bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Credit Definition and Aggregation Strategies on Multi-Objective Hyper-Heuristics
Authors: Hitomi Nozomi , Selva Daniel
Published: January 2016

Heuristics and meta-heuristics are often used to solve complex real-world problems such as the non-linear, non-convex, and multi-objective combinatorial optimization problems that regularly appear in system design and architecture. Unfortunately, the performance of a specific heuristic is largely dependent on the specific problem at hand. Moreover, a heuristic’s performance can vary throughout the optimization process. Hyper-heuristics is one approach that can maintain relatively good performance over the course of an optimization process and across a variety of problems without parameter retuning or major modifications. Given a set of domain-specific and domain-independent heuristics, a hyper-heuristic adapts its search strategy over time by selecting the most promising heuristics to use at a given point.

A hyper-heuristic must have: 1) a credit assignment strategy to rank the heuristics by their likelihood of producing improving solutions; and 2) a heuristic selection strategy based on the credits assigned to each heuristic. The literature contains many examples of hyper-heuristics with effective credit assignment and heuristic selection strategies for single-objective optimization problems. In multi-objective optimization problems, however, defining credit is less straightforward because there are often competing objectives. Therefore, there is a need to define and assign credit so that heuristics are rewarded for finding solutions with good trades between the objectives.

This paper studies, for the first time, different combinations of credit definition, credit aggregation, and heuristic selection strategies. Credit definitions are based on different applications of the notion of Pareto dominance, namely: A1) dominance of the offspring with respect to the parent solutions; A2) ability to produce non-dominated solutions with respect to the entire population; A3) Pareto ranking with respect to the entire population. Two different credit aggregation strategies for assigning credit are also examined. A heuristic will receive credit for: B1) only the solutions it created in the current iteration or B2) all solutions it created that are in the current population. Different heuristic selection strategies are considered including: C1) probability matching; C2) dynamic multi-armed bandit; and C3) Hyper-GA.

Thus, we conduct an experiment with three factors: credit definition (A1, A2, A3), credit aggregation (B1, B2), and heuristic selection (C1, C2, C3) and conduct a full factorial experiment. Performance is measured by hyper-volume of the last population. All algorithms are tested on a design problem for a climate monitoring satellite constellation instead of classical benchmarking problems to apply domain-specific heuristics within the hyper-heuristic.
Local Analysis of Closed-Loop Linkages: Mobility, Singularities, and Shakiness
Authors: Müller Andreas
Published: January 2016

The mobility of a linkage is determined by the constraints imposed on its members. The constraints define the configuration space (c-space) variety as the geometric entity in which the finite mobility of a linkage is encoded. The instantaneous motions are determined by the constraints, rather than by the c-space geometry. Shaky linkages are prominent examples that exhibit a higher instantaneous than finite DOF even in regular configurations. Inextricably connected to the mobility are kinematic singularities that are reflected in a change of the instantaneous DOF. The local analysis of a linkage, aiming at determining the instantaneous and finite mobility in a given configuration, hence needs to consider the c-space geometry as well as the constraint system.

A method for the local analysis is presented based on a higher-order local approximation of the c-space adopting the concept of the tangent cone to a variety. The latter is the best local approximation of the c-space in a general configuration. It thus allows for investigating the mobility in regular as well as singular configurations. Therewith the c-space is locally represented as an algebraic variety whose degree is the necessary approximation order. In regular configurations the tangent cone is the tangent space. The method is generally applicable and computationally simple. It allows for a classification of linkages as overconstrained and underconstrained, and to identify singularities.
Extraction of Manufacturing Rules From Unstructured Text Using a Semantic Framework
Authors: Kang SungKu , Patil Lalit , Rangarajan Arvind , Moitra Abha , Jia Tao , Robinson Dean , Dutta Debasish
Published: January 2016

Formal ontology and rule-based approaches founded on semantic technologies have been proposed as powerful mechanisms to enable early manufacturability feedback. A fundamental unresolved problem in this context is that all manufacturing knowledge is encoded in unstructured text and there are no reliable methods to automatically convert it to formal ontologies and rules. It is impractical for engineers to write accurate domain rules in a structured semantic languages such as Web Ontology Language (OWL) or Semantic Application Design Language (SADL). Previous efforts in manufacturing research that have targeted extraction of OWL ontologies from text have focused on basic concept names and hierarchies. This paper presents a semantics-based framework for acquiring more complex manufacturing knowledge, primarily rules, in a semantically-usable form from unstructured English text such as those written in manufacturing handbooks. The approach starts with existing domain knowledge in the form of OWL ontologies and applies natural language processing techniques to extract dependencies between different words in the text that contains the rule. Domain-specific triples capturing each rule are then extracted from each dependency graph. Finally, new computer-interpretable rules are composed from the triples. The feasibility of the framework has been evaluated by automatically and accurately generating rules for manufacturability from a manufacturing handbook. The paper also documents the cases that result in ambiguous results. Analysis of the results shows that the proposed framework can be extended to extract domain ontologies which forms part of the ongoing work that also focuses on addressing challenges to automate different steps and improve the reliability of the system.
Visual Performance Maps for Human Choice in Hybrid Electric Vehicle’s In-Wheel Motors: Part II — Operation, Maintenance, and Refreshment Criteria
Authors: Lee Hoon , Ashok Pradeepkumar , Tesar Delbert
Published: January 2016

Part I of this paper demonstrated how different human choices affect the selection of all basic components of a Hybrid Electric Vehicles (HEV) equipped with four-independent In-Wheel Motors (IWM) based on detailed human needs structured by visual performance maps to guide the customer in terms of purchase criteria: cost, weight, power, acceleration, gradeability, braking, handling, ride comfort, efficiency, and durability.

This Part II discusses ten operation criteria: cornering force margin, roll angle, sideslip angle, lateral acceleration, slip angle, yaw rate, acceleration force margin, braking force margin, pitch angle, and travel range. These visual performance maps show the effects of HEV weight on acceleration, braking, and cornering maneuvers under various road conditions (i.e., dry asphalt, wet asphalt, snowy or icy road) which are evaluated and compared based on the implementation of a nonlinear 14 DOF full-vehicle model based on ride (7 DOF), handling (3 DOF), tire (4 DOF), slip ratio, slip angle, and the tire magic formula. In addition, this paper demonstrates how different human choices affect the HEV’s expected performance. Lastly, maintenance and refreshment criteria are presented and explained.
Mechanism Design and Simulation of the ULTRA Spine: A Tensegrity Robot
Authors: Sabelhaus Andrew P. , Ji Hao , Hylton Patrick , Madaan Yakshu , Yang ChanWoo , Agogino Alice M. , Friesen Jeffrey , SunSpiral Vytas
Published: January 2016

The Underactuated Lightweight Tensegrity Robotic Assistive Spine (ULTRA Spine) project is an ongoing effort to create a compliant, cable-driven, 3-degree-of-freedom, underactuated tensegrity core for quadruped robots. This work presents simulations and preliminary mechanism designs of that robot. Design goals and the iterative design process for an ULTRA Spine prototype are discussed. Inverse kinematics simulations are used to develop engineering characteristics for the robot, and forward kinematics simulations are used to verify these parameters. Then, multiple novel mechanism designs are presented that address challenges for this structure, in the context of design for prototyping and assembly. These include the spine robot’s multiple-gear-ratio actuators, spine link structure, spine link assembly locks, and the multiple-spring cable compliance system.
Design and Kinematic Optimization of a Waterproof Shape-Shifting Surface (SSS)
Authors: Katz Andrew J. , Lusk Craig P.
Published: January 2016

The first objective of this paper is to take an existing design for a shape-shifting surface (SSS) and make it waterproof, making it an effective barrier to fluid flow. The second objective is to minimize internal stresses in the device during operation, by optimizing the kinematic geometry of the SSS. The first objective was achieved by adding a waterproof membrane between the layers of the SSS, where the membrane had an origami fold pattern that enables the membrane to mimic the kinematics of the SSS. The second objective was achieved by creating a two objective optimization routine, which determined the kinematic geometry of the SSS which would minimize the internal stresses due to compression/tension of the flexure portion of the SSS during operation. The resulting SSS is easier to operate due to lower stresses, and has a membrane which prevents transverse fluid flow and mimics its motion.
Learning Algorithm Based Modeling and Process Parameters Recommendation System for Binder Jetting Additive Manufacturing Process
Authors: Chen Han , Zhao Yaoyao F.
Published: January 2016

Binder Jetting (BJ) process is an additive manufacturing process in which powder materials are selectively joined by binder materials. Products can be manufactured layer by layer directly from 3D model data. It is not always easy for manufacturing engineers to choose proper BJ process parameters to meet the end-product quality and fabrication time requirements. This is because the quality properties of the products fabricated by BJ process are significantly affected by the process parameters. And the relationships between process parameters and quality properties are very complicated. In this paper, a process model is developed by Backward Propagation (BP) Neural Network (NN) algorithm based on 16 groups of orthogonal experiment designed by Taguchi Method to express the relationships between 4 key process parameters and 2 key quality properties. Based on the modeling results, an intelligent parameters recommendation system is developed to predict end-product quality properties and printing time, and to recommend process parameters selection based on the process requirements. It can be used as a guideline for selecting the proper printing parameters in BJ to achieve the desired properties and help to reduce the printing time.
In Vivo In Situ Experimentation Projects by Innovative Cleantech Start-Ups in Paris
Authors: Bekhradi Alborz , Yannou Bernard , Cluzel François , Chabbert Frédérique , Farel Romain
Published: January 2016

Cities play an essential role in facilitating and supporting the real-world experimentations (for instance in public spaces with real users) of innovative products and services in the field of clean technologies. In this respect, the City of Paris has implemented an experimentation mechanism to help innovative start-ups improving their solutions and robustifying their business models in a multi-stakeholder eco-system. Nonetheless, a primary investigation demonstrated that the efficiency of these in vivo in situ experimentations have means of being improved.

To deal with this issue, the current paper proposes a critical review and a characterization of the existing projects related to clean technology and sustainability themes. A study over 25 experimentation projects results in identifying matches and mismatches between the expectations and the obtained results of tests by innovative start-ups. We have statistically demonstrated that the most important purpose of running experimentation projects by start-ups is to test and build a relevant “stakeholders network” around their businesses. Furthermore, we have assessed the influence of these experimentations on the design of innovative products.
Changing Subsystem Information Strategies Using Weighted Objectives: Increasing Robustness to Biased Information Passing
Authors: Austin-Breneman Jesse , Yu Bo Yang , Yang Maria C.
Published: January 2016

Complex system design requires managing competing objectives between many subsystems. Previous field research has demonstrated that subsystem designers may use biased information passing as a negotiation tactic and thereby reach sub-optimal system-level results due to local optimization behavior. One strategy to combat the focus on local optimization is an incentive structure that promotes system-level optimization. This paper presents a new subsystem incentive structure based on Multi-disciplinary Optimization (MDO) techniques for improving robustness of the design process to such biased information passing strategies. Results from simulations of different utility functions for a test suite of multi-objective problems quantify the system robustness to biased information passing strategies. Results show that incentivizing subsystems with this new weighted structure may decrease the error resulting from biased information passing.
Planning and Control of Aggressive Maneuvers for Perching on Inclined and Vertical Surfaces
Authors: Thomas Justin , Loianno Giuseppe , Pope Morgan , Hawkes Elliot W. , Estrada Matthew A. , Jiang Hao , Cutkosky Mark R. , Kumar Vijay
Published: January 2016

It is important to enable micro aerial vehicles to land and perch on different surfaces to save energy by cutting power to motors and to perform tasks such as persistent surveillance. In many cases, the best available surfaces may be vertical windows, walls, or inclined roof tops. In this paper, we present approaches and algorithms for aggressive maneuvering to enable perching of underactuated quadrotors on surfaces that are not horizontal. We show the design of a custom foot/gripper for perching on smooth surfaces. Then, we present control and planning algorithms for maneuvering to land on specified surfaces while satisfying constraints on actuation and sensing. Experimental results that include successful perching on vertical, glass surfaces validate the proposed techniques.
Minimizing the Energy Loss of the Bi-Articular Actuation in Bipedal Robots
Authors: Lahr Derek , Yi Hak , Hong Dennis
Published: January 2016

In this work, we investigate the effect actuator position on the theoretical energy consumption of an electrically powered bipedal robot. Specifically, considerable gains are possible through the optimization of the actuator placement relative to joints and their axes, in particular biarticular actuators, are proposed. The energy losses of electric actuators on the two most powerful and inefficient joints of a biped, the hip and the knee, are considered. In standing or walking tasks of a biped’s legs within mathematical model, furthermore, imposing constraints on the actuator placement is used in a genetic algorithm to find the optimum configuration of various biarticular configurations.
Experimental and Numerical Investigation of Automotive Aerodynamics Using DrivAer Model
Authors: Miao Lu , Mack Steffen , Indinger Thomas
Published: January 2016

The use of experimental and numerical investigation to predict the aerodynamic characteristics of road vehicles is a standard practice in automotive design and development. Fundamental research has been often conducted on generic models with limited applicability to realistic cars. The DrivAer model developed in TU München possesses more representative car features. To encourage the use of the DrivAer model in independent research work, the experimental results and some numerical results were published.

In this paper, a new developed wind tunnel setup of the DrivAer model was introduced. A new suspension system was designed in such a way that drag and lift force could be measured whilst the wheels are rolling on the moving ground without wheel struts (In this paper we call it wheels-on setup). The more close-truth experimental results of different rear end configurations were obtained. The lift force of the total model was firstly obtained. Additionally, the influences of the wheel struts and top sting were studied.

Numerical investigation for performing finite-volume-based Reynolds-averaged Navier-Stokes (RANS) for the prediction of aerodynamic forces of passenger vehicles developed was presented, using the open-source CFD toolbox OpenFOAM®.

Validation of the predictions was done on the basis of detailed comparisons to experimental wind tunnel data, both of the basic body (wheelhouse covered and without wheels) and the new wheels-on model. Results of drag coefficient were found to compare favourably to the experiments.
Design and Fabrication of Safe, Light-Weight, Flying Robots
Authors: Mulgaonkar Yash , Kientz Terry , Whitzer Mickey , Kumar Vijay
Published: January 2016

This work presents the design, fabrication, and testing of a novel lightweight yet sturdy cage for micro aerial vehicles. Fabricated from a polymer infused 12k carbon-fiber using a smart liquid silicone rubber (LSR) molding process, the cage weighs only 3g and is capable of sustaining impacts at speeds up to 6m/s. We also quantitatively and qualitatively characterize the rigidity and stiffness of the cage using a universal testing machine.

This paper subsequently describes the fabrication methodology employed for designing the cage to achieve the high strength-weight ratio. This involves 3D printing, silicon rubber molding, plaster mold rotocasting, wet layup of carbon fiber and finally autoclaving. Finally we demonstrate a 23g autonomous, pico quadrotor capable of sustaining stable flight with collisions with the environment.
Incorporating Fixed-Point and -Line Constraints and Tolerance Based Synthesis in 4MDS
Authors: Purwar Anurag , Bhapkar Saurabh , Ge Q. J.
Published: January 2016

This paper presents implementation of fixed-pivots, ground-link line, and tolerance based motion synthesis in the 4MDS (Four-Bar Motion Design System). This is a continuation of the first work reported on 4MDS, which provides an interactive, graphical, and geometric constraint based mechanism design system for the exact- and approximate-motion synthesis problems. Theoretical foundation of the 4MDS is laid over a kinematic mapping based unified formulation of the geometric constraints (circle, fixed-line, line-tangent-to-a-circle) associated with the mechanical dyads (RR, PR, and RP) of a planar four-bar mechanism. An efficient algorithm extracts the geometric constraints of a given motion task and determines the best dyad types as well as their dimensions that best fit to the motion. Often, Mechanism designers need to impose additional geometric constraints, such as specification of location of fixed pivots or ground-link line. If synthesized mechanism suffers from branch, circuit, or order defect, they may also desire rectified solutions by allowing a tolerance to certain or all task positions. Such functions are crucial to a practitioner and much needed during the conceptual design stage of machine design process.
Application of Sustainability Assessment to a Novel Plastic Recycling Process
Authors: Nagarajan Hari P. N. , Haapala Karl R.
Published: January 2016

Plastic waste can be handled with several traditional waste management strategies, including landfilling, incineration, and recycling. Several novel strategies for recycling plastic waste have been proposed and researched for practical use, however the sustainability of the novel processes have not been analyzed in detail. This paper outlines a strategy for recycling polyethylene terephthalate (PET) waste through pyrolysis. A sustainability assessment of the process is conducted to analyze the environmental, economic, and social performance of recycling PET waste into crude oil. Environmental performance is evaluated using life cycle assessment, and the ReCiPe, cumulative energy demand (CED), and cumulative exergy demand (CExD) impact assessment methods. Net present value analysis is used to assess the economic impacts of the process. To complete a holistic sustainability assessment, social benefits and impacts are presented through a qualitative review of the process. In addition, an environmental impact analysis of the production of virgin PET using the recovered crude oil is presented and compared with traditional virgin PET production in terms of sustainability performance metrics. CED and CExD impact results emphasize the conceivable evidence of plastic waste as an energy source. The research highlights the use of standardized impact assessment methods to realize the environmental, economic, and social benefits of recycling PET into crude oil. Furthermore, a review of various process improvements broadens the potential for optimization of the novel process to further elucidate the benefits of plastic recycling.
The Active Safety of the Automobile in the Future
Authors: Wu Huyao
Published: January 2016

The automobile industry has come a long way since the day of invention. The automobile is undergoing the complex and profound changes. The main themes are focused on fuel economy, environment protection, safety, comfort, and intelligentization. From both the status and tendency [1], several main problems of active safety will be presented in this paper, including the cyber physical system, dynamics control and the closed-loop system consisting of driver-vehicle-infrastructure (DVI).
A Geometrical Approach to the Inverse Kinematics of 6R Serial Robots With Offset Wrists
Authors: Trinh Cuong , Zlatanov Dimiter , Zoppi Matteo , Molfino Rezia
Published: January 2016

The computation of the joint-angle values of a 6R serial manipulator for a given end-effector pose is more difficult for architectures lacking the conventional spherical wrist. Despite this added complexity, such arms have increasingly gained acceptance as they provide better dexterity for a number of tasks. The paper presents a geometric-analysis method for the inverse kinematics of a robot with an offset wrist. The sought postures are shown to correspond to the roots of four separate univariate trigonometric equations for the sixth joint angle. A standard numerical solver is applied to derive all sets of possible real solutions. By back-substitution, all the remaining angular variables are found in succession. Two particular arm designs are considered and full sets of solutions are obtained by the discussed approach. The method is easy to implement and can be applied to various 6R serial robots.
A Finite Element Approach to Estimate the Detailed Deviation Zone in Coordinate Metrology
Authors: Lalehpour Amirali , Barari Ahmad , Jamiolahmadi Saeed
Published: January 2016

The exact detailed knowledge of deviation zone in a manufactured surface needs measurement of infinite number of points when the coordinate metrology is utilized. The coordinate metrology process provides deviation of the limited number of discrete points on a measured surface, but typically the process is not capable to explore any information of the surface regions between these measured points. A Finite Element approach for Deviation Zone Evaluation (DZE) on the entire inspected surface is presented in this paper. The developed DZE solution estimates the deviation values at any unmeasured point of the inspected surface when a detailed understanding of the surface geometric deviations is required. Implementation of the developed methodology is described and case study for typical industrial parts is presented. This methodology can be used for closed-loop of inspection and manufacturing processes when a compensation scheme is available to compensate the manufacturing errors based on the DZE data.
Tensile Properties of Inkjet 3D Printed Parts: Critical Process Parameters and Their Efficient Analysis
Authors: Mueller Jochen , Kim Shi En , Shea Kristina , Daraio Chiara
Published: January 2016

To design and optimize for capabilities of additive manufacturing processes it is also necessary to understand and model their variations in geometric and mechanical properties. In this paper, such variations of inkjet 3D printed parts are systematically investigated by analyzing parameters of the whole process, i.e. storage of the material, printing, testing, and storage of finished parts. The goal is to both understand the process and determine the parameters that lead to the best mechanical properties and the most accurate geometric properties. Using models based on this understanding, we can design and optimize parts, and fabricate and test them successfully, thus closing the loop. Since AM materials change rapidly and this process will have to be repeated, it is shown how to create a cost and time efficient experimental design with the one-factor-at-a-time and design of experiments methods, yielding high statistical accuracies for both main and interaction effects. The results show that the number of intersections between layers and nozzles along the load-direction has the strongest impact on the mechanical properties followed by the UV exposure time, which is investigated by part spacing, the position on the printing table and the expiry date of the material. Minor effects are found for the storage time and the surface roughness is not affected by any factor. Nozzle blockage, which leads to a smaller flow-rate of printing material, significantly affected the width and waviness of the printed product. Furthermore, the machine’s warm-up time is found to be an important factor.
Folding Flat Crease Patterns With Thick Materials
Authors: Ku Jason S. , Demaine Erik D.
Published: January 2016

Modeling folding surfaces with nonzero thickness is of practical interest for mechanical engineering. There are many existing approaches that account for material thickness in folding applications. We propose a new systematic and broadly applicable algorithm to transform certain flat-foldable crease patterns into new crease patterns with similar folded structure but with a facet-separated folded state. We provide conditions on input crease patterns for the algorithm to produce a thickened crease pattern avoiding local self intersection, and provide bounds for the maximum thickness that the algorithm can produce for a given input. We demonstrate these results in parameterized numerical simulations and physical models.
A QP-Based Approach to Kinematic Motion Planning of Multibody Systems
Authors: Kim Junggon , Mukherjee Rudranarayan
Published: January 2016

This article presents a quadratic programming (QP) based approach to local kinematic motion planning of general multibody robotic systems. Given kinematic constraints and targets such as desired positions and orientations in Cartesian space, we find locally optimal joint velocities toward the targets at every time step by formulating the problem into a constrained optimization with a quadratic objective function and linear constraints in terms of the joint velocities. The solution is integrated to obtain the joint displacements at the next time step, and this process is repeated until reaching the targets or converging to a certain configuration. Our formulation based on relative Jacobian is particularly useful in handling constraints on relative motions, which arises in many practical problems such as dual-arm manipulation and self-collision avoidance, in a concise manner. A brief overview of our software implementation and its applications to manipulation and mobility planning of a simulated multi-limbed robot are also presented.
Optimization of oncological 18F‐FDG PET/CT imaging based on a multiparameter analysis
Authors: Menezes Vinicius O. , Machado Marcos A. D. , Queiroz Cleiton C. , Souza Susana O. , d'Errico Francesco , Namías Mauro , Larocca Ticiana F. , Soares Milena B. P.
Published: January 2016

Purpose:

This paper describes a method to achieve consistent clinical image quality in 18F‐FDG scans accounting for patient habitus, dose regimen, image acquisition, and processing techniques.

Methods:

Oncological PET/CT scan data for 58 subjects were evaluated retrospectively to derive analytical curves that predict image quality. Patient noise equivalent count rate and coefficient of variation (CV) were used as metrics in their analysis. Optimized acquisition protocols were identified and prospectively applied to 179 subjects.

Results:

The adoption of different schemes for three body mass ranges (<60 kg, 60–90 kg, >90 kg) allows improved image quality with both point spread function and ordered‐subsets expectation maximization‐3D reconstruction methods. The application of this methodology showed that CV improved significantly (p < 0.0001) in clinical practice.

Conclusions:

Consistent oncological PET/CT image quality on a high‐performance scanner was achieved from an analysis of the relations existing between dose regimen, patient habitus, acquisition, and processing techniques. The proposed methodology may be used by PET/CT centers to develop protocols to standardize PET/CT imaging procedures and achieve better patient management and cost‐effective operations.
Antiviral Activities of Different Interferon Types and Subtypes against Hepatitis E Virus Replication
Authors: Todt Daniel , François Catherine , Anggakusuma  , Behrendt Patrick , Engelmann Michael , Knegendorf Leonard , Vieyres Gabrielle , Wedemeyer Heiner , Hartmann Rune , Pietschmann Thomas , Duverlie Gilles , Steinmann Eike
Published: January 2016

Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus
Orthohepevirus
in the family
Hepeviridae
. HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients, and type I interferon (IFN) has been evaluated in a few infected transplant patients
in vivo
. In this study, the antiviral effects of different exogenously administered interferons were investigated by using state-of-the-art subgenomic replicon and full-length HEV genome cell culture models. Hepatitis C virus (HCV) subgenomic replicons based on the genotype 2a JFH1 isolate served as the reference. The experiments revealed that HEV RNA replication was inhibited by the application of all types of IFN, including IFN-α (type I), IFN-γ (type II), and IFN-λ3 (type III), but to a far lesser extent than HCV replication. Simultaneous determination of interferon-stimulated gene (ISG) expression levels for all IFN types demonstrated efficient downregulation by HEV. Furthermore, different IFN-α subtypes were also able to block viral replication in combination with ribavirin. The IFN-α subtypes 2a and 2b exerted the strongest antiviral activity against HEV. In conclusion, these data demonstrate for the first time moderate anti-HEV activities of types II and III IFNs and different IFN-α subtypes. As HEV employed a potent anti-interferon mechanism by restricting ISG expression, exogenous application of IFNs as immunotherapy should be carefully assessed.
The Investigational Fungal Cyp51 Inhibitor VT-1129 Demonstrates Potent
In Vitro
Activity against Cryptococcus neoformans and Cryptococcus gattii
Authors: Lockhart Shawn R. , Fothergill Annette W. , Iqbal Naureen , Bolden Carol B. , Grossman Nina T. , Garvey Edward P. , Brand Stephen R. , Hoekstra William J. , Schotzinger Robert J. , Ottinger Elizabeth , Patterson Thomas F. , Wiederhold Nathan P.
Published: January 2016

The
in vitro
activities of the novel fungal Cyp51 inhibitor VT-1129 were evaluated against a large panel of
Cryptococcus neoformans
and
Cryptococcus gattii
isolates. VT-1129 demonstrated potent activities against both
Cryptococcus
species as demonstrated by low MIC
50
and MIC
90
values. For
C. gattii
, the
in vitro
potency was maintained against all genotypes. In addition, significantly lower geometric mean MICs were observed for VT-1129 than for fluconazole against
C. neoformans
, including isolates with reduced fluconazole susceptibility.
Variation in Inflammatory Response during Pneumococcal Infection Is Influenced by Host-Pathogen Interactions but Associated with Animal Survival
Authors: Jonczyk Magda S. , Escudero Laura , Sylvius Nicolas , Norman Martin , Henriques-Normark Birgitta , Andrew Peter W.
Published: January 2016

Inflammation is a crucial part of innate immune responses but, if imbalanced, can lead to serious clinical conditions or even death. Cytokines regulate inflammation, and studies report their impact on clinical outcome. However, host and pathogen genetic backgrounds influence cytokine production, making it difficult to evaluate which inflammatory profiles (if any) relate to improved prognosis.
Streptococcus pneumoniae
is a common human pathogen associated with asymptomatic nasopharyngeal carriage. Infrequently, it can lead to a wide range of diseases with high morbidity and mortality rates. Studies show that both pneumococcal serotype and host genetic background affect the development of disease and contribute to variation in inflammatory responses. In this study, we investigated the impact of the host and pneumococcal genetic backgrounds on pulmonary cytokine responses and their relationship to animal survival. Two inbred mouse strains, BALB/c and CBA/Ca, were infected with 10 pneumococcal strains, and the concentrations of six pulmonary cytokines were measured at 6 h and 24 h postinfection. Collected data were analyzed by principal-component analysis to identify whether there is any pattern in the observed cytokine variation. Our results show that host-pneumococcus combination was at the core of observed variation in cytokine responses, yet the resulting cytokine profile discriminated only between survivors and fatalities but not mouse or pneumococcal strains used during infection. Therefore, our results indicate that although alternative inflammatory profiles are generated during pneumococcal infection, a common pattern emerged, which determined the clinical outcome of pneumococcal infections.
Insights into the Function of a Second, Nonclassical Ahp Peroxidase, AhpA, in Oxidative Stress Resistance in Bacillus subtilis
Authors: Broden Nicole J. , Flury Sarah , King Alyssa N. , Schroeder Braden W. , Coe Gabrielle Dierker , Faulkner Melinda J.
Published: January 2016

Organisms growing aerobically generate reactive oxygen-containing molecules, such as hydrogen peroxide (H
2
O
2
). These reactive oxygen molecules damage enzymes and DNA and may even cause cell death. In response,
Bacillus subtilis
produces at least nine potential peroxide-scavenging enzymes, two of which appear to be the primary enzymes responsible for detoxifying peroxides during vegetative growth: a catalase (encoded by
katA
) and an alkylhydroperoxide reductase (Ahp, encoded by
ahpC
). AhpC uses two redox-active cysteine residues to reduce peroxides to nontoxic molecules. A specialized thioredoxin-like protein, AhpF, is then required to restore oxidized AhpC back to its reduced state. Curiously,
B. subtilis
has two genes encoding Ahp:
ahpC
and
ahpA
. Although AhpC is well characterized, very little is known about AhpA. In fact, numerous bacterial species have multiple
ahp
genes; however, these additional Ahp proteins are generally uncharacterized. We seek to understand the role of AhpA in the bacterium's defense against toxic peroxide molecules in relation to the roles previously assigned to AhpC and catalase. Our results demonstrate that AhpA has catalytic activity similar to that of the primary enzyme, AhpC. Furthermore, our results suggest that a unique thioredoxin redox protein, AhpT, may reduce AhpA upon its oxidation by peroxides. However, unlike AhpC, which is expressed well during vegetative growth, our results suggest that AhpA is expressed primarily during postexponential growth.

IMPORTANCE
B. subtilis
appears to produce nine enzymes designed to protect cells against peroxides; two belong to the Ahp class of peroxidases. These studies provide an initial characterization of one of these Ahp homologs and demonstrate that the two Ahp enzymes are not simply replicates of each other, suggesting that they instead are expressed at different times during growth of the cells. These results highlight the need to further study the Ahp homologs to better understand how they differ from one another and to identify their function, if any, in protection against oxidative stress. Through these studies, we may better understand why bacteria have multiple enzymes designed to scavenge peroxides and thus have a more accurate understanding of oxidative stress resistance.
Anaerobic Growth of Haloarchaeon Haloferax volcanii by Denitrification Is Controlled by the Transcription Regulator NarO
Authors: Hattori Tatsuya , Shiba Hiromichi , Ashiki Ken-ichi , Araki Takuma , Nagashima Yoh-kow , Yoshimatsu Katsuhiko , Fujiwara Taketomo
Published: January 2016

The extremely halophilic archaeon
Haloferax volcanii
grows anaerobically by denitrification. A putative DNA-binding protein, NarO, is encoded upstream of the respiratory nitrate reductase gene of
H. volcanii
. Disruption of the
narO
gene resulted in a loss of denitrifying growth of
H. volcanii
, and the expression of the recombinant NarO recovered the denitrification capacity. A novel CX

n

CXCX
7
C motif showing no remarkable similarities with known sequences was conserved in the N terminus of the NarO homologous proteins found in the haloarchaea. Restoration of the denitrifying growth was not achieved by expression of any mutant NarO in which any one of the four conserved cysteines was individually replaced by serine. A promoter assay experiment indicated that the
narO
gene was usually transcribed, regardless of whether it was cultivated under aerobic or anaerobic conditions. Transcription of the genes encoding the denitrifying enzymes nitrate reductase and nitrite reductase was activated under anaerobic conditions. A putative
cis
element was identified in the promoter sequence of haloarchaeal denitrifying genes. These results demonstrated a significant effect of NarO, probably due to its oxygen-sensing function, on the transcriptional activation of haloarchaeal denitrifying genes.

IMPORTANCE
H. volcanii
is an extremely halophilic archaeon capable of anaerobic growth by denitrification. The regulatory mechanism of denitrification has been well understood in bacteria but remains unknown in archaea. In this work, we show that the helix-turn-helix (HTH)-type regulator NarO activates transcription of the denitrifying genes of
H. volcanii
under anaerobic conditions. A novel cysteine-rich motif, which is critical for transcriptional regulation, is present in NarO. A putative
cis
element was also identified in the promoter sequence of the haloarchaeal denitrifying genes.
Uncovering the Transmembrane Metal Binding Site of the Novel Bacterial Major Facilitator Superfamily-Type Copper Importer CcoA
Authors: Khalfaoui-Hassani Bahia , Verissimo Andreia F. , Koch Hans-Georg , Daldal Fevzi
Published: January 2016

Uptake and trafficking of metals and their delivery to their respective metalloproteins are important processes. Cells need precise control of each step to avoid exposure to excessive metal concentrations and their harmful consequences. Copper (Cu) is a required micronutrient used as a cofactor in proteins. However, in large amounts, it can induce oxidative damage; hence, Cu homeostasis is indispensable for cell survival. Biogenesis of respiratory heme-Cu oxygen (HCO) reductases includes insertion of Cu into their catalytic subunits to form heme-Cu binuclear centers. Previously, we had shown that CcoA is a major facilitator superfamily (MFS)-type bacterial Cu importer required for biogenesis ofcbb3-type cytochromecoxidase (cbb3-Cox). Here, usingRhodobacter capsulatus, we focused on the import and delivery of Cu tocbb3-Cox. By comparing the CcoA amino acid sequence with its homologues from other bacterial species, we located several well-conserved Met, His, and Tyr residues that might be important for Cu transport. We determined the topology of the transmembrane helices that carry these residues to establish that they are membrane embedded, and substituted for them amino acids that do not ligand metal atoms. Characterization of these mutants for their uptake of radioactive64Cu andcbb3-Cox activities demonstrated that Met233 and His261 of CcoA are essential and Met237 and Met265 are important, whereas Tyr230 has no role for Cu uptake orcbb3-Cox biogenesis. These findings show for the first time that CcoA-mediated Cu import relies on conserved Met and His residues that could act as metal ligands at the membrane-embedded Cu binding domain of this transporter.

IMPORTANCECu is a micronutrient that is both essential and toxic; hence, its cellular homeostasis is crucial. Respiratorycbb3-type cytochromecoxidases (cbb3-Cox) are Cu-containing energy-transducing enzymes that are important for many microaerophilic processes, including photosynthesis, respiration, and bacterial pathogenesis. How Cu is incorporated intocbb3-Cox enzymes is not well known. So far, CcoA is the only known major facilitator superfamily (MFS)-type transporter required for Cu import into the bacterial cytoplasm and forcbb3-Cox biogenesis. This study shows that the membrane-embedded, universally conserved Met and His residues of CcoA are essential for its Cu import function and also for its role incbb3-Cox biogenesis, shedding light on the mechanism of function of this bacterial prototypical Cu importer.
Physical activity and exercise lower blood pressure in individuals with hypertension: narrative review of 27 RCTs
Authors: Börjesson Mats , Onerup Aron , Lundqvist Stefan , Dahlöf Björn
Published: January 2016

Regular physical activity (PA) reduces the blood pressure (BP) of individuals with hypertension. The present review analysed the scientific evidence for the BP lowering effect of aerobic PA in 27 randomised controlled studies on individuals with hypertension, and shows that regular medium-to-high-intensity aerobic activity reduces the BP by a mean of 11/5 mm Hg (level of evidence, 3+). In addition, three randomised controlled trials (RCTs) on isometric (static) activity showed a BP reduction of similar magnitude in hypertensives; dynamic resistance training may show less effect, as shown in five available RCTs (level of evidence 2+). As both the prevalence of hypertension and physical inactivity are high and increasing in today's society, PA has a great role to play as a single (when indicated) or additive treatment for hypertension. Furthermore, as competitive athletes are getting older, it can be expected that more athletes at different competitive levels will have hypertension. Certain considerations must be applied regarding evaluation and treatment of hypertension in athletes. Eligibility for competitive sports may be affected if target organ damage (TOD) is present; however, an athlete with well-controlled BP, having no additional risk factors or TOD, is eligible for all sports.
‘Just so you know, the patient is staff’: healthcare professionals’ perceptions of caring for healthcare professional–patients
Authors: Svantesson Mia , Carlsson E , Prenkert M , Anderzén-Carlsson A
Published: January 2016

Objective

To explore healthcare professionals’ conceptions of the care of patients who are also healthcare professionals.

Design

Explorative, with a qualitative, phenomenographic approach.

Participants and setting

16 healthcare personnel within different professions (doctors, nurses, assistant nurses, physiotherapists, occupational therapists) were interviewed about the care of 32 patients who were themselves members of different healthcare professions, in one healthcare organisation in Sweden.

Results

The care of patients who are healthcare professionals was conceived in five different ways, as: usual, dutiful, prioritised and secure, insecure and responsive. An initial conception was that their care was usual, just as for any other patient, and also a perceived duty to treat them and to protect their right to be a patient—as any other patient. Exploring further, informants described that these patients did receive secure and prioritised care, as the informants experienced making a greater commitment, especially doctors giving privileges to doctor–patients. A conception of insecure care infused the informants’ descriptions. This comprised of them feeling intimidated in their professional role, feeling affected by colleagues’ stressful behaviour and ambiguity whether the healthcare professional–patient could be regarded as a competent professional. The deepest way of understanding care seemed to be responsive care, such as acknowledging and respecting the patient's identity and responding to their wishes of how treatment was to be met.

Conclusions

Caring for healthcare professionals seems to trigger different ethical approaches, such as deontology and ethics of care. According to ethics of care, the findings may indeed suggest that these patients should be cared for just as any other patients would be, but only if this means that they are cared for as persons, that is, they are given ‘person-centred care’. This would imply balancing between acknowledging the vulnerable patient in the colleague and acknowledging the identity of the colleague in the patient.
Unequal socioeconomic distribution of the primary care workforce: whole-population small area longitudinal study
Authors: Asaria Miqdad , Cookson Richard , Fleetcroft Robert , Ali Shehzad
Published: January 2016

Objective

To measure changes in socioeconomic inequality in the distribution of family physicians (general practitioners (GPs)) relative to need in England from 2004/2005 to 2013/2014.

Design

Whole-population small area longitudinal data linkage study.

Setting

England from 2004/2005 to 2013/2014.

Participants

32 482 lower layer super output areas (neighbourhoods of 1500 people on average).

Main outcome measures

Slope index of inequality (SII) between the most and least deprived small areas in annual full-time equivalent GPs (FTE GPs) per 100 000 need adjusted population.

Results

In 2004/2005, inequality in primary care supply as measured by the SII in FTE GPs was 4.2 (95% CI 3.1 to 5.3) GPs per 100 000. By 2013/2014, this SII had fallen to −0.7 (95% CI −2.5 to 1.1) GPs per 100 000. The number of FTE GPs per 100 000 serving the most deprived fifth of small areas increased over this period from 54.0 to 60.5, while increasing from 57.2 to 59.9 in the least deprived fifth, so that by the end of the study period there were more GPs per 100 000 need adjusted population in the most deprived areas than in the least deprived. The increase in GP supply in the most deprived fifth of neighbourhoods was larger in areas that received targeted investment for establishing new practices under the ‘Equitable Access to Primary Medical Care’.

Conclusions

There was a substantial reduction in socioeconomic inequality in family physician supply associated with national policy. This policy may not have completely eliminated socioeconomic inequality in family physician supply since existing need adjustment formulae do not fully capture the additional burden of multimorbidity in deprived neighbourhoods. The small area approach introduced in this study can be used routinely to monitor socioeconomic inequality of access to primary care and to indicate workforce shortages in particular neighbourhoods.http://creativecommons.org/licenses/by/4.0