bluuebunny/crossref_metadata_2025 huggingface dataset:
Light Microscopy, Culture, Molecular, and Serologic Methods for Detection of Herpes Simplex Virus
Authors: Anderson Neil W. , Buchan Blake W. , Ledeboer Nathan A.
Published: October 2013

Herpes simplex virus 1 (HSV-1) and 2 (HSV-2) cause a variety of human diseases, ranging from acute to chronic and mild to severe. The absence of curative therapy results in lifelong carriage marked by recurrent outbreaks and allows transmission of the virus to uninfected individuals. Nonspecific lesions, variable presentation, and chronic carriage necessitate the use of different laboratory testing methods appropriate for each presentation. A thorough understanding of the performance characteristics and limitations of available tests is critical for selection of the appropriate test and interpretation of results. Clinical sensitivity, specificity, and selection of the appropriate methodology is paramount to avoid misdiagnosis and guide therapy. In this article we review the different methods for detection and typing of HSV, including light microscopy, culture, serology, and nucleic acid-based tests. We discuss the strengths and weaknesses of each method for diagnosing HSV infection, cite performance characteristics, and review appropriate clinical uses.
Development and Application of a Multiplex PCR Method for Rapid Differential Detection of Subgroup A, B, and J Avian Leukosis Viruses
Authors: Gao Qi , Yun Bingling , Wang Qi , Jiang Lili , Zhu Haibo , Gao Yanni , Qin Liting , Wang Yongqiang , Qi Xiaole , Gao Honglei , Wang Xiaomei , Gao Yulong
Published: October 2013

Avian leukosis virus (ALV) subgroups A, B, and J are very common in poultry flocks and have caused serious economic losses in recent years. A multiplex PCR (mPCR) method for the detection of these three subgroups was developed and optimized in this study. We first designed a common forward primer, PF, and three downstream primers, AR, BR, and JR, which can amplify 715 bp for subgroup A, 515 bp for subgroup B, and 422 bp for subgroup J simultaneously in one reaction. The mPCR method produced neither cross-reactions with other subgroups of ALVs nor nonspecific reactions with other common avian viruses. The detection limit of the mPCR was as low as 1 × 10
3
viral DNA copies of each of the three subgroups. In animal experiments, the mPCR detected ALVs 2 to 4 days earlier than did virus isolation from whole-blood samples and cloaca swabs. Furthermore, a total of 346 clinical samples (including 127 tissue samples, 86 cloaca swabs, 59 albumen samples, and 74 whole-blood samples) from poultry flocks with suspected ALV infection were examined by mPCR, routine PCR, and virus isolation. The positive sample/total sample
ratios for ALV-A, ALV-B, and ALV-J were 48% (166/346) as detected by mPCR and 48% (166/346) as detected by routine PCR. However, the positive sample/total sample ratio detected by virus isolation was 40% (138/346). The results of the mPCR and routine PCR were confirmed by sequencing the specific fragments. These results indicate that the mPCR method is rapid, specific, sensitive, and convenient for use in epidemiological studies of ALV, clinical detection of ALV, and ALV eradication programs.
Gastroenteritis Caused by the Cryptosporidium Hedgehog Genotype in an Immunocompetent Man
Authors: Kváč Martin , Saková Kamila , Kvĕtoňová Dana , Kicia Marta , Wesołowska Maria , McEvoy John , Sak Bohumil
Published: October 2013

The
Cryptosporidium
hedgehog genotype, which has been reported previously in hedgehogs and horses, was identified as the cause of the diarrheal disease cryptosporidiosis in an immunocompetent man in the Czech Republic. This is the first report of human illness caused by the
Cryptosporidium
hedgehog genotype.
Elucidation of the Block to Herpes Simplex Virus Egress in the Absence of Tegument Protein UL16 Reveals a Novel Interaction with VP22
Authors: Starkey Jason L. , Han Jun , Chadha Pooja , Marsh Jacob A. , Wills John W.
Published: October 2013

UL16 is a tegument protein of herpes simplex virus (HSV) that is conserved among all members of the
Herpesviridae
, but its function is poorly understood. Previous studies revealed that UL16 is associated with capsids in the cytoplasm and interacts with the membrane protein UL11, which suggested a “bridging” function during cytoplasmic envelopment, but this conjecture has not been tested. To gain further insight, cells infected with UL16-null mutants were examined by electron microscopy. No defects in the transport of capsids to cytoplasmic membranes were observed, but the wrapping of capsids with membranes was delayed. Moreover, clusters of cytoplasmic capsids were often observed, but only near membranes, where they were wrapped to produce multiple capsids within a single envelope. Normal virion production was restored when UL16 was expressed either by complementing cells or from a novel position in the HSV genome. When the composition of the UL16-null viruses was analyzed, a reduction in the packaging of glycoprotein E (gE) was observed, which was not surprising, since it has been reported that UL16 interacts with this glycoprotein. However, levels of the tegument protein VP22 were also dramatically reduced in virions, even though this gE-binding protein has been shown not to depend on its membrane partner for packaging. Cotransfection experiments revealed that UL16 and VP22 can interact in the absence of other viral proteins. These results extend the UL16 interaction network beyond its previously identified binding partners to include VP22 and provide evidence that UL16 plays an important function at the membrane during virion production.
Haemolytic anaemia after ingestion of Neem (Azadirachta indica) tea
Authors: Page Cristy , Hawes Emily M
Published: October 2013

The authors report a clinically relevant and possible cause of haemolytic anaemia from ingestion of a Mexican tea from the Neem tree, also known asAzadirachta indica, in a 35-year-old Hispanic man who was found to have glucose-6-phosphate dehydrogenase deficiency.
Prevalence and incidence rates of autism in the UK: time trend from 2004–2010 in children aged 8 years
Authors: Taylor Brent , Jick Hershel , MacLaughlin Dean
Published: October 2013

Objectives

To update UK studies begun in the early 1990s on the annual prevalence and incidence rates of autism in children; undertaken in response to a March 2012 press release, widely covered by the media, from the US Centre for Disease Control (CDC) reporting that the autism prevalence rate in 2008 in 8-year-old US children was 1 in 88, a 78% increase from a CDC estimate in 2004. This finding suggested a continuation of the dramatic increase in children diagnosed as autistic, which occurred in the 1990s.

Design

Population study using the UK General Practice Research Database (GPRD).

Methods

Annual autism prevalence rates were estimated for children aged 8 years in 2004–2010 by dividing the number diagnosed as autistic in each or any previous year by the number of children active in the study population that year. We also calculated annual incidence rates for children aged 2–8 years, by dividing the number newly diagnosed in 2004–2010 by the same denominators.

Results

Annual prevalence rates for each year were steady at approximately 3.8/1000 boys and 0.8/1000 girls. Annual incidence rates each year were also steady at about 1.2/1000 boys and 0.2/1000 girls.

Conclusions

Following a fivefold increase in the annual incidence rates of autism during the 1990s in the UK, the incidence and prevalence rates in 8-year-old children reached a plateau in the early 2000s and remained steady through 2010. Whether prevalence rates have increased from the early 2000s in the USA remains uncertain.
Microwave-assisted reduction of F-BODIPYs and dipyrrins to generate dipyrromethanes
Authors: Melanson Jennifer A. , Smithen Deborah A. , Cameron T. Stanley , Thompson Alison
Published: October 2013

The reduction of BODIPYs and dipyrrins to dipyrromethanes, via a reaction involving ethylene glycol and sodium methoxide, is reported. When benzyl alcohol is used in place of ethylene glycol, the addition of 2,4-dinitrophenylhydrazine to the reaction mixture after microwave irradiation results in the production of 1-benzylidene-2-(2,4-dinitrophenyl)hydrazone, indicating concomitant production of aldehyde alongside the dipyrromethane.
A CLASS OF EFFICIENT QUANTUM INCREMENTER GATES FOR QUANTUM CIRCUIT SYNTHESIS
Authors: LI XIAOYU , YANG GUOWU , TORRES CARLOS MANUEL , ZHENG DESHENG , WANG KANG L.
Published: October 2013

The quantum incrementer is one of the simplest quantum operators, which exhibits basic arithmetic operations such as addition, the propagation of carry qubits and the resetting of carry qubits. In this paper, three quantum incrementer gate circuit topologies are derived and compared based upon their total number of gates, the complexity of the circuits, the types of gates used and the number of carry or ancilla qubits implemented. The first case is a generalized n-qubit quantum incrementer gate with the notation of (n:0). Two other quantum incrementer topologies are proposed with the notations of (n:n-1: RE ) and (n:n-1: RD ). A general method is derived to decompose complicated quantum circuits into simpler quantum circuits which are easier to manage and physically implement. Due to the cancelation of intermediate unitary gates, it is shown that adding ancilla qubits slightly increases the complexity of a given circuit by the order of 3n, which pales in comparison to the complexity of the original circuit of the order n2 without reduction. Finally, a simple application of the generalized n-qubit quantum incrementer gate is introduced, which is related to quantum walks.
Comparison of scaling relationships of extensional fault cores in tight carbonate and porous sandstone reservoirs
Authors: Bastesen Eivind , Braathen Alvar , Skar Tore
Published: October 2013

This paper presents a comparative analysis of the thicknesses–displacement relationships of fault cores in non-/low-porous carbonate and porous sandstone reservoirs. Fault thickness data were collected from extensional faults in mainly Cretaceous continental sandstones and Late Cretaceous–Paleogene marine carbonates exposed along the eastern flank of the Suez Rift, Egypt. The dataset consists of 730 thickness measurements, of which 313 are from 68 faults in carbonate rocks, and 417 are from 120 deformation band/microfaults and faults in sandstones. These data show that the increase in fault core thickness with displacement for the two lithologies is, overall, similar in log–log space, consistent with a power-law trend with an exponent of 0.5. However, for smaller faults, cores in carbonates are generally thicker than those in sandstones. The observation of nearly equal core thickness–displacement relationships for larger faults (>10 m displacement) suggests that increased displacement reduces the geomechanical influence of lithology. In a statistical analysis of bins of fault displacement, small displacement faults seem to follow a skewed distribution towards smaller fault core thicknesses, moderate displacement faults have a normal distribution, while large displacement faults have a distribution skewed towards large core thicknesses. Each thickness distribution can be estimated with a mean and standard deviation. Fault core thickness variations are caused by interplaying factors such as fault geometric development, spatial and temporal positioning of shear and volumetric strains, and rheological changes. The variability in core thickness and intrinsic architecture of fault cores for any given location will cause significant variation in across-fault fluid flow, even for the same juxtaposition style.
How far we've come
Authors: Chang Shih-Fu
Published: October 2013

This article reviews the major research trends that emerged in the last two decades within the broad area of multimedia information retrieval, with a focus on the ACM Multimedia community. Trends are defined (nonscientifically) to be topics that appeared in ACM multimedia publications and have had a significant number of citations. The article also assesses the impacts of these trends on real-world applications. The views expressed are subjective and likely biased but hopefully useful for understanding the heritage of the community and stimulating new research direction.
Navigating the worldwide community of photos
Authors: Szeliski Richard , Snavely Noah , Seitz Steven M.
Published: October 2013

The last decade has seen an explosion in the number of photographs available on the Internet. The sheer volume of interesting photos makes it a challenge to explore this space. Various Web and social media sites, along with search and indexing techniques, have been developed in response. One natural way to navigate these images in a 3D geo-located context. In this article, we reflect on our work in this area, with a focus on techniques that build partial 3D scene models to help find and navigate interesting photographs in an interactive, immersive 3D setting. We also discuss how finding such relationships among photographs opens up exciting new possibilities for multimedia authoring, visualization, and editing.
A personal look back at twenty years of research in multimedia content analysis
Authors: Effelsberg Wolfgang
Published: October 2013

This paper is a personal look back at twenty years of research in multimedia content analysis. It addresses the areas of audio, photo and video analysis for the purpose of indexing and retrieval from the perspective of a multimedia researcher. Whereas a general analysis of content is impossible due to the personal bias of the user, significant progress was made in the recognition of specific objects or events. The paper concludes with a brief outlook on the future.
Online video delivery
Authors: Hua Kien A.
Published: October 2013

Video streaming is the core technology for online video delivery systems. Initial research on this technology faced many challenges. In this article, lessons learned from beginning trials are discussed; some pioneering works that provided early solutions and inspired subsequent research are presented; and new techniques required for emerging applications are examined.
High-quality computational imaging through simple lenses
Authors: Heide Felix , Rouf Mushfiqur , Hullin Matthias B. , Labitzke Bjorn , Heidrich Wolfgang , Kolb Andreas
Published: October 2013

Modern imaging optics are highly complex systems consisting of up to two dozen individual optical elements. This complexity is required in order to compensate for the geometric and chromatic aberrations of a single lens, including geometric distortion, field curvature, wavelength-dependent blur, and color fringing.

In this article, we propose a set of computational photography techniques that remove these artifacts, and thus allow for postcapture correction of images captured through uncompensated, simple optics which are lighter and significantly less expensive. Specifically, we estimate per-channel, spatially varying point spread functions, and perform nonblind deconvolution with a novel cross-channel term that is designed to specifically eliminate color fringing.
Geometry and context for semantic correspondences and functionality recognition in man-made 3D shapes
Authors: Laga Hamid , Mortara Michela , Spagnuolo Michela
Published: October 2013

We address the problem of automatic recognition of functional parts of man-made 3D shapes in the presence of significant geometric and topological variations. We observe that under such challenging circumstances, the context of a part within a 3D shape provides important cues for learning the semantics of shapes. We propose to model the context as structural relationships between shape parts and use them, in addition to part geometry, as cues for functionality recognition. We represent a 3D shape as a graph interconnecting parts that share some spatial relationships. We model the context of a shape part as walks in the graph. Similarity between shape parts can then be defined as the similarity between their contexts, which in turn can be efficiently computed using graph kernels. This formulation enables us to: (1) find part-wise semantic correspondences between 3D shapes in a nonsupervised manner and without relying on user-specified textual tags, and (2) design classifiers that learn in a supervised manner the functionality of the shape components. We specifically show that the performance of the proposed context-aware similarity measure in finding part-wise correspondences outperforms geometry-only-based techniques and that contextual analysis is effective in dealing with shapes exhibiting large geometric and topological variations.
Geodesics in heat
Authors: Crane Keenan , Weischedel Clarisse , Wardetzky Max
Published: October 2013

We introduce the
heat method
for computing the geodesic distance to a specified subset (e.g., point or curve) of a given domain. The heat method is robust, efficient, and simple to implement since it is based on solving a pair of standard linear elliptic problems. The resulting systems can be prefactored once and subsequently solved in near-linear time. In practice, distance is updated an order of magnitude faster than with state-of-the-art methods, while maintaining a comparable level of accuracy. The method requires only standard differential operators and can hence be applied on a wide variety of domains (grids, triangle meshes, point clouds, etc.). We provide numerical evidence that the method converges to the exact distance in the limit of refinement; we also explore smoothed approximations of distance suitable for applications where greater regularity is required.
A theoretical analysis of the risk evaluation formulas for spectrum-based fault localization
Authors: Xie Xiaoyuan , Chen Tsong Yueh , Kuo Fei-Ching , Xu Baowen
Published: October 2013

An important research area of Spectrum-Based Fault Localization (SBFL) is the effectiveness of risk evaluation formulas. Most previous studies have adopted an empirical approach, which can hardly be considered as sufficiently comprehensive because of the huge number of combinations of various factors in SBFL. Though some studies aimed at overcoming the limitations of the empirical approach, none of them has provided a completely satisfactory solution. Therefore, we provide a theoretical investigation on the effectiveness of risk evaluation formulas. We define two types of relations between formulas, namely, equivalent and better. To identify the relations between formulas, we develop an innovative framework for the theoretical investigation. Our framework is based on the concept that the determinant for the effectiveness of a formula is the number of statements with risk values higher than the risk value of the faulty statement. We group all program statements into three disjoint sets with risk values higher than, equal to, and lower than the risk value of the faulty statement, respectively. For different formulas, the sizes of their sets are compared using the notion of subset. We use this framework to identify the maximal formulas which should be the only formulas to be used in SBFL.
Path- and index-sensitive string analysis based on monadic second-order logic
Authors: Tateishi Takaaki , Pistoia Marco , Tripp Omer
Published: October 2013

We propose a novel technique for statically verifying the strings generated by a program. The verification is conducted by encoding the program in Monadic Second-order Logic (M2L). We use M2L to describe constraints among program variables and to abstract built-in string operations. Once we encode a program in M2L, a theorem prover for M2L, such as MONA, can automatically check if a string generated by the program satisfies a given specification, and if not, exhibit a counterexample. With this approach, we can naturally encode relationships among strings, accounting also for cases in which a program manipulates strings using indices. In addition, our string analysis is path sensitive in that it accounts for the effects of string and Boolean comparisons, as well as regular-expression matches.

We have implemented our string analysis algorithm, and used it to augment an industrial security analysis for Web applications by automatically detecting and verifying
sanitizers
—methods that eliminate malicious patterns from untrusted strings, making these strings safe to use in security-sensitive operations. On the 8 benchmarks we analyzed, our string analyzer discovered 128 previously unknown sanitizers, compared to 71 sanitizers detected by a previously presented string analysis.
On software component co-installability
Authors: Vouillon Jérôme , Cosmo Roberto Di
Published: October 2013

Modern software systems are built by composing components drawn from large
repositories
, whose size and complexity is increasing at a very fast pace. A fundamental challenge for the maintainability and the scalability of such software systems is the ability to quickly identify the components that can or cannot be installed together: this is the
co-installability
problem, which is related to boolean satisfiability and is known to be algorithmically hard. This article develops a novel theoretical framework, based on formally certified semantic preserving graph-theoretic transformations, that allows us to associate to each concrete component repository a much smaller one with a simpler structure, that we call
strongly flat
, with equivalent co-installability properties. This flat repository can be displayed in a way that provides a concise view of the co-installability issues in the original repository, or used as a basis for various algorithms related to co-installability, like the efficient computation of strong conflicts between components. The proofs contained in this work have been machine checked using the Coq proof assistant.
A web-centred approach to end-user software engineering
Authors: Lizcano David , Alonso Fernando , Soriano Javier , Lopez Genoveva
Published: October 2013

This article addresses one of the major end-user software engineering (EUSE) challenges, namely, how to motivate end users to apply unfamiliar software engineering techniques and activities to achieve their goal: translate requirements into software that meets their needs. EUSE activities are secondary to the goal that the program is helping to achieve and end-user programming is opportunistic. The challenge is then to find ways to incorporate EUSE activities into the existing workflow without users having to make substantial changes to the type of work they do or their priorities. In this article, we set out an approach to EUSE for web-based applications. We also propose a software lifecycle that is consistent with the conditions and priorities of end users without programming skills and is well-aligned with EUSE's characteristic informality, ambiguity and opportunisticness. Users applying this lifecycle manage to find solutions that they would otherwise be unable to identify. They also develop quality products. Users of this approach will not have to be acquainted with software engineering, as a framework will take them through the web-centred EUSE lifecycle step-by-step. We also report a statistical experiment in which users develop web software with and without a framework to guide them through the lifecycle. Its aim is to validate the applicability of our framework-driven lifecycle.
Evaluating a query framework for software evolution data
Authors: Würsch Michael , Giger Emanuel , Gall Harald C.
Published: October 2013

With the steady advances in tooling to support software engineering, mastering all the features of modern IDEs, version control systems, and project trackers is becoming increasingly difficult. Answering even the most common developer questions can be surprisingly tedious and difficult. In this article we present a user study with 35 subjects to evaluate our quasi-natural language interface that provides access to various facets of the evolution of a software system but requires almost zero learning effort. Our approach is tightly woven into the Eclipse IDE and allows developers to answer questions related to source code, development history, or bug and issue management. The results of our evaluation show that our query interface can outperform classical software engineering tools in terms of correctness, while yielding significant time savings to its users and greatly advancing the state of the art in terms of usability and learnability.
Smart Everything: Will Intelligent Systems Reduce Resource Use?
Authors: Koomey Jonathan G. , Scott Matthews H. , Williams Eric
Published: October 2013

Until recently, the main environmental concerns associated with information and communication technologies (ICTs) have been their use-phase electricity consumption and the chemicals associated with their manufacture, and the environmental effects of these technologies on other parts of the economy have largely been ignored. With the advent of mobile computing, communication, and sensing devices, these indirect effects have the potential to be much more important than the impacts from the use and manufacturing phases of this equipment. This article summarizes the trends that have propelled modern technological societies into the ultralow-power design space and explores the implications of these trends for the direct and indirect environmental impacts associated with these new technologies. It reviews the literature on environmental effects of information technology (also with an emphasis on low-power systems) and suggests areas for further research.
An Inorganic/Organic Hybrid Coating for Low Cost Metal Mounted Dye-Sensitized Solar Cells
Authors: Vyas Niladri , Charbonneau Cecile , Carnie Matthew , Worsley David A. , Watson Trystan M.
Published: October 2013

Titanium nitride (TiN) incorporated polyimide (PI) is an inorganic/organic hybrid coating where TiN particles are evenly dispersed into a polyimide matrix. Once cured, this composite coating can withstand high temperature treatments (up to 500 °C) whilst maintaining excellent dimensional and chemical stability and electrical conductivity, with sheet reistance values comparable to thin films of transparent conducting oxides such as fluorine-doped tin oxide (FTO). The TiN/PI hybrid coating makes an attractive material that may be used as a strategic first layer in the working electrode of dye-sensitized solar cells (DSCs) mounted on metal substrates: while compatible with the deposition and high temperature processing of the mesoporous titanium dioxide layer, it is also expected to prevent corrosion from the aggressive I-/I3
- electrolyte whilst maintaining electrical conductivity. DSCs were fabricated using a TiN/PI coating on architectural steel substrates which demonstrated comparable photovoltaic characteristics to Ti-metal and FTO-coated glass based cells.
Electrocatalytic Reduction of Gas-Phased CO2 on Nano-Sized Sn Electrode Surface
Authors: Lee Seunghwa , Ju HyungKuk , Jeon Hongrae , Machunda Revocatus L , Kim Dahee , Lee Jae Kwang , Lee Jaeyoung
Published: October 2013

Electrochemical conversion of CO2 (ECC) is one of the promising approaches which may produce alternative organic chemicals such as HCOOH, CH3OH and C2H4. Use of efficient catalysts and systems are necessarily required to obtain high selectivity and high conversion rate. In this study, nano-sized Sn electrocatalyst for producing formic acid is sprayed onto the gas diffusion electrode and a zero-gap electrolytic cell with the membrane electrode assembly is applied. A constant production of formic acid analyzed by UV-spectroscopy is obtained.
Investigation on Electrical Properties of RF Sputtered Deposited BCN Thin Films
Authors: Prakash Adithya , Skaria Giji , Sundaram Kalpathy B
Published: October 2013

The ever increasing advancements in semiconductor technology and continuous scaling of CMOS devices mandate the need for new dielectric materials with low-k values. The interconnect delay can be reduced not only by the resistance of the conductor but also by decreasing the capacitance of dielectric layer. A wiring metal with low resistivity and a high quality insulating film with a low dielectric constant may lead to a reduction of the wiring capacitance. Boron carbon nitride (BCN) films are prepared by reactive magnetron sputtering from a B4C target and deposited to make metal-insulator-metal (MIM) sandwich structures using aluminum as the top and bottom electrodes. BCN films are deposited at various N2/Ar gas flow ratios, substrate temperatures and process pressures. The electrical characterization of the MIM devices includes capacitance vs. voltage (C-V), current vs voltage, and breakdown voltage characteristics. The above characterizations are performed as a function of deposition parameters.
Intravenous renal cell transplantation with SAA1-positive cells prevents the progression of chronic renal failure in rats with ischemic-diabetic nephropathy
Authors: Kelly Katherine J. , Zhang Jizhong , Han Ling , Wang Mingsheng , Zhang Shaobo , Dominguez Jesus H.
Published: October 2013

Diabetic nephropathy, the most common cause of progressive chronic renal failure and end-stage renal disease, has now reached global proportions. The only means to rescue diabetic patients on dialysis is renal transplantation, a very effective therapy but severely limited by the availability of donor kidneys. Hence, we tested the role of intravenous renal cell transplantation (IRCT) on obese/diabetic Zucker/SHHF F1 hybrid (ZS) female rats with severe ischemic and diabetic nephropathy. Renal ischemia was produced by bilateral renal clamping of the renal arteries at 10 wk of age, and IRCT with genetically modified normal ZS male tubular cells was given intravenously at 15 and 20 wk of age. Rats were euthanized at 34 wk of age. IRCT with cells expressing serum amyloid A had strong and long-lasting beneficial effects on renal function and structure, including tubules and glomeruli. However, donor cells were found engrafted only in renal tubules 14 wk after the second infusion. The results indicate that IRCT with serum amyloid A-positive cells is effective in preventing the progression of chronic kidney disease in rats with diabetic and ischemic nephropathy.
Genetics of hypertension: discoveries from the bench to human populations
Authors: Franceschini Nora , Le Thu H.
Published: October 2013

Hypertension is a complex trait that is influenced by both heritable and environmental factors. The search for genes accounting for the susceptibility to hypertension has driven parallel efforts in human research and in research using experimental animals in controlled environmental settings. Evidence from rodent models of genetic hypertension and human Mendelian forms of hypertension and hypotension have yielded mechanistic insights into the pathways that are perturbed in blood pressure homeostasis, most of which converge at the level of renal sodium reabsorption. However, the bridging of evidence from these very diverse approaches to identify mechanisms underlying hypertension susceptibility and the translation of these findings to human populations and public health remain a challenge. Furthermore, findings from genome-wide association studies still require functional validation in experimental models. In this review, we highlight results and implications from key studies in experimental and clinical hypertension to date.
Characterization of age-related changes in synaptic transmission onto F344 rat basal forebrain cholinergic neurons using a reduced synaptic preparation
Authors: Griffith William H. , DuBois Dustin W. , Fincher Annette , Peebles Kathryn A. , Bizon Jennifer L. , Murchison David
Published: October 2013

Basal forebrain (BF) cholinergic neurons participate in a number of cognitive processes that become impaired during aging. We previously found that age-related enhancement of Ca2+ buffering in rat cholinergic BF neurons was associated with impaired performance in the water maze spatial learning task (Murchison D, McDermott AN, Lasarge CL, Peebles KA, Bizon JL, and Griffith WH. J Neurophysiol 102: 2194–2207, 2009). One way that altered Ca2+ buffering could contribute to cognitive impairment involves synaptic function. In this report we show that synaptic transmission in the BF is altered with age and cognitive status. We have examined the properties of spontaneous postsynaptic currents (sPSCs) in cholinergic BF neurons that have been mechanically dissociated without enzymes from behaviorally characterized F344 rats. These isolated neurons retain functional presynaptic terminals on their somata and proximal dendrites. Using whole cell patch-clamp recording, we show that sPSCs and miniature PSCs are predominately GABAergic (bicuculline sensitive) and in all ways closely resemble PSCs recorded in a BF in vitro slice preparation. Adult (4–7 mo) and aged (22–24 mo) male rats were cognitively assessed using the water maze. Neuronal phenotype was identified post hoc using single-cell RT-PCR. The frequency of sPSCs was reduced during aging, and this was most pronounced in cognitively impaired subjects. This is the same population that demonstrated increased intracellular Ca2+ buffering. We also show that increasing Ca2+ buffering in the synaptic terminals of young BF neurons can mimic the reduced frequency of sPSCs observed in aged BF neurons.
Mechanisms of Glutamate Transport
Authors: Vandenberg Robert J. , Ryan Renae M.
Published: October 2013

l-Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and plays important roles in a wide variety of brain functions, but it is also a key player in the pathogenesis of many neurological disorders. The control of glutamate concentrations is critical to the normal functioning of the central nervous system, and in this review we discuss how glutamate transporters regulate glutamate concentrations to maintain dynamic signaling mechanisms between neurons. In 2004, the crystal structure of a prokaryotic homolog of the mammalian glutamate transporter family of proteins was crystallized and its structure determined. This has paved the way for a better understanding of the structural basis for glutamate transporter function. In this review we provide a broad perspective of this field of research, but focus primarily on the more recent studies with a particular emphasis on how our understanding of the structure of glutamate transporters has generated new insights.
Physiological Roles of Aquaporin-4 in Brain
Authors: Nagelhus Erlend A. , Ottersen Ole P.
Published: October 2013

Aquaporin-4 (AQP4) is one of the most abundant molecules in the brain and is particularly prevalent in astrocytic membranes at the blood-brain and brain-liquor interfaces. While AQP4 has been implicated in a number of pathophysiological processes, its role in brain physiology has remained elusive. Only recently has evidence accumulated to suggest that AQP4 is involved in such diverse functions as regulation of extracellular space volume, potassium buffering, cerebrospinal fluid circulation, interstitial fluid resorption, waste clearance, neuroinflammation, osmosensation, cell migration, and Ca2+signaling. AQP4 is also required for normal function of the retina, inner ear, and olfactory system. A review will be provided of the physiological roles of AQP4 in brain and of the growing list of data that emphasize the polarized nature of astrocytes.
Auditory Distortions: Origins and Functions
Authors: Avan Paul , Büki Béla , Petit Christine
Published: October 2013

To enhance weak sounds while compressing the dynamic intensity range, auditory sensory cells amplify sound-induced vibrations in a nonlinear, intensity-dependent manner. In the course of this process, instantaneous waveform distortion is produced, with two conspicuous kinds of interwoven consequences, the introduction of new sound frequencies absent from the original stimuli, which are audible and detectable in the ear canal as otoacoustic emissions, and the possibility for an interfering sound to suppress the response to a probe tone, thereby enhancing contrast among frequency components. We review how the diverse manifestations of auditory nonlinearity originate in the gating principle of their mechanoelectrical transduction channels; how they depend on the coordinated opening of these ion channels ensured by connecting elements; and their links to the dynamic behavior of auditory sensory cells. This paper also reviews how the complex properties of waves traveling through the cochlea shape the manifestations of auditory nonlinearity. Examination methods based on the detection of distortions open noninvasive windows on the modes of activity of mechanosensitive structures in auditory sensory cells and on the distribution of sites of nonlinearity along the cochlear tonotopic axis, helpful for deciphering cochlear molecular physiology in hearing-impaired animal models. Otoacoustic emissions enable fast tests of peripheral sound processing in patients. The study of auditory distortions also contributes to the understanding of the perception of complex sounds.
Large-scale Analysis of PDGFRA Mutations in Melanomas and Evaluation of Their Sensitivity to Tyrosine Kinase Inhibitors Imatinib and Crenolanib
Authors: Dai Jie , Kong Yan , Si Lu , Chi Zhihong , Cui Chuanliang , Sheng Xinan , Mao Lili , Li Siming , Lian Bin , Yang Ruifeng , Liu Shujing , Xu Xiaowei , Guo Jun
Published: October 2013

Purpose: Platelet-derived growth factor receptor α (PDGFRA) is a target for tyrosine kinase inhibitor (TKI)-based targeted therapy. Dysregulation of PDGFRA has been reported in many cancers. However, PDGFRA mutations in melanomas have not been well studied. We analyzed the genetic mutations of PDGFRA in Chinese patients with melanoma and determined the inhibitory potency of TKIs, such as imatinib and crenolanib, on mutant PDGFRA.

Experimental Design: Of note, 351 melanoma tissue samples were examined for genetic mutations in exons 12, 14, and 18 of PDGFRA. Activities of mutations in response to imatinib and crenolanib were analyzed by Western blotting of tyrosine-phosphorylated PDGFRA and cell proliferation assays.

Results: PDGFRA mutations were observed in 4.6% (16 of 351) of melanomas, and these mutations were mainly detected in acral and mucosal melanomas. PDGFRA mutations seem to be mutually exclusive with KIT mutations, but may coexist with BRAF and NRAS mutations. The genetic mutations of PDGFRA were unrelated to the age, thickness, and ulceration status of primary melanomas. Thirteen mutations were not reported before, and five (P577S, V658A, R841K, H845Y, and G853D) of them resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except that V658A mutation was imatinib-resistant, all the other mutations were sensitive to both imatinib and crenolanib.

Conclusions: PDGFRA mutations are detected in a small population of melanoma patients. Our study suggests that patients with melanoma harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment. Clin Cancer Res; 19(24); 6935–42. ©2013 AACR.
Two-Year Outcome after Combination Therapy for Polypoidal Choroidal Vasculopathy: Comparison with Photodynamic Monotherapy and Anti-Vascular Endothelial Growth Factor Monotherapy
Authors: Kang Hae Min , Koh Hyoung Jun
Published: October 2013

Purpose: To compare treatment outcomes of photodynamic therapy (PDT), anti-vascular endothelial growth factor (VEGF) therapy and PDT combined with anti-VEGF therapy for polypoidal choroidal vasculopathy (PCV). Procedures: A total of 62 eyes of 62 patients who had completed at least 2 years of follow-up were retrospectively reviewed; 19 eyes received PDT only, 23 had anti-VEGF therapy only and 20 underwent combination therapy. Best-corrected visual acuity at baseline and each follow-up visit was investigated as a primary outcome measure. Results: At year 2, the PDT and combination groups maintained significant visual improvement (p = 0.041 and p = 0.021), whereas the anti-VEGF group failed to do so (p = 0.673) when compared with the baseline. The combination group showed better visual outcome during follow-up, and significantly better visual outcome than the PDT group (p = 0.038) and the anti-VEGF group (p = 0.012) at year 2. Conclusions: Combination therapy leads to significantly better visual outcome than PDT and anti-VEGF monotherapy and is therefore a superior method for treating PCV, with a favorable visual outcome.
Describing the Silent Human Virome with an Emphasis on Giant Viruses
Authors: Popgeorgiev Nikolay , Temmam Sarah , Raoult Didier , Desnues Christelle
Published: October 2013

Viruses are the most abundant obligate intracellular entities in our body. Until recently, they were only considered to be pathogens that caused a broad array of pathologies, ranging from mild disease to deaths in the most severe cases. However, recent advances in unbiased mass sequencing techniques as well as increasing epidemiological evidence have indicated that the human body is home to diverse viral species under non-pathological conditions. Despite these studies, the description of the presumably healthy viral flora, i.e. the normal human virome, is still in its infancy regarding viral composition and dynamics. This review summarizes our current knowledge of the human virome under non-pathological conditions.
Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients
Authors: Wang Tzu-Fei , Milligan Paul E. , Wong Catherine A. , Deal Eli N. , Thoelke Mark S. , Gage Brian F.
Published: October 2013

Obesity increases the risk for venous thromboembolism (VTE), but whether high-dose thromboprophylaxis is safe and effective in morbidly obese inpatients is unknown. It was the objective of this study to quantify the efficacy and safety of high-dose thromboprophylaxis with heparin or enoxaparin in inpatients with weight > 100 kilograms (kg) within the BJC HealthCare system. In a retrospective cohort study, we analysed 9,241 inpatients with weight < 100 kg discharged from three hospitals in the BJC HealthCare system from 2010 through 2012. We compared the incidence of VTE in patients who received high-dose thromboprophylaxis (heparin 7,500 units three times daily or enoxaparin 40 mg twice daily) to those who received standard doses (heparin 5,000 units two or three times daily or enoxaparin 40 mg once daily). The primary efficacy outcome was hospital-acquired VTE identified by International Classification of Diseases (ICD)-9 diagnosis codes. The primary safety outcome was bleeding events identified by ICD-9 codes. Among the 3,928 morbidly obese inpatients (weight > 100 kg and body mass index [BMI] ≥ 40 kg/m2), high-dose thromboprophylaxis approximately halved the odds of symptomatic VTE (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.27–1.00; p = 0.050). The rate of VTE was 1.48% (35/2,369) in these morbidly obese inpatients who received standard doses of thromboprophylaxis, compared to 0.77% (12/1,559) in those who received high doses. High-dose thromboprophylaxis did not increase bleeding (OR 0.84, 95% CI 0.66–1.07, p = 0.15). Independent predictors of VTE were surgery, male sex, cancer, and BMI. In conclusion, high-dose thromboprophylaxis nearly halves the rate of VTE in morbidly obese inpatients.
New lipid interaction partners stimulate the inhibition of activated protein C by cell-penetrating protein C inhibitor
Authors: Wahlmüller Felix Christof , Sokolikova Barbora , Rieger Daniela , Geiger Margarethe
Published: October 2013

Protein C inhibitor (PCI, SerpinA5) is a heparin-binding serpin which can penetrate through cellular membranes. Selected negatively charged phospholipids like unsaturated phosphatidylserine and oxidised phosphatidylethanolamine bind to PCI and stimulate its inhibitory activity towards different proteases. The interaction of phospholipids with PCI might also alter the lipid distribution pattern of blood cells and influence the remodelling of cellular membranes. Here we showed that PCI is an additional binding partner of phosphatidic acid (PA), cardiolipin (CL), and phosphoinositides (PIPs). Protein lipid overlay assays exhibited a unique binding pattern of PCI towards different lipid species. In addition PA, CL, and unsaturated, monophosphorylated PIPs stimulated the inhibitory property of PCI towards activated protein C in a heparin like manner. As shown for kallistatin (SerpinA4) and vaspin (SerpinA12), the incubation of cells with PCI led to the activation of protein kinase B (AKT), which could be achieved through direct interaction of PCI with PIPs. This model is supported by the fact that PCI stimulated the PIP-dependent 5-phosphatase SHIP2 in vitro, which would result in AKT activation. Hence the interaction of PCI with different lipids might not only stimulate the inhibition of potential target protease by PCI, but could also alter intracellular lipid signalling.
The thrombomodulin lectin-like domain does not change host responses to tuberculosis
Authors: de Vos Alex F. , Roelofs Joris J. T. H. , van der Loos Chris M. , de Boer Onno J. , van’t Veer Cornelis , Conway Edward M. , Poll Tom van der , Kager Liesbeth M.
Published: October 2013

Tuberculosis (TB), caused by Mycobacterium (M.) tuberculosis, is a devastating infectious disease causing many deaths world-wide. Thrombomodulin (TM) is a multidomain glycoprotein expressed on all vascular endothelial cells. We here studied the role of the lectin-like domain of TM, responsible for a variety of anti-inflammatory properties of TM, during TB. We compared the extent of TM-expression in human lung tissue of TB and control patients. The, the role of the lectin-like domain of TM was investigated by comparing mice lacking this domain (TMLeD/LeD mice) with wild-type (WT) mice during experimental lung TB induced by infection with M. tuberculosis via the airways. Lungs were harvested for analyses at two, six and 29 weeks after infection. Lung TM-expression was downregulated in TB patients, which was not related to changes in the amount of endothelium in infected lungs. TMLeD/LeD mice showed unaltered mycobacterial loads in lungs, liver and spleen during experimental TB. Additionally, lung histopathology and cytokine concentrations were largely similar in TMLeD/LeD and WT mice, while total leukocyte counts were increased in lungs of TMLeD/LeD mice after 29 weeks of infection. Mortality did not occur in either group. The lectin-like domain of TM does not play an important role in the host response to M. tuberculosis infection in mice.
The Biblical Account of the Post-Diluvian Generation (Gen. 9:20-10:32) in the Light of Greek Genealogical Literature
Authors: Darshan Guy
Published: October 2013

Abstract

Despite the fact that the Flood narrative originates in Mesopotamia, neither of the two principal motifs discussed in this paper—the representation of the Flood hero and his offspring as the progenitors of the nations (Genesis 10) and the planting of the first vineyard in the first post-diluvian generation (Gen 9:20-27)—occur in the Mesopotamian versions of the Flood story. Scholars have thus opined that these two units constitute original Israelite literary creations penned by the biblical authors. A similar juxtaposition of material does appear, however, in the early Greek genealogical writings, that began to be committed to writing during the Archaic period (C7-6 b.c.e.). The relationship this literature bears to the biblical texts has yet to be examined. This article analyzes the parallels between the Greek genealogical writings and the biblical texts regarding the Flood hero and his descendants in the first post-diluvian generations and the central place these hold in both sets of literature. The results possess great significance for the question of the genre and development of the literary threads in the opening chapters of Genesis, as also for our understanding of the literary patterns and motifs prevalent in the ancient eastern Mediterranean cultures during the first third of the first millennium b.c.e. and the interest the latter exhibit in issues relating to ethnic identity.