bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding quit decisions in primary care: a qualitative study of older GPs
Authors: Sansom Anna , Calitri Raff , Carter Mary , Campbell John
Published: February 2016

Objective

To investigate the reasons behind intentions to quit direct patient care among experienced general practitioners (GPs) aged 50–60 years.

Design and setting

Qualitative study based on semistructured interviews with GPs in the South West region of England. Transcribed interviews were analysed thematically.

Participants

23 GPs aged 50–60 years: 3 who had retired from direct patient care before age 60, and 20 who intended to quit direct patient care within the next 5 years.

Results

The analysis identified four key themes: early retirement is a viable option for many GPs; GPs have employment options other than undertaking direct patient care; GPs report feeling they are doing an (almost) undoable job; and GPs may have other aspirations that pull them away from practice. Findings from this study confirmed those from earlier research, with high workload, ageing and health, family and domestic life, and organisational change all influencing GPs’ decisions about when to retire/quit direct patient care. However, in addition, GPs expressed feelings of insecurity and uncertainty regarding the future of general practice, low morale, and issues regarding accountability (appraisal and revalidation) and governance. Suggestions about how to help retain GPs within the active clinical workforce were offered, covering individual, practice and organisational levels.

Conclusions

This research highlights aspects of the current professional climate for GPs that are having an impact on retirement decisions. Any future changes to policy or practice to help retain experienced GPs will benefit from this informed understanding of GPs’ views. Key factors to take into account include: making the GP workload more manageable; managing change sympathetically; paying attention to GPs’ own health; improving confidence in the future of general practice; and improving GP morale.
Analysis of stand basal area development of thinned and unthinned Acer rubrum forests in the upper Great Lakes region, USA
Authors: Pszwaro Justin L. , D’Amato Anthony W. , Burk Thomas E. , Russell Matthew B. , Palik Brian J. , Strong Terry F.
Published: February 2016

Red maple (Acer rubrum L.), historically a common but not abundant tree species in North America, has increased in abundance throughout its range over the last several decades; however, it has received little attention in growth and yield studies. The objectives of this study were to (i) evaluate the effects of stocking level and stand density on overall patterns of red maple stand productivity and (ii) quantify these relationships across a wide range of stand age, site quality, geographic location, and climatic conditions. We used long-term measurements from 52 sites in Wisconsin and Michigan to examine growth responses of even-aged red maple stands to various levels of thinning. Using linear, mixed-effects modeling, future stand-level red maple basal area was modeled as a function of stand and plot characteristics and climatic variables. Growing season precipitation and its interaction with initial red maple basal area were significant predictors; however, they only collectively reduced the mean squared error by 2.1% relative to a base model containing solely stand and plot factors. Model projections indicated there was little difference in predicted future basal area for the range of climate conditions experienced by these stands highlighting red maple’s wide tolerance of environmental conditions across the region.
CAROTID WALL MEASUREMENT AND ASSESSMENT BASED ON PIXEL-BASED AND LOCAL TEXTURE DESCRIPTORS
Authors: ROSATI SAMANTA , MEIBURGER KRISTEN MARIKO , BALESTRA GABRIELLA , ACHARYA U. RAJENDRA , MOLINARI FILIPPO
Published: February 2016

Aim of this paper is to develop an automated system for the classification and characterization of carotid wall status and to develop a robust system based on local texture descriptors. A database of 200 longitudinal ultrasound images of carotid artery is used. One-hundred images with Intima-Media Thickness (IMT) value higher than 0.8[Formula: see text]mm are considered as high risk. Six different rectangular pixel neighborhoods were considered: four areas centered on the selected element, with sizes [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] pixels, and two noncentered areas with sizes [Formula: see text] pixels upwards and downwards. We have extracted various texture descriptors (31 based on the co-occurrence gray level matrix, 13 based on the spatial gray level dependence matrix, and 20 based on the gray level run length matrix (GLRLM) from neighborhood. We have used Quick Reduct Algorithm to select 12 most discriminant features from extracted 211 features. Each pixel is then assigned to the vessel lumen, to the intima-media complex, or to the adventitia by using an integrated system of three feed-forward neural networks. The boundaries between the three regions are used to estimate the IMT value. The texture features associated with GLRLM are found to be clinically most significant. We have obtained an overall classification accuracy of 79.5%, sensitivity of 87%, and specificity of 72%. We observed a unique classification pattern between low risk and high risk images: in the latter ones, a considerable number of pixels of the intima–media complex ([Formula: see text]) was classified as belonging to the adventitia. This percentage is statistically higher than that of low risk images ([Formula: see text]; [Formula: see text]). Locally extracted and pixel-based descriptors are able to capture the inner characteristics of the carotid wall. The presence of misclassified pixels in the intima–media complex is associated to higher cardiovascular risk.
Survival of Burgess Shale-type animals in a Middle Ordovician deep-water setting
Authors: Hearing Thomas W. , Legg David A. , Botting Joseph P. , Muir Lucy A. , McDermott Patrick , Faulkner Stephanie , Taylor Adam C. , Brasier Martin D.
Published: February 2016

Exceptional preservation of non-biomineralized arthropods, sponges and vermiform taxa occurs in the Darriwilian (Middle Ordovician) Llanfallteg Formation of South Wales, UK. The assemblage contains elements typical of Ordovician communities juxtaposed with those more commonly associated with Cambrian Konservat-Lagerstätten. This assemblage is preserved in rocks of a deep-marine succession dominated by fine-grained siliciclastic and volcaniclastic density-current deposits. Non-biomineralized taxa of Cambrian aspect are preserved as pyritized carbonaceous compressions on the spectrum of Burgess Shale-type preservation. Trilobites with phosphatized digestive structures have also been recovered. The assemblage of the Llanfallteg Formation Konservat-Lagerstätte demonstrates that some Burgess Shale-type faunal elements survived into the Middle Ordovician within cool, deep-water refugia in the Welsh Basin, offshore from communities dominated by typical Ordovician taxa.

Supplementary material:
Assemblage composition data and sedimentological images can be found at
https://doi.org/10.6084/m9.figshare.c.2182218
.
Variability and heterogeneity of the petrophysical properties of extensional carbonate fault rocks, Malta
Authors: Michie E. A. H. , Haines T. J.
Published: February 2016

Selected carbonate-hosted normal fault zones on the island of Malta have been analysed to assess the potential impact of fault rocks on fluid flow (i.e. fault seal). Fault displacement ranging from <1 to 90 m has allowed systematic investigation of the evolution of fault-rock types, distribution and properties with increasing displacement. The focus has been on examining locations of fault-rock formation, because this significantly affects fluid-flow pathways across and along faults, and the types of fault rock formed. The location of fault rock is dependent on the fault-zone architecture. Fault zones on Malta have architectures with multiple slip surfaces within weaker carbonate layers, distributing fault rock onto several slip surfaces. This distribution prevents formation of a continuous fault core, particularly at lower displacements (<30 m). The discontinuous fault core causes these faults to be transmissive, allowing fluids to flow across the fault. The hydraulic behaviour is also a function of the deformation mechanisms active in the formation of fault rocks. Lithological heterogeneity in a faulted carbonate succession leads to a variety of deformation mechanisms, generating up to nine different fault-rocks types with a range of deformation microstructures along a single slip surface. The type of fault rock formed is a function of the host rock texture, juxtaposition, displacement and deformation conditions. Each deformation microstructure has different petrophysical properties, causing the porosity and permeability to vary along-strike and downdip on any slip surface, affecting the fault’s hydraulic behaviour. The extent of the poroperm variation depends on lithofacies juxtaposition and displacement: juxtaposition of similar lithofacies reduces poroperm variation and juxtaposing different lithofacies at higher displacements (>30 m) increases the range of poroperm.
Reservoir characterization using electrofacies analysis in the sandstone reservoir of the Norne Field (offshore Norway)
Authors: Correia Gil G. , Schiozer Denis J.
Published: February 2016

The Norne Field reservoir sandstone comprises Early–Middle Jurassic interbedded sandstones and shales to massive sandstones with some thin continuous cemented interlayers. A detailed characterization of the geological heterogeneities through electrofacies analysis, together with the simulation grid refinement, has been used to derive representative facies and petrophysical models (porosity, net-to-gross (NtG) and permeability).

An electrofacies database was created comprising six rock types, ranging from cemented carbonates through shales and into clean sandstones. In the absence of available cored sections, the electrofacies scheme was validated by the geological and petrophysical reports of 26 wells using gamma-ray, neutron and density logs. An artificial neural network algorithm enabled the probabilistic discrimination of the different types of electrofacies, with a sampling rate of 0.125 m. This high-resolution electrofacies database, together with a high-resolution geomodel grid, enabled us to map the fine-scale heterogeneities mainly materialized by decimetre shales and cemented layers that could represent stratigraphic barriers to vertical fluid displacement.

The high-resolution datasets created in this study will form the working basis on which to perform a probabilistic and multi-objective history matching guided by production and 4D seismic data, and assisted by geostatistical parameterization techniques.
Real-Time Reachability for Verified Simplex Design
Authors: Johnson Taylor T. , Bak Stanley , Caccamo Marco , Sha Lui
Published: February 2016

The Simplex architecture ensures the safe use of an unverifiable complex/smart controller by using it in conjunction with a verified safety controller and verified supervisory controller (switching logic). This architecture enables the safe use of smart, high-performance, untrusted, and complex control algorithms to enable autonomy without requiring the smart controllers to be formally verified or certified. Simplex incorporates a supervisory controller that will take over control from the unverified complex/smart controller if it misbehaves and use a safety controller. The supervisory controller should (1) guarantee that the system never enters an unsafe state (safety), but should also (2) use the complex/smart controller as much as possible (minimize conservatism). The problem of precisely and correctly defining the switching logic of the supervisory controller has previously been considered either using a control-theoretic optimization approach or through an offline hybrid-systems reachability computation. In this work, we show that a combined online/offline approach that uses aspects of the two earlier methods, along with a real-time reachability computation, also maintains safety, but with significantly less conservatism, allowing the complex controller to be used more frequently. We demonstrate the advantages of this unified approach on a saturated inverted pendulum system, in which the verifiable region of attraction is over twice as large compared to the earlier approach. Additionally, to validate the claims that the real-time reachability approach may be implemented on embedded platforms, we have ported and conducted embedded hardware studies using both ARM processors and Atmel AVR microcontrollers. This is the first ever demonstration of a hybrid-systems reachability computation in real time on actual embedded platforms, which required addressing significant technical challenges.
Anarchy Is Free in Network Creation
Authors: Graham Ronald , Hamilton Linus , Levavi Ariel , Loh Po-Shen
Published: February 2016

The Internet has emerged as perhaps the most important network in modern computing, but rather miraculously, it was created through the individual actions of a multitude of agents rather than by a central planning authority. This motivates the game-theoretic study of network formation, and our article considers one of the most well-studied models, originally proposed by Fabrikant et al. In the model, each of
n
agents corresponds to a vertex, which can create edges to other vertices at a cost of α each, for some parameter α. Every edge can be freely used by every vertex, regardless of who paid the creation cost. To reflect the desire to be close to other vertices, each agent’s cost function is further augmented by the sum total of all (graph-theoretic) distances to all other vertices.

Previous research proved that for many regimes of the (α,
n
) parameter space, the total social cost (sum of all agents’ costs) of every Nash equilibrium is bounded by at most a constant multiple of the optimal social cost. In algorithmic game-theoretic nomenclature, this approximation ratio is called the price of anarchy. In our article, we significantly sharpen some of those results, proving that for all constant nonintegral α > 2, the price of anarchy is in fact 1 +
o
(1); that is, not only is it bounded by a constant, but also it tends to 1 as
n
→ ∞. For constant integral α ⩾ 2, we show that the price of anarchy is bounded away from 1. We provide quantitative estimates on the rates of convergence for both results.
Design and Implementation of Warbler Family of Lightweight Pseudorandom Number Generators for Smart Devices
Authors: Mandal Kalikinkar , Fan Xinxin , Gong Guang
Published: February 2016

With the advent of ubiquitous computing and the Internet of Things (IoT), the security and privacy issues for various smart devices such as radio-frequency identification (RFID) tags and wireless sensor nodes are receiving increased attention from academia and industry. A number of lightweight cryptographic primitives have been proposed to provide security services for resource-constrained smart devices. As one of the core primitives, a cryptographically secure pseudorandom number generator (PRNG) plays an important role for lightweight embedded applications. The most existing PRNGs proposed for smart devices employ true random number generators as a component, which generally incur significant power consumption and gate count in hardware. In this article, we present Warbler family, a new pseudorandom number generator family based on nonlinear feedback shift registers (NLFSRs) with desirable randomness properties. The design of the Warbler family is based on the combination of modified de Bruijn blocks together with a nonlinear feedback Welch-Gong (WG) sequence generator, which enables us to precisely characterize the randomness properties and to flexibly adjust the security level of the resulting PRNG. Some criteria for selecting parameters of the Warbler family are proposed to offer the maximum level of security. Two instances of the Warbler family are also described, which feature two different security levels and are dedicated to EPC C1 Gen2 RFID tags and wireless sensor nodes, respectively. The security analysis shows that the proposed instances not only can pass the cryptographic statistical tests recommended by the EPC C1 Gen2 standard and NIST but also are resistant to the cryptanalytic attacks such as algebraic attacks, cube attacks, time-memory-data tradeoff attacks, Mihaljević et al.’s attacks, and weak internal state and fault injection attacks. Our ASIC implementations using a 65nm CMOS process demonstrate that the proposed two lightweight instances of the Warbler family can achieve good performance in terms of speed and area and provide ideal solutions for securing low-cost smart devices.
Coderunner
Authors: Lobb Richard , Harlow Jenny
Published: February 2016

How should we assess programming skills? Asking students to write code in a traditional hand-written exam can produce results like those in Figure 1. It is nearly impossible to meaningfully grade such code. With sufficient effort one can get some idea of whether the general idea is correct, but to assess programming skill we need much more than this. For example, there will almost certainly be errors in the code; how do we know whether the student would be able to correct those errors or not?
Forbidden-Set Distance Labels for Graphs of Bounded Doubling Dimension
Authors: Abraham Ittai , Chechik Shiri , Gavoille Cyril , Peleg David
Published: February 2016

This article proposes a forbidden-set labeling scheme for the family of unweighted graphs with doubling dimension bounded by α. For an
n
-vertex graph
G
in this family, and for any desired precision parameter ϵ > 0, the labeling scheme stores an
O
(1 + ϵ
− 1
)
2α
log
2
n
-bit label at each vertex. Given the labels of two end-vertices
s
and
t
, and the labels of a set
F
of “forbidden” vertices and/or edges, our scheme can compute, in
O
(1 + ϵ
− 1
)
2α
· |
F
|
2
log
n
time, a 1 + ϵ stretch approximation for the distance between
s
and
t
in the graph
G
∖
F
. The labeling scheme can be extended into a forbidden-set labeled routing scheme with stretch 1 + ϵ for graphs of bounded doubling dimension.
Attack-Resilient Sensor Fusion for Safety-Critical Cyber-Physical Systems
Authors: Ivanov Radoslav , Pajic Miroslav , Lee Insup
Published: February 2016

This article focuses on the design of safe and attack-resilient Cyber-Physical Systems (CPS) equipped with multiple sensors measuring the same physical variable. A malicious attacker may be able to disrupt system performance through compromising a subset of these sensors. Consequently, we develop a precise and resilient sensor fusion algorithm that combines the data received from all sensors by taking into account their specified precisions. In particular, we note that in the presence of a shared bus, in which messages are broadcast to all nodes in the network, the attacker’s impact depends on what sensors he has seen before sending the corrupted measurements. Therefore, we explore the effects of communication schedules on the performance of sensor fusion and provide theoretical and experimental results advocating for the use of the
Ascending
schedule, which orders sensor transmissions according to their precision starting from the most precise. In addition, to improve the accuracy of the sensor fusion algorithm, we consider the dynamics of the system in order to incorporate past measurements at the current time. Possible ways of mapping sensor measurement history are investigated in the article and are compared in terms of the confidence in the final output of the sensor fusion. We show that the precision of the algorithm using history is never worse than the no-history one, while the benefits may be significant. Furthermore, we utilize the complementary properties of the two methods and show that their combination results in a more precise and resilient algorithm. Finally, we validate our approach in simulation and experiments on a real unmanned ground robot.
Concurrency Testing Using Controlled Schedulers
Authors: Thomson Paul , Donaldson Alastair F. , Betts Adam
Published: February 2016

We present an independent empirical study on concurrency testing using controlled schedulers. We have gathered 49 buggy concurrent software benchmarks, drawn from public code bases, which we call
SCTBench
. We applied a modified version of an existing concurrency testing tool to SCTBench, testing five controlled scheduling techniques: depth-first search, preemption bounding, delay bounding, a controlled random scheduler, and probabilistic concurrency testing (PCT). We attempt to answer several research questions: Which technique performs the best, in terms of bug finding ability? How effective are the two main schedule bounding techniques—preemption bounding and delay bounding—at finding bugs? What challenges are associated with applying concurrency testing techniques to existing code? Can we classify certain benchmarks as trivial or nontrivial? Overall, we found that PCT (with parameter
d
= 3) was the most effective technique in terms of bug finding; it found all bugs found by the other techniques, plus an additional three, and it missed only one bug. Surprisingly, we found that the naive controlled random scheduler, which randomly chooses one thread to execute at each scheduling point, performs well, finding more bugs than preemption bounding and just two fewer bugs than delay bounding. Our findings confirm that delay bounding is superior to preemption bounding and that schedule bounding is superior to an unbounded depth-first search. The majority of bugs in SCTBench can be exposed using a small schedule bound (1--2), supporting previous claims, although one benchmark requires five preemptions. We found that the need to remove nondeterminism and control all synchronization (as is required for
systematic
concurrency testing) can be nontrivial. There were eight distinct programs that could not easily be included in out study, such as those that perform network and interprocess communication. We report various properties about the benchmarks tested, such as the fact that the bugs in 18 benchmarks were exposed 50% of the time when using random scheduling. We note that future work should not use the benchmarks that we classify as trivial when presenting new techniques, other than as a minimum baseline. We have made SCTBench and our tools publicly available for reproducibility and use in future work.
Involvement of gap junctions between smooth muscle cells in sustained hypoxic pulmonary vasoconstriction development: a potential role for 15-HETE and 20-HETE
Authors: Kizub Igor V. , Lakhkar Anand , Dhagia Vidhi , Joshi Sachindra R. , Jiang Houli , Wolin Michael S. , Falck John R. , Koduru Sreenivasulu Reddy , Errabelli Ramu , Jacobs Elizabeth R. , Schwartzman Michal L. , Gupte Sachin A.
Published: February 2016

In response to hypoxia, the pulmonary artery normally constricts to maintain optimal ventilation-perfusion matching in the lung, but chronic hypoxia leads to the development of pulmonary hypertension. The mechanisms of sustained hypoxic pulmonary vasoconstriction (HPV) remain unclear. The aim of this study was to determine the role of gap junctions (GJs) between smooth muscle cells (SMCs) in the sustained HPV development and involvement of arachidonic acid (AA) metabolites in GJ-mediated signaling. Vascular tone was measured in bovine intrapulmonary arteries (BIPAs) using isometric force measurement technique. Expression of contractile proteins was determined by Western blot. AA metabolites in the bath fluid were analyzed by mass spectrometry. Prolonged hypoxia elicited endothelium-independent sustained HPV in BIPAs. Inhibition of GJs by 18β-glycyrrhetinic acid (18β-GA) and heptanol, nonspecific blockers, and Gap-27, a specific blocker, decreased HPV in deendothelized BIPAs. The sustained HPV was not dependent on Ca2+entry but decreased by removal of Ca2+and by Rho-kinase inhibition with Y-27632. Furthermore, inhibition of GJs decreased smooth muscle myosin heavy chain (SM-MHC) expression and myosin light chain phosphorylation in BIPAs. Interestingly, inhibition of 15- and 20-hydroxyeicosatetraenoic acid (HETE) synthesis decreased HPV in deendothelized BIPAs. 15-HETE- and 20-HETE-stimulated constriction of BIPAs was inhibited by 18β-GA and Gap-27. Application of 15-HETE and 20-HETE to BIPAs increased SM-MHC expression, which was also suppressed by 18β-GA and by inhibitors of lipoxygenase and cytochrome P450 monooxygenases. More interestingly, 15,20-dihydroxyeicosatetraenoic acid and 20-OH-prostaglandin E2, novel derivatives of 20-HETE, were detected in tissue bath fluid and synthesis of these derivatives was almost completely abolished by 18β-GA. Taken together, our novel findings show that GJs between SMCs are involved in the sustained HPV in BIPAs, and 15-HETE and 20-HETE, through GJs, appear to mediate SM-MHC expression and contribute to the sustained HPV development.
A Rare Concurrence of Leiomyomatosis Peritonealis Disseminata, Leiomyosarcoma of the Pelvis and Leiomyomatous Nodule of the Liver
Authors: Tun Aung Myint , Tun Nay Min , Zin Thein Kyaw , Naing Ei Ei , Giashuddin Shah , Shulimovich Maxim
Published: February 2016

Leiomyomatosis peritonealis disseminata (LPD) is a rare entity that is characterized by the presence of multiple subperitoneal or peritoneal smooth muscle nodules throughout the peritoneal surface mimicking a malignant process. LPD follows a benign course in general, and it is often found incidentally during abdominal surgery. There have been reported cases of LPD with malignant degeneration although the association is uncertain. Concurrent finding of LPD and leiomyosarcoma of the pelvis is very rare that could be coincidental, malignant transformation of LPD to leiomyosarcoma, or progression of undetected primary leiomyosarcoma. There are only a few previously reported cases in the literature. Herein, we report a case of 56-year-old woman with a history of leiomyoma of uterus who presented with progressive abdominal swelling secondary to mass lesions in the pelvis. The patient underwent exploratory laparotomy and debulking of the tumors, and the histologic examination of the tumors revealed coexistence of LPD and leiomyosarcoma. After recovery from the operation, core needle biopsy of the superficial, residual liver mass was obtained to investigate potential liver metastasis, and the histopathologic findings are consistent with leiomyoma which represents the first simultaneous occurrence of LPD, leiomyosarcoma, and leiomyomatous nodule of the liver.
The Efficacy and Safety of Fractional CO2Laser Combined with Topical Type A Botulinum Toxin for Facial Rejuvenation: A Randomized Controlled Split-Face Study
Authors: Zhu Jie , Ji Xi , Li Min , Chen Xiao-e , Liu Juan , Zhang Jia-an , Luo Dan , Zhou Bing-rong
Published: February 2016

Objective. We evaluated synergistic efficacy and safety of combined topical application of Botulinum Toxin Type A (BTX-A) with fractional CO2laser for facial rejuvenation.Methods. Twenty female subjects were included for this split-face comparative study. One side of each subject’s cheek was treated with fractional CO2plus saline solution, and the other side was treated with fractional CO2laser plus topical application of BTX-A. Patients received one session of treatment and evaluations were done at baseline, one, four, and twelve weeks after treatment. The outcome assessments included subjective satisfaction scale; blinded clinical assessment; and the biophysical parameters of roughness, elasticity, skin hydration, transepidermal water loss (TEWL), and the erythema and melanin index.Results. BTX-A combined with fractional CO2laser sides showed higher physician’s global assessment score, subject satisfaction score, roughness, skin hydration, and skin elasticity compared to that of fractional CO2plus saline solution side at 12 weeks after treatment. TEWL and erythema and melanin index showed no significant differences between two sides at baseline, one, four, and twelve weeks after treatment.Conclusion. Topical application of BTX-A could enhance the rejuvenation effect of fractional CO2laser.
Power Consumption, Mixing Time, and Oxygen Mass Transfer in a Gas-Liquid Contactor Stirred with a Dual Impeller for Different Spacing
Authors: Issa Hayder Mohammed
Published: February 2016

Multiple or dual impellers are widely implemented in stirred contactors used in various biological processes like fermentation, water treatment, and pharmaceutical production. The spacing between impellers is considered as a crucial factor in designing of these types of contactors resulting in variation of oxygen mass transfer, mixing time, or power consumption for such biological system. A study of three parts was conducted to characterize the effect of the spacing between impellers on the most important parameters that related to biological contactor performance: oxygen mass transfer coefficientklafrom the gas phase (air) to the liquid phase (water), mixing time, and power consumption for different operating rotational speeds (1.67–3.33 rps) and for three different spacing positions. The used impellers system in the study is a dual impeller system which consists of an inverted and bladed rotated cone (IBRC) and a pitched-blade up-flow propeller (PBPU). The experimental results showed that the shorter spacing (the lower PBPU in a higher position) is more convenient, as the achieved oxygen mass transfer coefficient has showed an improvement in its values with lower mixing time and with a slight alteration in power consumption.
ROS and ROS‐Mediated Cellular Signaling
Authors: Zhang Jixiang , Wang Xiaoli , Vikash Vikash , Ye Qing , Wu Dandan , Liu Yulan , Dong Weiguo
Published: February 2016

It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell‐signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell‐signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS impacting on cell‐signaling proteins (NF‐κB, MAPKs, Keap1‐Nrf2‐ARE, and PI3K‐Akt), ion channels and transporters (Ca2+ and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System.
Improved Biodegradable Radiation Cured Polymeric Film Prepared from Chitosan-Gelatin Blend
Authors: Nasreen Zinia , Khan Mubarak A. , Mustafa A. I.
Published: February 2016

The mechanical, thermal, swelling, and release properties of chitosan-gelatin (CG) films have been investigated in order to verify the influence of UV and gamma radiation on the stability of the films. Thin films of chitosan and gelatin (1 : 3, w/w) that were radiated with 100 krad of gamma dose showed the best performance and the TS values reached 25, 45, and 49 MPa, respectively, for chitosan, gelatin, and blend. The corresponding highest TS values were 23, 42, and 45 MPa, respectively, for 10 passes of UV radiation. The effect of radiation over gelatin, chitosan, and CG blend caused modification in the arrangement of molecules in the crystal lattice that is significant by XRD analysis. Surfaces of the films were also investigated by scanning electron microscope (SEM). Fourier transform infrared spectroscopy (FTIR) studies further revealed structural changes of the films. These changes were attributed to understanding the behavior of the irradiated chitosan, gelatin, and CG blend on application of thermal energy using DSC and TGA studies, water uptake of the films in aqueous medium, and soil degradation properties to observe the best possibility for its application.
Analysis of Simplifications Applied in Vibration Damping Modelling for a Passive Car Shock Absorber
Authors: Konieczny Łukasz
Published: February 2016

The paper presents results of research on hydraulic automotive shock absorbers. The considerations provided in the paper indicate certain flaws and simplifications resulting from the fact that damping characteristics are assumed as the function of input velocity only, which is the case of simulation studies. An important aspect taken into account when determining parameters of damping performed by car shock absorbers at a testing station is the permissible range of characteristics of a shock absorber of the same type. The aim of this study was to determine the damping characteristics entailing the stroke value. The stroke and rotary velocities were selected in a manner enabling that, for different combinations, the same maximum linear velocity can be obtained. Thus the influence of excitation parameters, such as the stroke value, on force versus displacement and force versus velocity diagrams was determined. The 3D characteristics presented as the damping surface in the stoke and the linear velocity function were determined. An analysis of the results addressed in the paper highlights the impact of such factors on the profile of closed loop graphs of damping forces and point-type damping characteristics.
Indefinite LQ Optimal Control with Terminal State Constraint for Discrete-Time Uncertain Systems
Authors: Chen Yuefen , Yang Minghai
Published: February 2016

Uncertainty theory is a branch of mathematics for modeling human uncertainty based on the normality, duality, subadditivity, and product axioms. This paper studies a discrete-time LQ optimal control with terminal state constraint, whereas the weighting matrices in the cost function are indefinite and the system states are disturbed by uncertain noises. We first transform the uncertain LQ problem into an equivalent deterministic LQ problem. Then, the main result given in this paper is the necessary condition for the constrained indefinite LQ optimal control problem by means of the Lagrangian multiplier method. Moreover, in order to guarantee the well-posedness of the indefinite LQ problem and the existence of an optimal control, a sufficient condition is presented in the paper. Finally, a numerical example is presented at the end of the paper.
IFNγ and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma
Authors: Long Kristen B. , Gladney Whitney L. , Tooker Graham M. , Graham Kathleen , Fraietta Joseph A. , Beatty Gregory L.
Published: February 2016

Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise mechanism and therapeutic implications of this antifibrotic activity, though, remain unclear. Here, we report that IFNγ and CCL2 released systemically in response to a CD40 agonist cooperate to redirect a subset of Ly6C+CCR2+ monocytes/macrophages to infiltrate tumors and deplete fibrosis. Whereas CCL2 is required for Ly6C+ monocyte/macrophage infiltration, IFNγ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMP) in tumors, leading to MMP-dependent fibrosis degradation. In addition, MMP13-dependent loss of extracellular matrix components induced by a CD40 agonist increased PDAC sensitivity to chemotherapy. Our findings demonstrate that fibrosis in PDAC is a bidirectional process that can be rapidly altered by manipulating a subset of tumor-infiltrating monocytes, leading to enhanced chemotherapy efficacy.

Significance: We report that CD40 agonists improve chemotherapy efficacy in pancreatic carcinoma by redirecting tumor-infiltrating monocytes/macrophages to induce fibrosis degradation that is dependent on MMPs. These findings provide novel insight into the plasticity of monocytes/macrophages in cancer and their capacity to regulate fibrosis and modulate chemotherapy efficacy in pancreatic carcinoma. Cancer Discov; 6(4); 400–13. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 331
Inhibition of Soluble Tumor Necrosis Factor Prevents Chemically Induced Carcinogenesis in Mice
Authors: Sobo-Vujanovic Andrea , Vujanovic Lazar , DeLeo Albert B. , Concha-Benavente Fernando , Ferris Robert L. , Lin Yan , Vujanovic Nikola L.
Published: February 2016

TNF is a potent promoter of carcinogenesis and potentially important target for cancer prevention. TNF is produced as functionally distinct transmembrane and soluble molecules (tmTNF and sTNF, respectively), but their individual roles in carcinogenesis are unexplored. We investigated the participation of tmTNF and sTNF in chemically induced carcinogenesis in mice. We found that injection of XPro1595, a dominant-negative TNF biologic (DN-TNF) and specific antagonist of sTNF, decreased tumor incidence and growth, and prolonged survival of 3-methylcholanthrene (MCA)–injected mice. Similar results were obtained following the exclusion of both TNF forms by either TNF-receptor 2–Fc fusion protein (TNFR2-Fc) treatment or TNF gene deletion. In addition, gene deletion of TNFR1, which is preferentially triggered by sTNF, was temporarily blocked, whereas gene deletion of TNFR2, which is preferentially triggered by tmTNF, enhanced MCA-induced carcinogenesis. Concomitantly with carcinogenesis induction, MCA increased circulating IL1α, accumulation of myeloid-derived suppressor cells (MDSC), STAT3 phosphorylation, and immunosuppression in the spleen. In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2. These findings reveal that sTNF is both an essential promoter of carcinogenesis and a pivotal regulator of MDSCs, and indicate that sTNF could be a significant target for cancer prevention and therapy. Cancer Immunol Res; 4(5); 441–51. ©2016 AACR.
Advanced Analysis of Pharmaco-EEG Data in Humans
Authors: Jobert Marc , Wilson Frederick J.
Published: February 2016

Pharmaco-electroencephalography (EEG) is a non-invasive method used to assess the effects of pharmacological compounds on the central nervous system by processing the EEG signals which directly reveal the spontaneous synchronised postsynaptic neuronal activity of the cortex with high temporal resolution. The International Pharmaco-Encephalography Society (IPEG) has recently published guidelines, which were produced by a global panel of EEG experts, with the goal to increase the standardisation of pharmaco-EEG studies in human subjects and facilitate the comparability of data across laboratories, thus enabling data-pooling and meta-analyses. The recommended standard experimental procedure is to measure EEG activity under vigilance-controlled and resting conditions. The IPEG guidelines thoroughly present the technical details and therefore constitute a robust reference. The complementary aim of the present paper is to focus on practical aspects, pitfalls and precautions to be considered when processing pharmaco-EEG data by covering the following topics: (1) investigate the stability and reliability of 5-min EEG recordings under both vigilance-controlled and resting conditions; (2) assess the spontaneous time-dependent changes in spectral activity over time, and (3) apply the data-processing strategies suggested in the pharmaco-EEG guidelines and designed to optimally capture drug effects. For this purpose, the EEG data from a randomised, double-blind, crossover trial aimed at comparing the effect of diazepam (10 mg) and placebo in 16 healthy male volunteers is used to illustrate the discussion of the processing techniques and difficulties commonly faced when analysing pharmaco-EEG data.
Advanced Analysis of Pharmaco-Sleep Data in Humans
Authors: Anderer Peter
Published: February 2016

Pharmaco-sleep studies in humans aim at the description of the effects of drugs, most frequently substances that act on the central nervous system, by means of quantitative analysis of biosignals recorded in subjects during sleep. Up to 2007, the only standard for the classification of sleep macrostructure that found worldwide acceptance were the rules published in 1968 by Rechtschaffen and Kales. In May 2007, the AASM Manual for the Scoring of Sleep and Associated Events was published by the American Academy of Sleep Medicine, and concerning the classification of sleep stages, these new rules are supposed to replace those developed by Rechtschaffen and Kales. As compared to the rather low interrater reliability of manual sleep scoring, semiautomated approaches may achieve a reliability close to 1 (Cohen's kappa 0.99 for 2 semiautomated scorings as compared to 0.76 for 2 manual scorings) without any decline in validity. Depending on the aim of the pharmaco-sleep study, additional analyses concerning sleep fragmentation, sleep microstructure, sleep depth, sleep processes and local aspects of sleep should be considered. For some of these additional features, rules for visual scoring have been established, while for others automatic analysis is obligatory. Generally, for reasons of cost-effectiveness but also reliability, automatic analysis is preferable to visual analysis. However, the validity of the automatic method applied has to be proven.
Personalized Medicine: Review and Perspectives of Promising Baseline EEG Biomarkers in Major Depressive Disorder and Attention Deficit Hyperactivity Disorder
Authors: Olbrich Sebastian , van Dinteren Rik , Arns Martijn
Published: February 2016

Personalized medicine in psychiatry is in need of biomarkers that resemble central nervous system function at the level of neuronal activity. Electroencephalography (EEG) during sleep or resting-state conditions and event-related potentials (ERPs) have not only been used to discriminate patients from healthy subjects, but also for the prediction of treatment outcome in various psychiatric diseases, yielding information about tailored therapy approaches for an individual. This review focuses on baseline EEG markers for two psychiatric conditions, namely major depressive disorder and attention deficit hyperactivity disorder. It covers potential biomarkers from EEG sleep research and vigilance regulation, paroxysmal EEG patterns and epileptiform discharges, quantitative EEG features within the EEG main frequency bands, connectivity markers and ERP components that might help to identify favourable treatment outcome. Further, the various markers are discussed in the context of their potential clinical value and as research domain criteria, before giving an outline for future studies that are needed to pave the way to an electrophysiological biomarker-based personalized medicine.
Der Placeboeffekt in der antidepressiven Behandlung
Authors: Kirsch Irving
Published: February 2016

Die vorherrschende Annahme zur Wirkung von Antidepressiva ist, dass diese durch die Behebung eines chemischen Ungleichgewichts, speziell eines Serotoninmangels im Gehirn, zustande kommt. Auswertungen der publizierten und nicht publizierten, d.h. von Pharmaunternehmen zurückgehaltenen Daten zeigen jedoch, dass der meiste (wenn nicht gar komplette) Nutzen durch den Placeboeffekt bewirkt wird. Einige Antidepressiva steigern die Serotoninspiegel, manche senken sie, und andere haben überhaupt keine Auswirkung auf Serotonin. Dennoch zeigen sie alle den gleichen therapeutischen Nutzen. Anstatt Depression zu behandeln, könnten gängige Antidepressiva eine biologische Vulnerabilität verursachen, die das Risiko einer zukünftigen Depression erhöht. Andere Behandlungsarten (z.B. Psychotherapie und körperliche Betätigung) erzeugen den gleichen Kurzzeitnutzen wie Antidepressiva, zeigen bessere Langzeitwirkung und tun dies ohne die Nebenwirkungen und Gesundheitsrisiken der Medikamente.
Characterization of a Complex Chromosomal Rearrangement Involving a de novo Duplication of 9p and 9q and a Deletion of 9q
Authors: Martín-De Saro Mónica D. , Valdés-Miranda Juan M. , Plaza-Benhumea Lautaro , Pérez-Cabrera Adrián , Gonzalez-Huerta Luz M. , Guevara-Yañez Roberto , Cuevas-Covarrubias Sergio A.
Published: February 2016

Rearrangements of the distal region of 9p are important chromosome imbalances in human beings. Trisomy 9p is the fourth most frequent chromosome anomaly and is a clinically recognizable syndrome. Kleefstra syndrome, previously named 9q subtelomeric deletion syndrome, is either caused by a submicroscopic deletion in 9q34.3 or an intragenic mutation of EHMT1. We report a Mexican male patient with abnormal development, dysmorphism, systemic anomalies and a complex chromosomal rearrangement (CCR). GTG-banding revealed a 46,XY,add(9)(q34.3) karyotype, whereas array analysis resulted in arr[hg19] 9p24.3p23(203,861-11,842,172)×3, 9q34.3(138,959,881-139,753,294)×3, 9q34.3(139,784,913-141,020,389)×1. Array and karyotype analyses were normal in both parents. Partial duplication of 9p is one of the most commonly detected autosomal structural abnormalities in liveborn infants. A microdeletion in 9q34.3 corresponds to Kleefstra syndrome, whereas a microduplication in 9q34.3 shows a great clinical variability. Here, we present a CCR in a patient with multiple congenital anomalies who represents the first case with partial 9p trisomy, partial 9q trisomy and partial 9q monosomy.
THC:CBD Observational Study Data: Evolution of Resistant MS Spasticity and Associated Symptoms
Authors: Trojano Maria
Published: February 2016

Background: The prospective observational MObility ImproVEment (MOVE) 2 study is collecting real-life clinical outcomes data on patients with treatment-resistant multiple sclerosis (MS) spasticity treated with THC:CBD oromucosal spray in routine clinical practice. The MOVE 2 study has been ongoing in Italy, involving more than 30 MS centres across the country, since 2013. Methods: Web-based real-time data collection techniques are combined with traditional patients' diaries to capture a wide spectrum of outcomes associated with this innovative cannabis-based medication. After surpassing the recruitment threshold of 300 patients, an interim analysis was performed to determine whether the data collected to date align with those from MOVE 2-Germany and the largest phase III randomized controlled trial (RCT) of THC:CBD oromucosal spray. Results: In the Italian cohort, THC:CBD oromucosal spray was added mainly to oral baclofen. Similar to MOVE 2-Germany, during 3 months' observation, treatment discontinuations were limited and patients recorded meaningful improvements on the patient-based 0-10 numerical rating scale and physician-rated modified Ashworth scale at mean daily doses that were about one-third lower than those used in the RCT. Also, similar to MOVE 2-Germany, the proportion of patients reporting adverse events was about one-third of the rate recorded in the RCT. Conclusions: While MOVE 2-Italy continues, this interim analysis has enabled us to better define the place in therapy of THC:CBD oromucosal spray within the context of daily management of our patients with MS spasticity.