bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety Functions of Accumulator Battery Systems and Improvement Possibilities
Authors: Andel Jan
Published: November 2014

Accumulator batteries installed in electrical emergency power systems of NPPs are power storages that secure quality and continuity of power supply for safety important and other sensitive systems. Key important function and characteristic of batteries is discharging time for which are batteries able to supply consumers. Better knowledge and improvement (prolonging) of this capability has been accented as one of “Stress tests” measures.

This paper deals with conceptual design considerations and limitations related to battery system, comparison of discharging capabilities of various types of batteries, identification of typical power and safety requirements of consumers supplied form batteries. Next part of paper is focused on calculation and simulation methods of complex discharging load profiles targeted to determine realistic limits of discharging times.

Finally there are described and technically commented/evaluated various possibilities to prolong power supply of vital systems from batteries in really difficult accident situation of NPP. All above mentioned is based on ENERGOPROJEKT PRAHA design experience from NPPs in Czech Republic and Slovak Republic.
The IAEA Programme in Support of the Development, Design and Safety Analysis of Innovative Fast Neutron Systems
Authors: Monti S. , Toti A.
Published: November 2014

The International Atomic Energy Agency (IAEA) recognizes the importance of the development and deployment of innovative fast neutron systems to assure the long-term sustainability of nuclear power. In this area the IAEA — with the fundamental support of its Technical Working Group on Fast Reactors (TWG-FR) where all the Member States with a programme on fast neutron systems are represented — acts as the major forum for international cooperation. On the basis of the recommendations provided by the TWG-FR, the IAEA defines and implements multiannual programmes which, in particular, are intended to help Member States in improving their capabilities in the development, design and safety analyses of innovative fast neutron systems. Thanks to the information and experimental data provided by the Member States, the IAEA is in the position to carry out benchmark exercises on different aspects of fast reactors, which contribute to the verification, validation and qualification of the simulation codes to be used for the design and the safety analyses of innovative concepts. Examples of such initiatives are the concluded coordinated research projects (CRPs) on BN-600, Monju and Phenix reactors, the on-going CRP on the EBR-II reactor and the planned CRPs on PFBR, CEFR, BN-800 and Monju reactors. The exchange of information and the collection of technical data within the TWG-FR also allow the IAEA to publish status reports and technical documents, as well as to develop databases with the most up-to-date information on existing and planned fast neutron systems. Furthermore, the IAEA is committed to promote the international harmonization of many aspects of the fast reactor technology. A major example is the development — together with the Generation IV International Forum — of internationally agreed Safety Design Criteria for sodium cooled fast reactors (SFR), which is a major step forward for the licensing of GEN-IV SFR prototypes and industrial demonstrators. Finally, a new CRP on “Sodium properties and safe operation of experimental facilities in support of the development and deployment of Sodium-cooled Fast Reactors (SFR) - NAPRO” has been recently launched in order to harmonize sodium physical and chemical properties to be used in the design of innovative SFRs, and to develop agreed design rules and best practices for sodium experimental facilities, as well as guidelines for the safe handling of sodium. With complementary objectives, the IAEA is also developing a catalogue of existing and planned experimental facilities in support of fast neutron system R&D programmes.
Development of Inherently Safe Technologies for Large Scale BWRs: (1) Plant System
Authors: Kitou Kazuaki , Ishida Naoyuki , Tamura Akinori , Ishibashi Ryou , Kanada Masaki , Kamoshida Mamoru
Published: November 2014

The Fukushima Daiichi nuclear accident and their consequences have led to some rethinking about the safety technologies used in boiling water reactors (BWRs). We have been developing the following various safe technologies: a passive water-cooling system, an infinite-time air-cooling system, a hydrogen explosion prevention system, and an operation support system to better deal with reactor accidents. The above mentioned technologies are referred to as “inherently safe technologies”.

The passive water-cooling system and infinite-time air-cooling system achieve core cooling without electricity. These systems are intended to cope with a long-term station black out (SBO), such as that which occurred at the Fukushima facility. Both these cooling systems remove relatively high decay heat for the initial 10 days after an accident, and then the infinite-time air-cooling system is used alone to remove attenuated decay heat after 10 days.

The hydrogen explosion prevention system consists of a high-temperature resistant fuel cladding made of silicon-carbide (SiC cladding) and a passive autocatalytic recombiner (PAR). Since the SiC cladding generates less hydrogen gas than the current zircaloy fuel cladding when core damage occurs, the risk of hydrogen leakage from a primary containment vessel (PCV) to a reactor building (R/B), such as an operating floor, can be reduced because the pressure in the PCV can be kept lower with less hydrogen gas generation. The leaked hydrogen gas is recombined by the PAR.

When a large-scale natural disaster occurs, fast event diagnosis and recognition of damaged equipment are necessary. Therefore, the operation support system consists of event identification and progress prediction functions to reduce the occurrence of false recognitions and human errors.

This paper describes the following items: the targeted plant system; the heat exchange tests conducted for both water-cooling and air-cooling systems; the air-cooling enhancing technology for air-cooling in a 4700 MW thermal power class reactor; hydrogen generation tests for SiC material; and the concept of the operation support system.
A Simple One-Dimensional Model of a Passive Hydrogen Recombiner
Authors: Rożeń Antoni
Published: November 2014

A simple one-dimensional model allowing fast predictions of: a gas composition and temperature profiles, a catalyst temperature profile and an overall hydrogen recombination degree has been developed for a passive catalytic recombiner. The model assumes that heat and mass transport processes, taking place in vertical channels between catalyst plates, occur in a highly non-isothermal, developing laminar gas flow and in conditions of mixed convection. A kinetic model of heterogeneous catalysis was implemented into the model and the heat radiation from the catalyst surface was accounted for. The model with no adjustable parameters was verified against experimental results available in literature and results of numerical simulations obtained by CFD methods.
Standard Analysis and Tool-Based Assessment Technique of NPP I&C Systems Diversity
Authors: Kharchenko Vyacheslav S. , Siora Olexandr A. , Duzhyi Vyacheslav I. , Rusin Dmytro O.
Published: November 2014

Diversity is the general approach used for decreasing common cause failure (CCF) risks of instrumentation and control (I&C) systems. Differences in equipment, development and verification technologies, implemented functions, etc. can mitigate the potential for common faults. Diversity and defense-in-depth (D3) is the required attribute of Nuclear Power Plant (NPP) I&C systems important for safety. One of the key theoretical and practical problems is diversity estimation and optimization of used version redundancy capacity. Existing NUREG guidelines published in reports CR-7007 and CR-6303 present the technical basis for establishing acceptable mitigating strategies that resolve D3 assessment findings. These approaches work in the terms of diversity attributes and associated criteria aimed at the potential for CCF vulnerabilities and make possible to choose I&C system architecture based on combinations of diversity criteria. But they do not provide measures (diversity indexes or metrics) to calculate reliability of such system in the context of CCF. In the report some other techniques for diversity assessment are analyzed, as well as advantages and disadvantages of these techniques in comprising with NUREG-based method are described. Possibilities of their joint applications and tool support are considered. The combined use of reliability models, diversity metrics and reliability indexes of system components allows enhancement of estimation sensitivity, making sufficiency criteria for diversity and redundancy more concrete and choice of technical solutions more informed and confident at the early stages of NPP I&C system design. The problems for future research are stated as creation of Safety-Case-oriented techniques and tools for multi-version NPP I&C systems assessment.
A RISMC Perspective of the Reasonable Risk-Protection Measures
Authors: Zheng Gangyang , Nelson Paul , Moiseytseva Vera , Kee Ernie , Yilmaz Fatma
Published: November 2014

The U.S. Nuclear Regulatory Commission (NRC) is mandated to ensure “adequate protection” to the public health and safety, regardless of cost. It also has steadfastly declined to specify precisely what constitutes “adequate protection,” except that it does not mean “zero risk.” Rather it judges on a case-by-case basis whether the “adequate protection” standard has been met. NRC also seems to reserve the right to require an even higher level of protection, when that can be achieved in a manner that it judges to meet similarly imprecisely specified criteria such as “practicality” and “reasonableness.” In Regulatory Guide 1.174 NRC comes close to a concrete specification of “adequate protection,” albeit one that depends upon the historical licensing basis for a specific plant. And the technical portion of this paper begins with a description of how the approach of Regulatory Guide 1.174 can be viewed from the perspective of Risk-Informed Safety Margin Characterization. Meanwhile, in this research, in order to better understand the role of regulation, a microeconomic model of a price-taking nuclear power plant is constructed, particularly of the cost (C) of achieving any specified level of core damage frequency (CDF). Solution of this model reveals an economic optimum, at a point that balances plant value against risk of losing the plant via an accident involving core damage. For CDFs slightly smaller than this economic optimum there is scope for a regulatory mandate of even smaller CDF, should that be deemed either necessary to attain “adequate protection,” or reasonably attainable in order to achieve greater than adequate protection of the public health and safety. It is argued that regulatory bodies must have scope for discretionary decisions, because the information necessary to formulate a reasonable approximation to the cost curve C (fortunately) does not exist.
Underground Siting of Nuclear Power Plants: Enhancing Safety and Reducing Construction Cost
Authors: Kunze Jay F. , Mahar James M. , Giraud Kellen M. , Myers Carl W.
Published: November 2014

It has been shown, in a number of papers presented by the authors, that the construction of a nuclear power park underground, involving a number (six or more) of conventional Generation III+ LWR units, plus reprocessing, fuel re-manufacturing, and waste storage facilities is cost effective (both capital construction cost and operating costs) compared to the construction of similar facilities above ground (even if all such facilities are co-located). These papers have addressed the protection provided for both security from domestic acts of terror and natural hazards, and the ultimate containment of nuclear contamination in the event of accidents. However, as a result of the Fukushima tsunami and its effect on the six reactors at that location, issues are raised concerning the worst possible accident scenarios that could occur as a result of siting of nuclear plants underground. This paper addresses those highly unlikely events, with extremely low probabilities of occurrence, and shows that the effect of underground siting has advantages has over at ground locations.
Recognition Statistic and Analysis of Bubbles in Flow Boiling
Authors: Wang Zhongyi , Gao Pu-zhen , Yu Dali , Yang Zheng , Chen Hanying , Zou Chong , Chen Chong
Published: November 2014

Void fraction measurement is very important in the thermal-hydraulic experiments. In this work, a new measuring method was proposed to detect the bubbles’ size and sketch by using the high-speed camera. To check the accuracy of this method, flow boiling condition in the vertical rectangular narrow channel was considered. Firstly, boiling phenomenon was observed in the test pipe. Then recognition and statistic of bubbles were performed to obtain the bubbles’ quantity, size and speed. The conclusion of this work is that the bubble images can be divided into nearly round bubbles and irregular bubbles and this method have a good performance in the bubble s’ recognition and statistic.
Reliability Allocation to I&C Sub-Systems: A Practical Methodology
Authors: Rajamani Dheenadhayalan , Arokiaswamy John Arul , Kanakkil Madhusoodanan , Perumal Chellapandi
Published: November 2014

As part of probabilistic safety assessment for a nuclear plant, regulators around the globe specify global limits for frequency of nuclear incidents like core damage frequency (CDF), lethal dose to the public, etc. Further allocation of individual targets to subsystems of the plant is left to plant designers normally. In this paper, a workable methodology for reliability allocation is illustrated with Instrumentation and Control (I&C) sub-systems of a Fast Breeder Reactor (FBR). Here, plant I&C is modeled as a set of systems grouped into four categories namely 1) control systems 2) mitigating systems 3) support systems 4) Plant protection systems. From the global limit on core damage frequency, the reliability allocation for I&C subsystems are done based on the hypothesized demand from the subsystems for plant protection. It is illustrated that all I&C sub-systems with varying functions can be linked to the global target directly or indirectly. A case study with entire I&C subsystems which are designed based on functional consideration in Prototype Fast Breeder Reactor is shown as a proof of concept. While it is widely agreed that probabilistic approach is supplementary to deterministic approaches for enhanced safety, the paper argues that probabilistic targets have to be plant wide to have maximum benefits.
A Model for Prediction of Maximum Post-Dryout Temperature in Decay-Heated Debris Bed
Authors: Yakush Sergey E. , Kudinov Pavel
Published: November 2014

Several designs of light water reactors consider melt fragmentation and cooling of corium debris bed in a deep pool as important part of their severe accident management strategies. Traditional approach to assessment of debris coolability is based on the bed dryout criterion. However, this is the most conservative criterion which doesn’t take into account possibility of debris temperature stabilization in steam cooling regime. In this work numerical simulations of cooling of a decay heat-releasing porous debris bed in a water pool are carried out for the conditions where local dryout of porous material occurs. It is shown that the temperature of solid material in the dry zone can be stabilized if sufficient vapor flow is generated in the wetted part of the debris bed beneath the dry zone. A simple one-dimensional model which connects the maximum temperature and the relative size of the dry zone is proposed and verified against the numerical simulations with DECOSIM code for different shapes of the debris beds relevant to severe accident conditions in a Nordic type boiling water reactor (BWR). On the basis of this model, a criterion is obtained which defines the critical relative height of the dry zone corresponding to specific temperature of debris material which can be considered as a safety limit (e.g. start of zirconium oxidation, remelting of metallic debris or oxidic corium, etc.). The criterion allows one to evaluate the safety margins and degree of conservatism introduced by the dryout-based approach to assessment of debris coolability.
Correction of Zero-Drift of Differential Pressure Flow Meters of ACME Facility
Authors: Cui Mingtao , Zhang Tao
Published: November 2014

ACME facility (Advanced Core-cooling Mechanism Experiment) is a large-scale test facility used to validate the performance of passive core-cooling system under SBLOCA (Small Break Lost of Coolant Accident) for the CAP1400, an upgraded passive safety nuclear power plant of AP1000. To simulate the features of passive safety system properly, DELTABAR, a kind of differential pressure flow meter, is designed to measure different mass flow of ACME. Because of the low pressure loss of DELTABAR, Zero-Drift problem of differential pressure flow meters in ACME is amplified, and some of the measured values are distorted seriously. To minimize the influence of Zero-Drift, analysis on zero-drift phenomenon is made, and a compensation method is proposed. The method is applying to PBL flow meters, and the result shows that the method is applicable.
On Safety Assessment of Structures Containing Cracks: Deterministic Analysis
Authors: Zeng Lingfu , Jansson Lennart G.
Published: November 2014

In this paper, safety assessment of structures of nuclear power facilities, containing cracks or crack-like defects, is addressed. A so-called deterministic procedure recommended by Swedish Radiation Safety Agency is reviewed and discussed. The procedure provides a possibility for evaluation of crack growth due to courses of fatigue and stress corrosion, and for prediction of safety reservation margin due to fracture and plastic failure. The review and discussion focus on various assumptions and limitations behind this procedure, and cares that must be taken of when using this procedure for safety assessment. Applications recently conducted for a defect tolerance analysis of aging BWR components are used as examples to address the reliability and accuracy of the assessment and its relevance to rules given by ASME BPV code. It is concluded that for some cases the reliability of such an assessment need to be carefully questioned and there is a great need for alternative procedures for fully achieving a reliable, accurate and effective assessment.
Mechanical Stresses Affecting Deep Borehole Disposal of High Level Nuclear Waste
Authors: Bates Ethan A. , Buongiorno Jacopo , Baglietto Emilio , Driscoll Michael J.
Published: November 2014

While extensive stress field data are available from crystalline rock boreholes drilled in France (Soultz), Germany (KTB), and the USA (Cajon Pass, Monticello Reservoir), Canada and Sweden, the data and methods used to analyze them have yet to be applied to very deep geologic disposal facilities. Typically, to alleviate the stress fields that are intensified in a borehole, muds (mixtures of clay and water) are a critical component and are widely used in the drilling industry. In the first portion of this paper, we review the available mechanical data and analysis methods. Based on the most applicable measurements (in Canada and Germany), we propose values of stress fields and rock properties to be used for generic assessment of deep borehole disposal. The minimum horizontal stress can be approximated as Sh=23.2D, the maximum horizontal stress as SH=43.1D, and the vertical stress as SV=27.5D, where the stresses are in MPa and D is depth in km. This analysis also incorporates the effect of thermal stresses (relieved) by the cool drilling mud. Using an average uniaxial compressive strength results (C=212 MPa) and conservatively neglecting the increase in strength of crystalline rock under polyaxial conditions, a stable borehole can be drilled to 4.55 km with mud density of 1020 kg/m3. This is based on a stability limit such that at the bottom of the hole, a significant portion of the wall (180°/360°) reaches a critical state of stress (i.e., experiences spalling). Using relations developed for shallow mines (which may be overly conservative) the spalled zone is estimated to have a radius that is approximately twice that of the borehole. To reach 5 km, the mud density should be raised to 1420 kg/m3, or be actively cooled (90°C) below the ambient temperature of the rock (∼135°C) at that depth.
Modifications in the Structure of Oxide Corium Melt and Phase Formation During Its Crystallization Caused by Interaction With Sacrificial Concretes of Core Catcher
Authors: Udalov Yurij P. , Poznyak Igor , Šrank Jiří , Sázávaský Petr , Kiselová Monika , Strejc Martin , Votava Pavel
Published: November 2014

The article presents the results of the experimental study carried on molten corium and its crystallization products resulted from contact with sacrificial concretes. Experiments were carried out at COMETA installation using induction melting in cold crucible technology in air. The results of the physical-chemical analysis of the examined composite system U4+-U6+-Zr4+-Fe3+-Fe2+-Si4+-Al3+-Ca2+-O2− presented in this paper are based on computational diagram of fusibility of quasi ternary oxide systems. This work was carried out within the framework program KONTAKT-II project, LH12224 “Modeling and investigation of hypothetical non-standard situations at nuclear reactors of new type”, experimental work has been partly supported by the SUSEN Project CZ.1.05/2.1.00/03.0108 (European Regional Development Fund (ERDF)). Recommendations for further investigation are presented in this paper.
Sensitivity Analysis of a PWR Response During a Loss of Coolant Accident Under a Hypothetical Core Blockage Scenario Using RELAP5-3D
Authors: Crook Timothy , Vaghetto Rodolfo , Vanni Alessandro , Hassan Yassin A.
Published: November 2014

During a Loss of Coolant Accident (LOCA) a substantial amount of debris may be generated in containment during the blowdown phase. This debris can become a major safety concern since it can potentially impact the Emergency Core Cooling System (ECCS). Debris, produced by the LOCA break flow and transported to the sump, could pass through the filtering systems (debris bed and sump strainer) in the long term cooling phase. If the debris were to sufficiently accumulate at the core inlet region, the core flow could theoretically decrease, affecting the core coolability. Under such conditions, the removal of decay heat would only be possible by coolant flow reaching the core through alternative flow paths, such as the core bypass (baffle). There are certain plant specific features that can play a major role in core cooling from this bypass flow. One of these of key interest is the pressure relief holes. A typical 4-loop Pressurized Water Reactor (PWR) was modeled using RELAP5-3D to simulate the reactor system response during the phases of a large break LOCA and the effectiveness of core cooling under full core blockage was analyzed. The simulation results showed that the presence of alternative flow paths may significantly increase core coolability and prevent cladding temperatures from reaching safety limits, while the lack of LOCA holes may lead to a conservative over-prediction of the cladding temperature.
Global Balance of Plant in NPPs Using Process Data Reconciliation According to VDI 2048
Authors: Langenstein Magnus , Laipple Bernd
Published: November 2014

The large quantities of measurement information gathered throughout a plant process make the closing of the mass and energy balance nearly impossible without the help of additional tools. For this reason, a variety of plant monitoring tools for closing plant balances was developed. A major problem with the current tools lies in the non-consideration of redundant measurements which are available throughout the entire plant process.

The online monitoring reconciliation system is based on the process data reconciliation according to VDI 2048 standard and is using all redundant measurements within the process to close mass and energy balances. As a result, the most realistic process with the lowest uncertainty can be monitored. This system is installed in more than 35 NPPs worldwide and is used

○ as a basis for correction of feed water mass flow and feed water temperature measurements (recover of lost Megawatts).

○ as a basis for correction of Taverage (Tav) (recover of steam generator outlet pressure in PWRs).

○ for maintaining the thermal core power and the feed water mass flow under continuous operation conditions.

○ for automatic detection of erroneous measurements and measurement drift.

○ for detection of inner leakages, non-condensable gases and system losses.

○ for calculating non measured values (e.g. heat transfer coefficients, ΔT, preheater loads,…).

○ as a monitoring system for the main thermodynamic process.

○ for verifying warranty tests more accurate.

○ as a application of condition-based maintenance and component monitoring.

○ for What-if scenarios (simulation, not PDR)

This paper describes the methodology according to VDI 2048 (use of Gaussian correction principle and quality criterias). The benefits gained from the use of the online monitoring system are demonstrated.
Roll-to-roll sputtered Si-doped In2O3/Ag/Si-doped In2O3 multilayer as flexible and transparent anodes for flexible organic solar cells
Authors: Cho Da-Young , Shin Yong-Hee , Kim Han-Ki , Noh Yong-Jin , Na Seok-In , Chung Kwun-Bum
Published: November 2014

Amorphous Si-doped In2O3 (a-ISO), crystalline Ag, and a-ISO layers were sputtered onto a flexible polyethylene terephthalate substrate by using a lab-scale roll-to-roll (RTR) sputtering system. The resulting a-ISO/Ag/a-ISO multilayer was studied to optimize their characteristics for use as flexible and transparent anodes in flexible organic solar cells (FOSCs). To optimize the electrical and optical properties of the a-ISO/Ag/a-ISO multilayer, the thicknesses of each a-ISO and Ag layer were varied by controlling the DC power applied on ISO and Ag targets during the RTR sputtering process. Compared to the top and bottom a-ISO layer, controlling the thickness of the Ag layer is more effective for realizing a low sheet resistance and high transmittance a-ISO/Ag/a-ISO multilayer. At optimized thicknesses of a-ISO (30 nm) and Ag (10 nm), a symmetric a-ISO/Ag/a-ISO multilayer showed a sheet resistance of 5.256 Ω/sq and a high optical transmittance of 83.9%. Various bending test results showed that the high failure strain of the Ag interlayer led to good flexibility of the multilayer films. Furthermore, the authors discuss the effect of each a-ISO and Ag layer thickness on the performance of FOSCs fabricated on RTR-sputtered a-ISO/Ag/a-ISO anodes.
MomL, a Novel Marine-Derived
N
-Acyl Homoserine Lactonase from Muricauda olearia
Authors: Tang Kaihao , Su Ying , Brackman Gilles , Cui Fangyuan , Zhang Yunhui , Shi Xiaochong , Coenye Tom , Zhang Xiao-Hua
Published: November 2014

Gram-negative bacteria use
N
-acyl homoserine lactones (AHLs) as quorum sensing (QS) signaling molecules for interspecies communication, and AHL-dependent QS is related with virulence factor production in many bacterial pathogens. Quorum quenching, the enzymatic degradation of the signaling molecule, would attenuate virulence rather than kill the pathogens, and thereby reduce the potential for evolution of drug resistance. In a previous study, we showed that
Muricauda olearia
Th120, belonging to the class
Flavobacteriia
, has strong AHL degradative activity. In this study, an AHL lactonase (designated MomL), which could degrade both short- and long-chain AHLs with or without a substitution of
oxo
-group at the C-3 position, was identified from Th120. Liquid chromatography-mass spectrometry analysis demonstrated that MomL functions as an AHL lactonase catalyzing AHL degradation through lactone hydrolysis. MomL is an AHL lactonase belonging to the metallo-β-lactamase superfamily that harbors an N-terminal signal peptide. The overall catalytic efficiency of MomL for C
6
-HSL is ∼2.9 × 10
5
s
−1
M
−1
. Metal analysis and site-directed mutagenesis showed that, compared to AiiA, MomL has a different metal-binding capability and requires the histidine and aspartic acid residues for activity, while it shares the “HXHXDH” motif with other AHL lactonases belonging to the metallo-β-lactamase superfamily. This suggests that MomL is a representative of a novel type of secretory AHL lactonase. Furthermore, MomL significantly attenuated the virulence of
Pseudomonas aeruginosa
in a
Caenorhabditis elegans
infection model, which suggests that MomL has the potential to be used as a therapeutic agent.
Metabolic Engineering of Escherichia coli for the Synthesis of the Plant Polyphenol Pinosylvin
Authors: van Summeren-Wesenhagen Philana Veronica , Marienhagen Jan
Published: November 2014

Plant polyphenols are of great interest for drug discovery and drug development since many of these compounds have health-promoting activities as treatments against various diseases, such as diabetes, cancer, or heart diseases. However, the limited availability of polyphenols represents a major obstacle to clinical applications that must be overcome. In comparison to the quantities of these compounds obtained by isolation from natural sources or costly chemical synthesis, the microbial production of these compounds could provide sufficient quantities from inexpensive substrates. In this work, we describe the development of an
Escherichia coli
platform strain for the production of pinosylvin, a stilbene found in the heartwood of pine trees which could aid in the treatment of various cancers and cardiovascular diseases. Initially, several configurations of the three-step biosynthetic pathway to pinosylvin were constructed from a set of two different enzymes for each enzymatic step. After optimization of gene expression and evaluation of different construct environments, low pinosylvin concentrations up to 3 mg/liter could be detected. Analysis of the precursor supply and a comparative analysis of the intracellular pools of pathway intermediates and product identified the limited malonyl coenzyme A (malonyl-CoA) availability and low stilbene synthase activity in the heterologous host to be the main bottlenecks during pinosylvin production. Addition of cerulenin for increasing intracellular malonyl-CoA pools and the
in vivo
evolution of the stilbene synthase from
Pinus strobus
for improved activity in
E. coli
proved to be the keys to elevated product titers. These measures allowed product titers of 70 mg/liter pinosylvin from glucose, which could be further increased to 91 mg/liter by the addition of
l
-phenylalanine.
Transcriptomic and Physiological Insights into the Robustness of Long Filamentous Cells of Methanosaeta harundinacea, Prevalent in Upflow Anaerobic Sludge Blanket Granules
Authors: Zhou Liguang , Yu Haiying , Ai Guomin , Zhang Bo , Hu Songnian , Dong Xiuzhu
Published: November 2014

Methanosaeta
spp. are widely distributed in natural environments, and their filamentous cells contribute significantly to sludge granulation and the good performance of anaerobic reactors. A previous study indicated that
Methanosaeta harundinacea
6Ac displays a quorum sensing-regulated morphological transition from short to long filaments, and more acetate is channeled into methane production in long filaments, whereas more is channeled into biomass synthesis in short filaments. Here, we performed transcriptomic and physiological analysis to gain insights into active methanogenesis in long filaments of
M. harundinacea
6Ac. Both RNA sequencing (RNA-seq) and quantitative reverse transcription-PCR indicated that transcription of the genes involved in aceticlastic methanogenesis and energy metabolism was upregulated 1.2- to 10.3-fold in long filaments, while transcription of the genes for the methyl oxidative shunt was upregulated in short filaments. [2-
13
C]acetate trace experiments demonstrated that a relatively higher portion of the acetate methyl group was oxidized to CO
2
in short filaments than in long filaments. The long filaments exhibited higher catalase activity and oxygen tolerance than the short ones, which is consistent with increased transcription of the oxidant-scavenging genes. Moreover, transcription of genes for cell surface structures was upregulated in the long filaments, and transmission electron microscopy revealed a thicker cell envelope in the filaments. RNA-seq determined a >2-fold upregulation of a variety of antistress genes in short filaments, like those encoding chaperones and DNA repair systems, which implies that the short filaments can be stressed. This study reveals the genetic basis for the prevalence of the long filamentous morphology of
M. harundinacea
cells in upflow anaerobic sludge blanket granules.
Risk factors for and perinatal outcomes of major depression during pregnancy: a population-based analysis during 2002–2010 in Finland
Authors: Räisänen Sari , Lehto Soili M , Nielsen Henriette Svarre , Gissler Mika , Kramer Michael R , Heinonen Seppo
Published: November 2014

Objectives

To identify risk factors for and the consequences (several adverse perinatal outcomes) of physician-diagnosed major depression during pregnancy treated in specialised healthcare.

Design

A population-based cross-sectional study.

Setting

Data were gathered from Finnish health registers for 1996–2010.

Participants

All singleton births (n=511 938) for 2002–2010 in Finland.

Primary outcome measures

Prevalence, risk factors and consequences of major depression during pregnancy.

Results

Among 511 938 women, 0.8% experienced major depression during pregnancy, of which 46.9% had a history of depression prior to pregnancy. After history of depression, the second strongest associated factor for major depression was fear of childbirth, with a 2.6-fold (adjusted OR (aOR=2.63, 95% CI 2.39 to 2.89) increased prevalence. The risk profile of major depression also included adolescent or advanced maternal age, low or unspecified socioeconomic status (SES), single marital status, smoking, prior pregnancy terminations, anaemia and gestational diabetes regardless of a history of depression. Outcomes of pregnancies were worse among women with major depression than without. The contribution of smoking was substantial to modest for small-for-gestational age newborn (<−2 SD below mean birth), low birth weight (<2500 g), preterm birth (<37 weeks) and admission to neonatal intensive care associated with major depression, whereas SES made only a minor contribution.

Conclusions

Physician-diagnosed major depression during pregnancy was found to be rare. The strongest risk factor was history of depression prior to pregnancy. Other associated factors were fear of childbirth, low SES, lack of social support and unhealthy reproductive behaviour such as smoking. Outcomes of pregnancies were worse among women with major depression than without. Smoking during pregnancy made a substantial to modest contribution to adverse outcomes associated with depression during pregnancy.
Patients with nodding syndrome in Uganda improve with symptomatic treatment: a cross-sectional study
Authors: Idro Richard , Namusoke Hanifa , Abbo Catherine , Mutamba Byamah B , Kakooza-Mwesige Angelina , Opoka Robert O , Musubire Abdu K , Mwaka Amos D , Opar Bernard T
Published: November 2014

Objectives

Nodding syndrome (NS) is a poorly understood neurological disorder affecting thousands of children in Africa. In March 2012, we introduced a treatment intervention that aimed to provide symptomatic relief. This intervention included sodium valproate for seizures, management of behaviour and emotional difficulties, nutritional therapy and physical rehabilitation. We assessed the clinical and functional outcomes of this intervention after 12 months of implementation.

Design

This was a cross-sectional study of a cohort of patients with NS receiving the specified intervention. We abstracted preintervention features from records and compared these with the current clinical status. We performed similar assessments on a cohort of patients with other convulsive epilepsies (OCE) and compared the outcomes of the two groups.

Participants

Participants were patients with WHO-defined NS and patients with OCE attending the same centres.

Outcome measures

The primary outcome was the proportion of patients with seizure freedom (≥1 month without seizures). Secondary outcome measures included a reduction in seizure frequency, resolution of behaviour and emotional difficulties, and independence in basic self-care.

Results

Patients with NS had had a longer duration of symptoms (median 5 (IQR 3, 6) years) compared with those with OCE (4 (IQR 2, 6) years), p<0.001. The intervention resulted in marked improvements in both groups; compared to the preintervention state, 121/484 (25%) patients with NS achieved seizure freedom and there was a >70% reduction in seizure frequency; behaviour and emotional difficulties resolved in 194/327 (59%) patients; 193/484 (40%) patients had enrolled in school including 17.7% who had earlier withdrawn due to severe seizures, and over 80% had achieved independence in basic self-care. These improvements were, however, less than that in patients with OCE of whom 243/476 (51.1%) patients were seizure free and in whom the seizure frequency had reduced by 86%.

Conclusions

Ugandan children with NS show substantial clinical and functional improvements with symptomatic treatments suggesting that NS is probably a reversible encephalopathy.
Pre-existing atrial fibrillation and risk of arterial thromboembolism and death following pneumonia: a population-based cohort study
Authors: Gamst Jacob , Christiansen Christian Fynbo , Rasmussen Bodil Steen , Rasmussen Lars Hvilsted , Thomsen Reimar Wernich
Published: November 2014

Objectives

To examine the effect of pre-existing atrial fibrillation (AF) and associated therapy on the risk of arterial thromboembolism (ATE) and death following pneumonia.

Design, setting and participants

Population-based cohort study (1997–2012) of 88 315 patients with first-time hospitalisation with pneumonia in Northern Denmark.

Results

Of the included patients (median age 73.4 years), 8880 (10.1%) had pre-existing AF. The risk of ATE within 30 days of admission was 5.2% in patients with AF and 3.6% in patients without AF. After adjustment for higher age and comorbidity, the adjusted HR (aHR) with AF was 1.06 (95% CI 0.96 to 1.18). Among patients with AF, reduced risk of ATE was observed in vitamin-K antagonist users compared with non-users (aHR 0.74 (95% CI 0.61 to 0.91)). Thirty-day mortality was 20.1% in patients with AF and 13.9% in patients without AF. Corresponding 1-year mortalities were 43.7% and 30.3%. The aHRs for 30-day and 1-year mortality with AF were 1.00 (95% CI 0.94 to 1.05) and 1.01 (95% CI 0.98 to 1.05). In patients with AF, reduced mortality risk was observed in users of vitamin-K antagonists (aHR 0.70 (95% CI 0.63 to 0.77)) and β-blockers (aHR 0.77 (95% CI 0.70 to 0.85). Increased mortality was found in digoxin users (aHR 1.16 (95% CI 1.06 to 1.28)).

Conclusions

Pre-existing AF is frequent in patients hospitalised with pneumonia and a marker of increased risk of ATE and death, explained by higher patient age and comorbidity. Prognosis is closely related to preadmission medical treatment for AF.
A new hemodynamic model for the study of cerebral venous outflow
Authors: Gadda G. , Taibi A. , Sisini F. , Gambaccini M. , Zamboni P. , Ursino M.
Published: November 2014

We developed a mathematical model of the cerebral venous outflow for the simulation of the average blood flows and pressures in the main drainage vessels of the brain. The main features of the model are that it includes a validated model for the simulation of the intracranial circulation and it accounts for the dependence of the hydraulic properties of the jugular veins with respect to the gravity field, which makes it an useful tool for the study of the correlations between extracranial blood redistributions and changes in the intracranial environment. The model is able to simulate the average pressures and flows in different points of the jugular ducts, taking into account the amount of blood coming from the anastomotic connections; simulate how the blood redistribution due to change of posture affects flows and pressures in specific points of the system; and simulate redistributions due to stenotic patterns. Sensitivity analysis to check the robustness of the model was performed. The model reproduces average physiologic behavior of the jugular, vertebral, and cerebral ducts in terms of pressures and flows. In fact, jugular flow drops from ∼11.7 to ∼1.4 ml/s in the passage from supine to standing. At the same time, vertebral flow increases from 0.8 to 3.4 ml/s, while cerebral blood flow, venous sinuses pressure, and intracranial pressure are constant around the average value of 12.5 ml/s, 6 mmHg, and 10 mmHg, respectively. All these values are in agreement with literature data.
A preterm pig model of lung immaturity and spontaneous infant respiratory distress syndrome
Authors: Caminita Frank , van der Merwe Marie , Hance Brittany , Krishnan Ramesh , Miller Sarah , Buddington Karyl , Buddington Randal K.
Published: November 2014

Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia remain the leading causes of preterm infant morbidity, mortality, and lifelong disability. Research to improve outcomes requires translational large animal models for RDS. Preterm pigs delivered by caesarian section at gestation days (GD) 98, 100, 102, and 104 were provided 24 h of neonatal intensive care, monitoring (pulse oximetry, blood gases, serum biomarkers, radiography), and nutritional support, with or without intubation and mechanical ventilation (MV; pressure control ventilation with volume guarantee). Spontaneous development of RDS and mortality without MV are inversely related with GD at delivery and correspond with inadequacy of tidal volume and gas exchange. GD 98 and 100 pigs have consolidated lungs, immature alveolar architecture, and minimal surfactant protein-B expression, and MV is essential at GD 98. Although GD 102 pigs had some alveoli lined by pneumocytes and surfactant was released in response to MV, blood gases and radiography revealed limited recruitment 1–2 h after delivery, and mortality at 24 h was 66% (35/53) with supplemental oxygen provided by a mask and 69% (9/13) with bubble continuous positive airway pressure (8–9 cmH2O). The lungs at GD 104 had higher densities of thin-walled alveoli that secreted surfactant, and MV was not essential. Between GD 98 and 102, preterm pigs have ventilation inadequacies and risks of RDS that mimic those of preterm infants born during the saccular phase of lung development, are compatible with standards of neonatal intensive care, and are alternative to fetal nonhuman primates and lambs.
A mathematical model to predict protein wash out kinetics during whole-lung lavage in autoimmune pulmonary alveolar proteinosis
Authors: Akasaka Keiichi , Tanaka Takahiro , Maruyama Takashi , Kitamura Nobutaka , Hashimoto Atsushi , Ito Yuko , Watanabe Hiroyoshi , Wakayama Tomoshige , Arai Takero , Hayashi Masachika , Moriyama Hiroshi , Uchida Kanji , Ohkouchi Shinya , Tazawa Ryushi , Takada Toshinori , Yamaguchi Etsuro , Ichiwata Toshio , Hirose Masaki , Arai Toru , Inoue Yoshikazu , Kobayashi Hirosuke , Nakata Koh
Published: November 2014

Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5–2.0 l of saline aliquots for 10–30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and β2-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of β2-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.
Tropomodulin 1 Expression Driven by NF-κB Enhances Breast Cancer Growth
Authors: Ito-Kureha Taku , Koshikawa Naohiko , Yamamoto Mizuki , Semba Kentaro , Yamaguchi Noritaka , Yamamoto Tadashi , Seiki Motoharu , Inoue Jun-ichiro
Published: November 2014

Triple-negative breast cancers (TNBC), which include the basal-like and claudin-low disease subtypes, are aggressive malignancies for which effective therapeutic targets are lacking. NF-κB activation has an established role in breast malignancy, and it is higher in TNBC than other breast cancer subtypes. On this basis, we hypothesized that proteins derived from NF-κB target genes might be molecular targets for TNBC therapy. In this study, we conducted a microarray-based screen for novel NF-κB–inducible proteins as candidate therapeutic targets, identifying tropomodulin 1 (TMOD1) as a lead candidate. TMOD1 expression was regulated directly by NF-κB and was significantly higher in TNBC than other breast cancer subtypes. TMOD1 elevation is associated with enhanced tumor growth in a mouse tumor xenograft model and in a 3D type I collagen culture. TMOD1-dependent tumor growth was correlated with MMP13 induction, which was mediated by TMOD1-dependent accumulation of β-catenin. Overall, our study highlighted a novel TMOD1-mediated link between NF-κB activation and MMP13 induction, which accounts in part for the NF-κB–dependent malignant phenotype of TNBC. Cancer Res; 75(1); 62–72. ©2014 AACR.
Mdm2 and Aurora Kinase A Inhibitors Synergize to Block Melanoma Growth by Driving Apoptosis and Immune Clearance of Tumor Cells
Authors: Vilgelm Anna E. , Pawlikowski Jeff S. , Liu Yan , Hawkins Oriana E. , Davis Tyler A. , Smith Jessica , Weller Kevin P. , Horton Linda W. , McClain Colt M. , Ayers Gregory D. , Turner David C. , Essaka David C. , Stewart Clinton F. , Sosman Jeffrey A. , Kelley Mark C. , Ecsedy Jeffrey A. , Johnston Jeffrey N. , Richmond Ann
Published: November 2014

Therapeutics that induce cancer cell senescence can block cell proliferation and promote immune rejection. However, the risk of tumor relapse due to senescence escape may remain high due to the long lifespan of senescent cells that are not cleared. Here, we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wild-type 53. In the model studied, this effect is accompanied by proliferation arrest, mitochondrial depolarization, apoptosis, and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon Ccl5, Ccl1, and Cxcl9. The AURKA/MDM2 combination therapy shows adequate bioavailability and low toxicity to the host. Moreover, the prominent response of patient-derived melanoma tumors to coadministered MDM2 and AURKA inhibitors offers a sound rationale for clinical evaluation. Taken together, our work provides a preclinical proof of concept for a combination treatment that leverages both senescence and immune surveillance to therapeutic ends. Cancer Res; 75(1); 181–93. ©2014 AACR.