid. The method developed by Marquez et al. enables researchers to measure how molecules produced by host cells interact with the viral capsid, a structure that is fundamental for the virus to establish an infection. It could also be used to test the effects of antiviral drugs that have been designed to target the capsid. The new technique has already been instrumental in related research by Mallery et al., which identifies a molecule found in host cells that stabilizes the capsid of HIV.

I agree to certain extent with Costica Dumbrava that ius sanguinis encompasses certain problematic issues, especially where it concerns newer forms of procreation, like IVF for lesbian couples and surrogacy. However, the origin of the problem cannot be attributed to ius sanguinis, but to non-solidarity of states that overuse the ordre public exemption for the denial of the recognition of parentage. Ius sanguinis is still the most suitable option for the main purposes of nationality law where it concerns children. I like Baubock’s proposal of a ius filiationis. I see it, however, more as a change from ‘law by blood’, meaning parentage ties based on blood relationship, to a ‘blood by law’ relationship, meaning that parentage ties are seen to be established by the law. This thus means only an extension of the ‘blood’ definition.

The transcription factor GATA1 helps regulate the expression of thousands of genes involved in blood development, by binding to single or double GATA sites on DNA. An important part of gene activation is chromatin looping, the bringing together of DNA elements that lie up to many thousands of basepairs apart in the genome. It was recently suggested, based on studies of the closely related protein GATA3, that GATA-mediated looping may involve interactions of each of two zinc fingers (ZF) with distantly spaced DNA elements. Here we present a structure of the GATA1 ZF region bound to pseudopalindromic double GATA site DNA, which is structurally equivalent to a recently-solved GATA3-DNA complex. However, extensive analysis of GATA1-DNA binding indicates that although the N-terminal ZF (NF) can modulate GATA1-DNA binding, under physiological conditions the NF binds DNA so poorly that it cannot play a direct role in DNA-looping. Rather, the ability of the NF to stabilize transcriptional complexes through protein-protein interactions, and thereby recruit looping factors such as Ldb1, provides a more compelling model for GATA-mediated looping.

The objective of this study was to investigate the bioleaching of heavy metals from contaminated sediments by Aspergillus niger strain SY1. To achieve this, three targets were identified: (1) identify organic acids produced by the isolated A. niger strain SY1 from contaminated sediments, (2) compare the leaching ability and transformation of chemical speciation of heavy metals during the bioleaching processes, and (3) determine the toxic characteristic of sediment before and after bioleaching. The contaminated sediment was collected from the dredging of the Xihe River, China. The A. niger strain SY1 was isolated from this sediment. Bioleaching experiments were carried out in 250 ml autoclaved conical flasks with 10 g autoclaved sediment, 1 ml of spore suspension, and 99 ml culture medium; the flasks were placed in a shaking incubator (220 rpm) at 30 °C for 7 days. Toxicity characteristic leaching procedure (TCLP) tests were carried out according to USEPA-SW846 Method 1311, and the wheat and earthworm toxicity tests were carried out according to OECD “Guidelines for the Testing of Chemicals.” Fractionation of heavy metals was undertaken by the three-step sequential extraction procedure. The metabolites were determined with a HPLC system. There was 11.5 % leaching efficiency of Pb from the polluted sediment in the one-step bioleaching process; while in the two-step bioleaching process, the highest extraction efficiency of Pb was 65.4 %. In one-step bioleaching, 93.5 % Cd, 62.3 % Cu, and 68.2 % Zn were leached out; whereas, the highest metal extraction efficiencies of Cd, Cu, and Zn were 99.5, 56, 71.9, and 76.4 %, respectively, in two-step bioleaching. After the bioleaching, the metals remaining in the sediment were mainly found in the stable fractions. Cd, Pb, Cu, and Zn concentrations in extracted liquor of TCLP tests were reduced to far below the levels in two Chinese standards, and the sediment after bioleaching had a lower toxicity on wheat and earthworm. A. niger strain SY1 can effectively remove heavy metals in contaminated sediment. The bioleaching efficiencies of heavy metals in the two-step bioleaching were better than that in one-step bioleaching. After the bioleaching, metals remaining in the sediment were mainly found in the stable fractions, and the toxicity of it was reduced to a level for it to be used safely in landfill or used in land application. A. niger strain SY1 is a cost-effective, environmentally friendly, and efficient bioleacher of heavy metals.

Quantum key distribution (QKD) is an innovative technology that exploits the laws of quantum mechanics to generate and distribute unconditionally secure shared key for use in cryptographic applications. However, QKD is a relatively nascent technology where real-world system implementations differ significantly from their ideal theoretical representations. In this paper, we introduce a modeling framework built upon the OMNeT++ discrete event simulation framework to study the impact of implementation nonidealities on QKD system performance and security. Specifically, we demonstrate the capability to study the device imperfections and practical engineering limitations through the modeling and simulation of a polarization-based, prepare and measure BB84 QKD reference architecture. The reference architecture allows users to model and study complex interactions between physical phenomenon and system-level behaviors representative of real-world design and implementation tradeoffs. Our results demonstrate the flexibility of the framework to simulate and evaluate current, future, and notional QKD protocols and components.

This paper describes a research effort to employ modern Systems Modeling Language (SysML) tools to inform early architecture-level analysis of alternatives by integrating existing performance calculations through parametric diagrams. The purpose of this effort is twofold. First, it serves as a proving ground for the use of SysML to capture both the system architecture and the corresponding analysis framework. Second, it illustrates how to support specialty engineering performance calculations for a range of architectural options. The findings are illustrated using a collection of heterogeneous optical systems located at the Air Force Institute of Technology and used for observation of satellites. The model will include system elements decomposed to the level at which they are generally purchased, e.g., telescopes, cameras, telescope mounts, computers, etc. The range of options explored will be based on varying telescope aperture, sensor responsivity and noise, total system coverage, and background light as they affect systems performance. Metrics are examined based on calculation of the dimmest object detectable and time required to survey a band of sky containing geostationary satellites.

Levels of Autonomy (LoA) provide a method for describing authority granted to operators and autonomous system elements. Unfortunately, LoA does not provide the user interface designer a clear method to distinguish interface concepts which impose varying levels of operator workload or result in human or system performance changes. The current research suggests an alternate classification framework for vehicle control, referred to as the Level of Human Control Abstraction (LHCA). LHCA describes how an operator controls a system based on the control tasks performed and the level of detail of decisions made by the operator. The proposed framework consists of five levels: Direct Control, Augmented Control, Parametric Control, Goal-Oriented Control, and Mission-Capable Control. It is suggested that as the level of detail of control is reduced through progression from Direct Control to Mission-Capable Control, the level of human attention, and workload will be reduced.

Updated guidelines are presented for publishing biomolecular small-angle scattering (SAS) experiments so that readers can independently assess the quality of the data and models presented. The focus is on solution scattering experiments with either X-rays (SAXS) or neutrons (SANS), where the primary goal is the generation and testing of three-dimensional models, particularly in the context of integrative/hybrid structural modelling., In 2012, preliminary guidelines were published addressing sample quality, data acquisition and reduction, presentation of scattering data and validation, and modelling for biomolecular small-angle scattering (SAS) experiments. Bio­molecular SAS has since continued to grow and authors have increasingly adopted the preliminary guidelines. In parallel, integrative/hybrid determination of biomolecular structures is a rapidly growing field that is expanding the scope of structural biology. For SAS to contribute maximally to this field, it is essential to ensure open access to the information required for evaluation of the quality of SAS samples and data, as well as the validity of SAS-based structural models. To this end, the preliminary guidelines for data presentation in a publication are reviewed and updated, and the deposition of data and associated models in a public archive is recommended. These guidelines and recommendations have been prepared in consultation with the members of the International Union of Crystallography (IUCr) Small-Angle Scattering and Journals Commissions, the Worldwide Protein Data Bank (wwPDB) Small-Angle Scattering Validation Task Force and additional experts in the field.

LIM-Homeodomain (LIM-HD) transcription factors are highly conserved in animals where they are thought to act in a transcriptional ‘LIM code’ that specifies cell types, particularly in the central nervous system. In chick and mammals the interaction between two LIM-HD proteins, LHX3 and Islet1 (ISL1), is essential for the development of motor neurons. Using yeast two-hybrid analysis we showed that the Caenorhabditis elegans orthologs of LHX3 and ISL1, CEH-14 and LIM-7 can physically interact. Structural characterisation of a complex comprising the LIM domains from CEH-14 and a LIM-interaction domain from LIM-7 showed that these nematode proteins assemble to form a structure that closely resembles that of their vertebrate counterparts. However, mutagenic analysis across the interface indicates some differences in the mechanisms of binding. We also demonstrate, using fluorescent reporter constructs, that the two C. elegans proteins are co-expressed in a small subset of neurons. These data show that the propensity for LHX3 and Islet proteins to interact is conserved from C. elegans to mammals, raising the possibility that orthologous cell specific LIM-HD-containing transcription factor complexes play similar roles in the development of neuronal cells across diverse species., Scientific Reports, 7 (1), ISSN:2045-2322

In this paper, we present modeling a Quantum Key Distribution (QKD) system with its components using the Discrete Event System Specification (DEVS) formalism. The DEVS formalism assures the developed component models are composable and exhibit well-defined temporal behavior independent of the simulation environment. These attributes enable users to assemble a valid simulation using any collection of compatible components to represent complete QKD system architectures. To illustrate the approach, we introduce a prototypical “prepare and measure” QKD system, decompose one of its subsystems, and present the detailed modeling of the subsystem using the DEVS formalism. The developed models are provably composable and exhibit behavior suitable for the intended analytic purpose, thus improving the validity of the simulation. Finally, we examine issues identified during the verification of the conceptual DEVS model and discuss the impact of these findings on implementing a hybrid QKD simulation framework.

Adult haemoglobin (Hb) is made up of two α and two β subunits. Mutations that reduce expression of the α- or β-globin genes lead to the conditions α- or β-thalassaemia, respectively. Whilst both conditions are characterized by anaemia of variable severity, other details of their pathophysiology are different, in part owing to the greater stability of the β chains that is conferred through β self-association. In contrast, α subunits interact weakly, and in the absence of stabilizing quaternary interactions the α chain (α) is prone to haem loss and denaturation. The molecular contacts that confer weak self-association of α have not been determined previously. Here, the first structure of an α2homodimer is reported in complex with one domain of the Hb receptor fromStaphylococcus aureus. The α2dimer interface has a highly unusual, approximately linear, arrangement of four His side chains within hydrogen-bonding distance of each other. Some interactions present in the α1β1 dimer interface of native Hb are preserved in the α2dimer. However, a marked asymmetry is observed in the α2interface, suggesting that steric factors limit the number of stabilizing interactions that can form simultaneously across the interface.

29th European Photovoltaic Solar Energy Conference and Exhibition; 3625-3629, An assessment of roof-mounted PV capacity over a local region can be accurately calculated by established roof segmentation algorithms using high-resolution light detection and ranging (LiDAR) datasets. However, over larger city regions often only low-resolution LiDAR data is available where such algorithms prove unreliable for small rooftops. A methodology optimised for low-resolution LiDAR datasets is presented, where small and large buildings are considered separately. The roof segmentation algorithm for small buildings, which are typically residential properties, assigns a roof profile to each building from a catalogue of common profiles after identifying LiDAR points within the building footprint. Large buildings, such as warehouses, offer a more diverse range of roof profiles but geometric features are generally large, so a direct approach is taken to segmentation where all the LiDAR points are considered individually and then connected segmentally. The methodology is demonstrated by application to the city region of Leeds, UK. Validation by comparison to aerial photography indicates that the assignment of an appropriate roof profile to a small building is correct in 81% of cases.

Dismount skin detection from an aerial platform has posed challenges compared to ground-based platforms. A small, area scanning multispectral imager was constructed and tested on a Small Unmanned Aerial System (SUAS). Computer vision registration, stereo camera calibration, and geolocation from autopilot telemetry were utilized to design a dismount detection platform. The test expedient prototype was 2kg and exhibited skin detection performance similar to a larger line scan hyperspectral imager (HSI). Outdoor tests with a line scan HSI and the prototype resulted in an average 5.112% difference in Receiver Operating Characteristic (ROC) Area Under Curve (AUC). This research indicated that SUAS-based Spectral Imagers are capable tools in dismount detection protocols.

Review of how cells can sense their own infection, and their attempts to eliminate pathogens., Historically, once a cell became infected, it was considered to be beyond all help. By this stage, the invading pathogen had breached the innate defenses and was beyond the reach of the humoral arm of the adaptive immune response. The pathogen could still be removed by cell-mediated immunity (e.g., by NK cells or cytotoxic T lymphocytes), but these mechanisms necessitated the destruction of the infected cell. However, in recent years, it has become increasingly clear that many cells possess sensor and effector mechanisms for dealing with intracellular pathogens. Most of these mechanisms are not restricted to professional immune cells nor do they all necessitate the destruction of the host. In this review, we examine the strategies that cells use to detect and destroy pathogens once the cell membrane has been penetrated.

In this paper, we classify the carbon emission inventories into three perspectives through a case study in Beijing: territory account (TA), production account (PA) and consumption account (CA). A single-regional–input–output (SRIO) method was used to calculate production account and consumption account with a traditional competitive input–output (IO) table. Results show that both TA and PA have the same final values, but disparity exists at the sectoral distribution level. Both PA and CA increased from 2000 to 2007, but CA was bigger than PA and increased faster than PA. This indicates that Beijing was a carbon importer with an increasing trend. Sectoral analysis shows that “melting and pressing of metals (14)”, “Nonmetal mineral products (13)” and “Petroleum processing, coking, and nuclear fuel processing (11)” have higher direct carbon emissions from production perspective (TA), whilst “Construction” and “Service” sectors have higher emissions from consumption perspective (PA and TA). High embodied emission sectors in PA/TA, particularly the “Construction” sector, deserve more attentions for carbon emission mitigation.

Feed-in Tariffs (FiTs) in the UK have been introduced to stimulate growth in small-scale renewables such as photovoltaics and micro-wind. They form one of the UK’s key policies to decarbonise electricity by 2030. However, the evidence used to inform the policy was predominantly related to costs, capacity and deployment; not contribution to meeting decarbonisation targets. This paper employs an integrated hybrid lifecycle assessment method, which overcomes boundary limitations of traditional process-based assessments, to measure the full lifecycle emissions of solar PV and micro-wind technologies eligible under FiTs. Environmental assessments of policies often do not take account of the lifecycle emissions of technologies, therefore underestimating their emissions contribution and overestimating the success of policies towards decarbonisation targets. Considering the full lifecycle emissions, the paper assesses the effectiveness of FiTs for driving the UK’s low carbon transition. The results demonstrate that, while there is still significant variation and uncertainty with such estimates, even with the most conservative figures, both the technologies can offer substantial emission savings compared to fossil fuel alternatives when installed in suitable locations. However, the renewable resource of installation sites is critical to the carbon intensity that the technologies can offer. Under a poor renewable resource their impacts can be as high as fossil fuels alternatives. As FiTs makes no distinction between installation sites this should form part of the assessment of funding. Finally, despite their potential for carbon reduction, with the full lifecycle of the considered technologies taken into account, a target of 50 gCO2e/kW h is not possible with the current technology generation efficiencies. The paper concludes that a complete re-assessment of the role of technologies in the decarbonisation of electricity is required to take into account the full lifecycle impacts to gain a more realistic picture of the mitigation potential.

The combustion of fossil fuel contributes to not only global warming but also the emissions of air pollutants. In China, the rapid growth of energy consumption leads to a large quantity of greenhouse gas (GHG) and air pollutant emissions. Although many measures have been proposed by the local governments to mitigate the GHG emissions and improve air quality, limited economic resources slow the efforts of the local government to implement measures to control both types of emissions. The co-benefits approach can use resources efficiently to solve multiple environmental problems. In this study, we first calculated the CO2 and air pollutants (SO2, NOx and PM2.5) emissions in Xinjiang Uygur Autonomous Region. Then, the co-benefits of wind power, including mitigation of CO2 and air pollutants (SO2, NOx and PM2.5) emissions and water savings, were assessed and quantified in the Xinjiang Uygur Autonomous Region. The results demonstrate that, during the 11th five-year period (2006–2010), emissions mitigation by wind power accounted for 4.88% (1065 × 104 t) of CO2, 4.31% (4.38 × 104 t) of SO2, 8.23% (3.41 × 104 t) of NOx and 4.23% (0.32 × 104 t) of PM2.5 emission by the thermal power sector. The total economic co-benefits of wind power accounted for 0.46% (1.38 billion 2009US$) of the GDP of Xinjiang during 2006–2010.

Islet 1 (Isl1) is a transcription factor of the LIM-homeodomain (LIM-HD) protein family and is essential for many developmental processes. LIM-HD proteins all contain two protein-interacting LIM domains, a DNA-binding homeodomain (HD), and a C-terminal region. In Isl1, the C-terminal region also contains the LIM homeobox 3 (Lhx3)-binding domain (LBD), which interacts with the LIM domains of Lhx3. The LIM domains of Isl1 have been implicated in inhibition of DNA binding potentially through an intramolecular interaction with or close to the HD. Here we investigate the LBD as a candidate intramolecular interaction domain. Competitive yeast-two hybrid experiments indicate that the LIM domains and LBD from Isl1 can interact with apparently low affinity, consistent with no detection of an intermolecular interaction in the same system. Nuclear magnetic resonance studies show that the interaction is specific, whereas substitution of the LBD with peptides of the same amino acid composition but different sequence is not specific. We solved the crystal structure of a similar but higher affinity complex between the LIM domains of Isl1 and the LIM interaction domain from the LIM-HD cofactor protein LIM domain-binding protein 1 (Ldb1) and used these coordinates to generate a homology model of the intramolecular interaction that indicates poorer complementarity for the weak intramolecular interaction. The intramolecular interaction in Isl1 may provide protection against aggregation, minimize unproductive DNA binding, and facilitate cofactor exchange within the cell.

With ever growing urgency, climate change mitigation is fast becoming a priority for China. A successful policy of implementing and expanding sustainable development and the use of renewable energy is therefore vital. As well as long-term and near-term targets for installed capacity of renewable energy, in its 12th five-year plan, China has created strict and ambitious carbon intensity targets for each province. This study proposes an inter-provincial clean development mechanism to assist in meeting these targets. This mechanism will create potential co-benefits of assisting in sustainable development in lesser developed provinces, increasing local air quality and supporting the growth of China's renewable energy sector. This paper also highlights the potential that this inter-provincial clean development mechanism has in accelerating the growth of the domestic solar photovoltaics (PV) sector, for which the market in China is still in its infancy.

Classical zinc fingers (ZFs) are one of the most abundant and best characterized DNA-binding domains. Typically, tandem arrays of three or more ZFs bind DNA target sequences with high affinity and specificity, and the mode of DNA recognition is sufficiently well understood that tailor-made ZF-based DNA-binding proteins can be engineered. We have shown previously that a two-zinc finger unit found in the transcriptional coregulator ZNF217 recognizes DNA but with an affinity and specificity that is lower than other ZF arrays. To investigate the basis for these differences, we determined the structure of a ZNF217-DNA complex. We show that although the overall position of the ZFs on the DNA closely resembles that observed for other ZFs, the side-chain interaction pattern differs substantially from the canonical model. The structure also reveals the presence of two methyl-π interactions, each featuring a tyrosine contacting a thymine methyl group. To our knowledge, interactions of this type have not previously been described in classical ZF-DNA complexes. Finally, we investigated the sequence specificity of this two-ZF unit and discuss how ZNF217 might discriminate its target DNA sites in the cell.

For decades, the Department of Defense (DoD) has employed numerous reporting and monitoring tools for characterizing the acquisition cost estimates of its programs. These tools have led to dozens of studies thoroughly documenting the magnitude and extent of DoD acquisition cost growth. However, little attention has been paid to the behavior of the other main cost component of a system's life cycle cost: Operating and Support (O&S) costs. Consequently, the DoD has little knowledge regarding the accuracy of O&S cost estimates or how that accuracy changes over time. In a previous paper, the authors described an analytical methodology for remedying this deficiency via a study to characterize the historical accuracy of O&S cost estimates. The results are presented here, and indicate there tend to be large errors in DoD O&S cost estimates, and that the accuracy of the estimates improves little over time

The authors present a prognostic cost model that is shown to provide significantly more accurate estimates of life cycle costs for Department of Defense programs. Unlike current cost estimation approaches, this model does not rely on the assumption of a fixed program baseline. Instead, the model presented here adopts a stochastic approach to program uncertainty, seeking to identify and incorporate top-level (i.e., “macro”) drivers of estimating error to produce a cost estimate that is likely to be more accurate in the real world of shifting program baselines. The predicted improvement in estimating accuracy provided by this macro-stochastic cost model translates to hundreds of billions of dollars across the Department of Defense portfolio. Furthermore, improved cost estimate accuracy could reduce actual life cycle costs and/or allow defense acquisition officials the ability to make better decisions on the basis of more accurate assessments of value and affordability.

The DoD has frequently demonstrated its ability to procure phenomenal systems; however, these accomplishments are often tarnished by substantial cost and schedule overruns. While defense acquisition policies are continually being revised to address these perennial problems, many believe that a more fundamental source of these overruns is the lack of flexibility in the systems being developed, which tend to preclude effective responses to unexpected events. However, providing justification to invest in flexibility is a tough sell when the measure of value is a military capability or political outcome, as there is no extant method to demonstrate the potential return on investment. This paper introduces a decision tool for valuing the inherent ability of different systems or designs to respond to uncertainty. The proposed tool is essentially a modification of the current life cycle cost model and is premised on the notion that the need for capability changes in a system arises in a stochastic manner that can be incorpo- rated into a continually updated, expected value model presented in terms of total life cycle cost. The cost-based decision tool presented here quantifies the ability of competing designs to respond to these capability changes via a cumulative distribution function (CDF). The design with the most favorable CDF (i.e., the one that is most likely to meet the most likely set of require- ments at the lowest expected value curve of life cycle cost) is deemed to be the “best” design.

© 2016 Macmillan Publishers Limited. All rights reserved. During the early stages of infection, the HIV-1 capsid protects viral components from cytosolic sensors and nucleases such as cGAS and TREX, respectively, while allowing access to nucleotides for efficient reverse transcription. Here we show that each capsid hexamer has a size-selective pore bound by a ring of six arginine residues and a â molecular iris' formed by the amino-terminal β-hairpin. The arginine ring creates a strongly positively charged channel that recruits the four nucleotides with on-rates that approach diffusion limits. Progressive removal of pore arginines results in a dose-dependent and concomitant decrease in nucleotide affinity, reverse transcription and infectivity. This positively charged channel is universally conserved in lentiviral capsids despite the fact that it is strongly destabilizing without nucleotides to counteract charge repulsion. We also describe a channel inhibitor, hexacarboxybenzene, which competes for nucleotide binding and efficiently blocks encapsidated reverse transcription, demonstrating the tractability of the pore as a novel drug target.

The DoD has introduced the concept of Manned-Unmanned Teaming, a subset of which is the loyal wingman. Optimal control techniques have been proposed as a method for rapidly solving the intermediate-target (mid-point constraint) optimal control problem. Initial results using direct orthogonal collocation and a gradient-based method for solving the resulting nonlinear program reveals a tendency to converge to or to get `stuck’ in locally optimal solutions. The literature suggested a hybrid technique in which a particle swarm optimization is used to quickly find a neighborhood of a more globally minimal solution, at which point the algorithm switches to a gradient-based nonlinear programming solver to converge on the globally optimal solution. The work herein applies the hybrid optimization technique to rapidly solve the loyal wingman optimal control problem. After establishing the background and describing the loyal wingman particle swarm optimization algorithm, the problem is solved first using the gradient-based direct orthogonal collocation method, then re-solved using a hybrid approach in which the results of the particle swarm optimization algorithm are used as the initial guess for the gradient-based direct orthogonal collocation method. Results comparing the final trajectory and convergence time, demonstrate the hybrid technique as a reliable method for producing rapid, autonomous, and feasible solutions to the loyal wingman optimal control problem.

Despite its ubiquity in the systems engineering literature, flexibility remains an ambiguous concept. There exist a multitude of definitions, which vary not only by domain, but within domains as well. Furthermore, these definitions often conflict with one another, making it difficult to discern the intended meaning in a given study or to form generalizations across studies. Complicating matters, there is a plethora of related terminology that is often used carelessly and/or inter-changeably with flexibility. In this paper, we employ a novel ontological framework for clarifying salient aspects of extant flexibility-related terminology. While it was not possible to distill consensus definitions from the literature, we did identify certain dominant characteristics that enabled us to formulate a set of democratic definitions for flexibility, adaptability, and robustness, as well as recommended definitions for agility and versatility. We believe that the proposed definitions of these key system design principles may provide a baseline for improving analysis and communication among systems engineering practitioners and academics. © 2012 Wiley Periodicals, Inc. Syst Eng 16

For decades, the DoD has employed numerous reporting and monitoring tools for characterizing the acquisition cost estimates of its major programs. These tools have resulted in dozens of studies thoroughly documenting the magnitude and extent of DoD acquisition cost growth. However, little attention has been paid to the behavior of the larger cost component of a system's life cycle cost: Operating and Support (O&S) costs. Consequently, the DoD has little knowledge of how O&S cost estimates behave over time, and virtually no insights regarding their accuracy. In a previous paper, the authors describe an analytical methodology for remedying this deficiency via a study to characterize the historical accuracy of O&S cost estimates. The results of this study are presented here, and indicate there tend to be large errors in DoD O&S cost estimates, and that the accuracy of the estimates improves little over time. However, the results also suggest the possibility of improving the accuracy of these estimates via a stochastically-based predictive cost model.

Small-angle scattering is becoming a mainstream technique for structural molecular biology. As such, it is important to establish guidelines for publication that will ensure that there is adequate reporting of the data and its treatment so that reviewers and readers can independently assess the quality of the data and the basis for any interpretations presented. This article presents a set of preliminary guidelines that emerged after consultation with the IUCr Commission on Small-Angle Scattering and other experts in the field and discusses the rationale for their application. At the 2011 Congress of the IUCr in Madrid, the Commission on Journals agreed to adopt these preliminary guidelines for the presentation of biomolecular structures from small-angle scattering data in IUCr publications. Here, these guidelines are outlined and the reasons for standardizing the way in which small-angle scattering data are presented. © 2012 International Union of Crystallography Printed in Singapore - all rights reserved.

A vector approach, previously developed by the authors, is used to assess the modularity of the 35 kg, low-Earthorbit, plug-and-play satellite (PnPSat). PnPSat is being developed by the Air Force ResearchLaboratory in response to the need for an operationally responsive space capability. The modularity assessment addresses module-tomodule interfaces along with several fundamental benefits of modularity. These benefits include reusability, flexibility, reconfigurability, and extensibility. A PnPSat function structure was developed first using a functional basis language, followed bymodule identification using a dominant flow heuristic. PnPSat functions weremapped to modules, andmodule-to-module interfaceswere determined. Finally, the vectormodularitymeasure, which includes the reconfigurabilitymeasure,was calculated andassessed for thePnPSat. The results of the assessment show the two benefits of modularity being realized themost by the PnPSat are reusability and extensibility. This application of the modularity assessment extends the initial application from simple products, precision guided munitions, to a more complex product, PnPSat.

Pathogens must steal iron from their hosts to establish infection. In mammals, hemoglobin (Hb) represents the largest reservoir of iron, and pathogens express Hb-binding proteins to access this source. Here, we show how one of the commonest and most significant human pathogens, Staphylococcus aureus, captures Hb as the first step of an iron-scavenging pathway. The x-ray crystal structure of Hb bound to a domain from the Isd (iron-regulated surface determinant) protein, IsdH, is the first structure of a Hb capture complex to be determined. Surface mutations in Hb that reduce binding to the Hb-receptor limit the capacity of S. aureus to utilize Hb as an iron source, suggesting that Hb sequence is a factor in host susceptibility to infection. The demonstration that pathogens make highly specific recognition complexes with Hb raises the possibility of developing inhibitors of Hb binding as antibacterial agents. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

The DOD routinely demonstrates its capability to develop phenomenal systems; however, these accomplishments are often tarnished by substantial cost and schedule overruns. While defense policies are continually being revised to address these problems, many believe that a more fundamental source of these overruns is the lack of flexibility in the systems being developed. But providing justification to invest in flexibility is a tough sell, as stakeholders struggle to quantitatively demonstrate the potential return on investment. Therefore, this paper introduces an alternative methodology for valuing the inherent ability of a system or design to accommodate change. The proposed methodology is essentially a modification of the current life cycle model and is premised on the notion that the need for capability changes in a program arise in a stochastic manner that can be incorporated into a continually updated, expected value model presented in terms of total program cost.

This paper developed guidance laws to optimally and autonomously position a relay Micro Aerial Vehicle (MAV) to provide an operator with real-time Intelligence, Surveillance, and Reconnaissance (ISR) by relaying communication and video signals from a rover MAV to the base, thus extending the rover's reach. The ISR system is comprised of two MAVs, the Relay and the Rover, and a Base. The Relay strives to position itself so as to minimize the radio frequency (RF) power required for maintaining communications between the Rover and the Base, while the Rover performs the ISR mission, which may maximize the required RF power. The optimal control of the Relay MAV then entails the solution of a differential game. Applying Pontryagin's Maximum Principle yields a standard, albeit nonlinear, Two-Point Boundary Value Problem (TPBVP). Suboptimal solutions are first obtained as an aid in solving the TPBVP which yields the solution of the differential game. One suboptimal approach is based upon the geometry of the ISR system: The midpoint between the Rover and the Base is the ideal location which minimizes the RF power required, so the Relay heads toward that point—assuming that the Rover is stationary. At the same time, to maximize the rate of required RF power, the Rover moves in the opposite direction of the Relay—assuming the Relay is stationary. These are optimal strategies in the end-game, but it is suboptimal to use them throughout the game. Another suboptimal approach investigated envisions the Rover to remain stationary and solves for the optimal path for the Relay to minimize the RF power requirement. This one-sided optimization problem is analyzed using a Matlab-based optimization program, GPOCS, which uses the Gauss pseudospectral method of discretization. The results from GPOCS corroborated with the geometry-based suboptimal Relay strategy of heading straight toward the midpoint between the Rover and the Base. The suboptimal solutions are readily implementable for real-time operation and are used to facilitate the solutions of the TPBVP.

A method to assess product modularity using a vector approach is presented and demonstrated using two precision guided munitions. Modularity has several fundamental benefits agreed upon by industry including reusability, flexibility, reconfigurability and extensibility. Current modularity measures focus on interfaces within or between modules in provide/depend relationships. A new method that assesses the module interfaces as well as captures and addresses each of the recognized modularity benefits is presented in a Vector Modularity Measure (VMM). Components of the VMM include terms for degree of coupling, reusability, and flexibility. Flexibility is assessed in terms of reconfigurability and extensibility. The overall evaluation method is then summarized, followed by an application using two similar precision guided munitions in the U.S. Air Force inventory: the Guided Bomb Unit-24 (GBU-24), referred to as the laser guided bomb (LGB); and the Guided Bomb Unit-31 (GBU-31), referred to as the Joint Direct Attack Munition (JDAM).

The existing literature on system modularity postulates several benefits of modular systems. One reason the military has taken an interest in modularity is to allow responsive design, build, and launch of space vehicles. Researchers have developed modularity metrics, but the literature acknowledges a lack of application of modularity metrics. This paper describes some of the salient modularity metrics and applies them to a case study involving two modular precision guided munitions (PGM) as an illustrative example for potential application to motivating challenge of responsive space vehicle launches. A discrete event simulation model of the assembly process for each system in the case study is described, followed by an examination of modularity metrics with respect to system assembly times. Finally, a discussion regarding the relationship between modularity and system assembly time is presented with possible implications.

The last decade has seen a dramatic increase in the use of small-angle scattering for the study of biological macromolecules in solution. The drive for more complete structural characterization of proteins and their interactions, coupled with the increasing availability of instrumentation and easy-to-use software for data analysis and interpretation, is expanding the utility of the technique beyond the domain of the biophysicist and into the realm of the protein scientist. However, the absence of publication standards and the ease with which 3D models can be calculated against the inherently 1D scattering data means that an understanding of sample quality, data quality, and modeling assumptions is essential to have confidence in the results. This review is intended to provide a road map through the small-angle scattering experiment, while also providing a set of guidelines for the critical evaluation of scattering data. Examples of current best practice are given that also demonstrate the power of the technique to advance our understanding of protein structure and function.

Optimal employment of autonomous wide area search munitions or unmanned aerial vehicles is considered. The air vehicle searches a battle space for stationary targets in the presence of false targets and/or clutter. Control problems are formulated to achieve optimal scheduling of the control variables P TR, the probability of target report, which is a reflection of the sensor's threshold setting, and Q, the area coverage rate. These optimal control problem formulations yield solutions that maximize the probability of target attack, and constraints to also satisfy hard bounds on the probability of false target attacks may also be applied. Analysis has shown that the optimal solutions are sensitive to the particular relationship between the autonomous target recognition module's receiver operating characteristic parameter, c , and area coverage rate, Q . In this paper the relationship is developed from first principles for both passive and active sensors, and the optimal P TR and Q schedules are obtained.

The systems engineering technical processes often lack the support of methods and tools that quantitatively integrate human considerations into early system design decisions. Because of this, engineers generally rely on qualitative judgments or delay critical decisions until late in the system lifecycle. Studies have revealed that this frequently results in cost, schedule, and effectiveness consequences. We begin this paper with a study of current issues in the application of systems engineering as a whole. We then examine how the challenges of human systems integration are a pervasive factor in those issues. Finally, we propose how to improve system engineering by better addressing the identified challenges.