bluuebunny/crossref_metadata_2025 huggingface dataset:
Herpes Simplex Virus 1 ICP22 but Not US1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation
Authors: Mostafa Heba H. , Davido David J.
Published: October 2013

The herpes simplex virus 1 (HSV-1) immediate-early protein, infected cell protein 22 (ICP22), is required for efficient replication in restrictive cells, for virus-induced chaperone-enriched (VICE) domain formation, and for normal expression of a subset of viral late proteins. Additionally, ICP22 is important for optimal acute viral replicationin vivo. Previous studies have shown that the US1 gene that encodes ICP22, produces an in-frame, N-terminally truncated form of ICP22, known as US1.5. To date, studies conducted to characterize the functions of ICP22 have not separated its functions from those of US1.5. To determine the individual roles of ICP22 and US1.5, we made viral mutants that express either ICP22 with an M90A mutation in the US1.5 initiation codon (M90A) or US1.5 with three stop codons introduced upstream of the US1.5 start codon (3×stop). Our studies showed that, in contrast to M90A, 3×stop was unable to replicate efficiently in the eyes and trigeminal ganglia of mice during acute infection, to efficiently establish a latent infection, or to induce VICE domain formation and was only mildly reduced in its replication in restrictive HEL-299 cells and murine embryonic fibroblasts (MEFs). Both mutants enhanced the expression of the late viral proteins virion host shutoff (vhs) and glycoprotein C (gC) and inhibited viral gene expression mediated by HSV-1 infected cell protein 0 (ICP0). When we tested our mutants' sensitivity to type I interferon (beta interferon [IFN-β]) in restrictive cells, we noticed that the plating of the ICP22 null (d22) and 3×stop mutants was reduced by the addition of IFN-β. Overall, our data suggest that US1.5 partially complements the functions of ICP22.
Impact of Prior Seasonal H3N2 Influenza Vaccination or Infection on Protection and Transmission of Emerging Variants of Influenza A(H3N2)v Virus in Ferrets
Authors: Houser Katherine V. , Pearce Melissa B. , Katz Jacqueline M. , Tumpey Terrence M.
Published: October 2013

Influenza H3N2 A viruses continue to circulate in swine and occasionally infect humans, resulting in outbreaks of variant influenza H3N2 [A(H3N2)v] virus. It has been previously demonstrated in ferrets that A(H3N2)v viruses transmit as efficiently as seasonal influenza viruses, raising concern over the pandemic potential of these viruses. However, A(H3N2)v viruses have not acquired the ability to transmit efficiently among humans, which may be due in part to existing cross-reactive immunity to A(H3N2)v viruses. Although current seasonal H3N2 and A(H3N2)v viruses are antigenically distinct from one another, historical H3N2 viruses have some antigenic similarity to A(H3N2)v viruses and previous exposure to these viruses may provide a measure of immune protection sufficient to dampen A(H3N2)v virus transmission. Here, we evaluated whether prior seasonal H3N2 influenza virus vaccination or infection affects virus replication and transmission of A(H3N2)v virus in the ferret animal model. We found that the seasonal trivalent inactivated influenza virus vaccine (TIV) or a monovalent vaccine prepared from an antigenically related 1992 seasonal influenza H3N2 (A/Beijing/32/1992) virus failed to substantially reduce A(H3N2)v (A/Indiana/08/2011) virus shedding and subsequent transmission to naive hosts. Conversely, ferrets primed by seasonal H3N2 virus infection displayed reduced A(H3N2)v virus shedding following challenge, which blunted transmission to naive ferrets. A higher level of specific IgG and IgA antibody titers detected among infected versus vaccinated ferrets was associated with the degree of protection offered by seasonal H3N2 virus infection. The data demonstrate in ferrets that the efficiency of A(H3N2)v transmission is disrupted by preexisting immunity induced by seasonal H3N2 virus infection.
Evasion of Superinfection Exclusion and Elimination of Primary Viral RNA by an Adapted Strain of Hepatitis C Virus
Authors: Webster Brian , Ott Melanie , Greene Warner C.
Published: October 2013

Cells that are productively infected by hepatitis C virus (HCV) are refractory to a second infection by HCV via a block in viral replication known as superinfection exclusion. The block occurs at a postentry step and likely involves translation or replication of the secondary viral RNA, but the mechanism is largely unknown. To characterize HCV superinfection exclusion, we selected for an HCV variant that could overcome the block. We produced a high-titer HC-J6/JFH1 (Jc1) viral genome with a fluorescent reporter inserted between NS5A and NS5B and used it to infect Huh7.5 cells containing a Jc1 replicon. With multiple passages of these infected cells, we isolated an HCV variant that can superinfect cells at high levels. Notably, the superinfectious virus rapidly cleared the primary replicon from superinfected cells. Viral competition experiments, using a novel strategy of sequence-barcoding viral strains, as well as superinfection of replicon cells demonstrated that mutations in E1, p7, NS5A, and the poly(U/UC) tract of the 3′ untranslated region were important for superinfection. Furthermore, these mutations dramatically increased the infectivity of the virus in naive cells. Interestingly, viruses with a shorter poly(U/UC) and an NS5A domain II mutation were most effective in overcoming the postentry block. Neither of these changes affected viral RNA translation, indicating that the major barrier to postentry exclusion occurs at viral RNA replication. The evolution of the ability to superinfect after less than a month in culture and the concomitant exclusion of the primary replicon suggest that superinfection exclusion dramatically affects viral fitness and dynamics
in vivo
.
The Viral Ubiquitin Ligase ICP0 Is neither Sufficient nor Necessary for Degradation of the Cellular DNA Sensor IFI16 during Herpes Simplex Virus 1 Infection
Authors: Cuchet-Lourenço Delphine , Anderson Gail , Sloan Elizabeth , Orr Anne , Everett Roger D.
Published: October 2013

The cellular protein IFI16 colocalizes with the herpes simplex virus 1 (HSV-1) ubiquitin ligase ICP0 at early times of infection and is degraded as infection progresses. Here, we report that the factors governing the degradation of IFI16 and its colocalization with ICP0 are distinct from those of promyelocytic leukemia protein (PML), a well-characterized ICP0 substrate. Unlike PML, IFI16 colocalization with ICP0 was dependent on the ICP0 RING finger and did not occur when proteasome activity was inhibited. Expression of ICP0 in the absence of infection did not destabilize IFI16, the degradation occurred efficiently in the absence of ICP0 if infection was progressing efficiently, and IFI16 was relatively stable in wild-type (wt) HSV-1-infected U2OS cells. Therefore, IFI16 stability appears to be regulated by cellular factors in response to active HSV-1 infection rather than directly by ICP0. Because IFI16 is a DNA sensor that becomes associated with viral genomes during the early stages of infection, we investigated its role in the recruitment of PML nuclear body (PML NB) components to viral genomes. Recruitment of PML and hDaxx was less efficient in a proportion of IFI16-depleted cells, and this correlated with improved replication efficiency of ICP0-null mutant HSV-1. Because the absence of interferon regulatory factor 3 (IRF3) does not increase the plaque formation efficiency of ICP0-null mutant HSV-1, we speculate that IFI16 contributes to cell-mediated restriction of HSV-1 in a manner that is separable from its roles in IRF3-mediated interferon induction, but that may be linked to the PML NB response to viral infection.
Two Independent Regions of Simian Virus 40 T Antigen Increase CBP/p300 Levels, Alter Patterns of Cellular Histone Acetylation, and Immortalize Primary Cells
Authors: Sáenz Robles Maria Teresa , Shivalila Chikdu , Wano Jeremy , Sorrells Shelly , Roos Alison , Pipas James M.
Published: October 2013

Simian virus 40 (SV40) large T antigen (SVT) interferes with normal cell regulation and thus has been used to identify cellular components controlling proliferation and homeostasis. We have previously shown that SVT-mediated transformation requires interaction with the histone acetyltransferases (HATs) CBP/p300 and now report that the ectopic expression of SVT in several cell types
in vivo
and
in vitro
results in a significant increase in the steady-state levels of CBP/p300. Furthermore, SVT-expressing cells contain higher levels of acetylated CBP/p300, a modification that has been linked to increased HAT activity. Concomitantly, the acetylation levels of histone residues H3K56 and H4K12 are markedly increased in SVT-expressing cells. Other polyomavirus-encoded large T antigens also increase the levels of CBP/p300 and sustain a rise in the acetylation levels of H3K56 and H4K12. SVT does not affect the transcription of CBP/p300, but rather, alters their overall levels through increasing the loading of CBP/p300 mRNAs onto polysomes. Two distinct regions within SVT, one located in the amino terminus and one in the carboxy terminus, can independently alter both the levels of CBP/p300 and the loading of CBP/p300 transcripts onto polysomes. Within the amino-terminal fragment, a functional J domain is necessary for increasing CBP/p300 and specific histone acetylation levels, as well as for immortalizing primary cells. These studies uncover the action of polyomavirus T antigens on cellular CBP/p300 and suggest that additional mechanisms are used by T antigens to induce cell immortalization and transformation.
First Insights into the Entry Process of Hyperthermophilic Archaeal Viruses
Authors: Quemin Emmanuelle R. J. , Lucas Soizick , Daum Bertram , Quax Tessa E. F. , Kühlbrandt Werner , Forterre Patrick , Albers Sonja-Verena , Prangishvili David , Krupovic Mart
Published: October 2013

A decisive step in a virus infection cycle is the recognition of a specific receptor present on the host cell surface, subsequently leading to the delivery of the viral genome into the cell interior. Until now, the early stages of infection have not been thoroughly investigated for any virus infecting hyperthermophilic archaea. Here, we present the first study focusing on the primary interactions between the archaeal rod-shaped virusSulfolobus islandicus rod-shaped virus 2(SIRV2) (familyRudiviridae) and its hyperthermoacidophilic host,S. islandicus. We show that SIRV2 adsorption is very rapid, with the majority of virions being irreversibly bound to the host cell within 1 min. We utilized transmission electron microscopy and whole-cell electron cryotomography to demonstrate that SIRV2 virions specifically recognize the tips of pilus-like filaments, which are highly abundant on the host cell surface. Following the initial binding, the viral particles are found attached to the sides of the filaments, suggesting a movement along these appendages toward the cell surface. Finally, we also show that SIRV2 establishes superinfection exclusion, a phenomenon not previously described for archaeal viruses.
Peripancreatic cystic lymphangioma diagnosed by endoscopic ultrasound/fine-needle aspiration: a rare mesenchymal tumour
Authors: Tanimu Sabo , Rafiullah  , Resnick Jeffrey , Onitilo Adedayo A
Published: October 2013

A 73-year-old man presented with a 5-month history of intermittent nausea, vomiting, central abdominal discomfort and a 17-pound weight loss over the past year. Laboratory testing, including a complete blood count with differential, liver function testing, amylase and lipase studies were normal. A CT scan showed a bilobed cystic lesion inferior to the body of the pancreas. An endoscopic ultrasound revealed a 5.3×3.9 cm, anechoic, bilobed cystic lesion, extrinsic to the body of the pancreas with a 1–2 mm septation and a normal pancreas. Fine-needle aspiration revealed a milky-white aspirate with negative cytology. Laboratory assessment of the cystic aspirant revealed carcinoembryonic antigen 1.7 ng/mL, amylase 148 units/L, cholesterol 300 mg/dL, and carbohydrate antigen 19-9 3 units/mL. He underwent resection of the mass, with the histopathology confirming a diagnosis of peripancreatic lymphangioma. He did well after the surgery with interval resolution of his symptoms.
Quinine-induced severe thrombocytopenia: the importance of taking a detailed drug history
Authors: Mohamed Muhajir , Hayes Robert
Published: October 2013

Drugs can lead to severe life-threatening thrombocytopenia. The mechanisms of drug-induced thrombocytopenia are increased destruction by immune-mediated platelet destruction or decreased platelet production by bone marrow suppression. Quinine is a drug used for the treatment of malaria and nocturnal leg cramps and is also an important ingredient in some herbal preparations. Quinine can very rarely cause thrombocytopenia by immune-mediated platelet destruction. In a patient with thrombocytopenia, a detailed history of all the medications including over-the-counter medications and herbal preparations is very important.
Polycystic kidney disease and chronic renal failure in tuberous sclerosis
Authors: Dhakal Mona , Dhakal O P , Bhandari Dhurba
Published: October 2013

Tuberous sclerosis is a rare genetic disease which leads to formation of benign tumours in the brain and other organs of the body. It is a multisystem disease with various clinical manifestations. Renal angiomyolipomas are the most common renal manifestations whereas renal cell carcinoma is the least. Renal cysts are found in around 20% of the patients but polycystic kidney disease is present in less than 2% cases and is relatively rare manifestation of the disease. We present a case of tuberous sclerosis in a 60-year-old man who presented to the medicine outpatient department for routine evaluation of his hypertension. He was diagnosed as tuberous sclerosis. His ultrasound and CT scan of abdomen revealed polycystic kidney disease. His kidney function test and urine analysis were suggestive of chronic kidney disease.
Cardiac arrest: first presentation of anorexia nervosa
Authors: Ewan Sian-Lee , Moynihan Patricia C
Published: October 2013

A 16-year-old girl collapsed in cardiac arrest in a hospital car park. Investigations revealed a potassium level of 1.8. Following a 5-day intensive care unit admission she described behaviours consistent with restrictive-purging type anorexia nervosa, which had been concealed from her parents and health professionals. Long-term management has been difficult due to poor patient engagement. Further, recurrent episodes of hypokalaemia continue to feature. Here we explore the cardiac complications of anorexia nervosa and challenges with long-term management of this condition.
BOUNCE OF GRAVITONS EMITTED FROM THE BRANE TO THE BULK BACK TO THE BRANE
Authors: IOFA MIKHAIL Z.
Published: October 2013

Solutions of geodesic equations describing propagation of gravitons in the bulk are studied in a cosmological model with one extra dimension. Brane with matter is embedded in the bulk. It is shown that in the period of early cosmology gravitons emitted from the brane to the bulk under certain conditions can return back to the brane. The model is discussed in two alternative approaches: (i) brane with static metric moving in the AdS space, and (ii) brane located at a fixed position in extra dimension with nonstatic metric. Transformation of coordinates from the one picture to another is performed. In both approaches, conditions for gravitons emitted to the bulk to come back to the brane are found.
On cellular automata models of traffic flow with look-ahead potential
Authors: Hauck Cory , Sun Yi , Timofeyev Ilya
Published: October 2013

We study the statistical properties of a cellular automata model of traffic flow with the look-ahead potential. The model defines stochastic rules for the movement of cars on a lattice. We analyze the underlying statistical assumptions needed for the derivation of the coarse-grained model and demonstrate that it is possible to relax some of them to obtain an improved coarse-grained ODE model. We also demonstrate that spatial correlations play a crucial role in the presence of the look-ahead potential and propose a simple empirical correction to account for the spatial dependence between neighboring cells.
SCALING TRANSFORMATION IN THE REMBRANDT TECHNIQUE: EXAMINATION OF THE PROGRESSION FACTORS
Authors: BARFOD MICHAEL BRUHN , LELEUR STEEN
Published: October 2013

This paper examines a decision support system (DSS) for the appraisal of complex decision problems using multi-criteria decision analysis (MCDA). The DSS makes use of a structured hierarchical approach featuring the multiplicative AHP also known as the REMBRANDT technique. The paper addresses the influence of the progression factor used when transforming the decision makers' verbal responses from a semantic to a geometric scale in REMBRANDT. Conventionally, the progression factor 2 is used for calculating scores of alternatives and √2 for calculation of criteria weights. Tests are conducted on the magnitude of these progression factors in order to examine the sensitivity towards the final outcome of an analysis. For illustration a case study concerning the appraisal of a large infrastructure project is presented. The results of the sensitivity calculations are compared with the results of a conventional AHP calculation in order to examine what impact the choice of progression factors as well as the choice of technique have on the decision making. Based on this a modified progression factor for the calculation of scores for the alternatives in REMBRANDT is suggested while the progression factor for the criteria weights is suggested to be kept unchanged. Finally, conclusions and perspectives are set out.
A COMPROMISE PROGRAMMING APPROACH TO MULTIOBJECTIVE MARKOV DECISION PROCESSES
Authors: OGRYCZAK WLODZIMIERZ , PERNY PATRICE , WENG PAUL
Published: October 2013

A Markov decision process (MDP) is a general model for solving planning problems under uncertainty. It has been extended to multiobjective MDP to address multicriteria or multiagent problems in which the value of a decision must be evaluated according to several viewpoints, sometimes conflicting. Although most of the studies concentrate on the determination of the set of Pareto-optimal policies, we focus here on a more specialized problem that concerns the direct determination of policies achieving well-balanced tradeoffs. To this end, we introduce a reference point method based on the optimization of a weighted ordered weighted average (WOWA) of individual disachievements. We show that the resulting notion of optimal policy does not satisfy the Bellman principle and depends on the initial state. To overcome these difficulties, we propose a solution method based on a linear programming (LP) reformulation of the problem. Finally, we illustrate the feasibility of the proposed method on two types of planning problems under uncertainty arising in navigation of an autonomous agent and in inventory management.
MARKET INTRODUCTION AND DIFFUSION OF NEW PRODUCTS: RECENT DEVELOPMENTS IN AGENT-BASED MODELING
Authors: WAKOLBINGER LEA M. , STUMMER CHRISTIAN , GÜNTHER MARKUS
Published: October 2013

Market introduction and diffusion of new products is complex and multifaceted since it involves spatially dispersed customers with individual preferences who may be exposed to a wide range of influences including word-of-mouth communication within a social network. During the past decade agent-based modeling approaches for simulating this process have become increasingly popular, because they not only capture the customers' behavior more realistically, but also allow for new insights for innovation management. The aim of this work is to provide an overview of recent developments, to discuss challenges, and to highlight promising directions for future research.
BEHAVIOR PREDICTION FOR DECISION AND CONTROL IN COGNITIVE AUTONOMOUS SYSTEMS
Authors: RAY ASOK , PHOHA SHASHI , SARKAR SOUMIK
Published: October 2013

This paper presents an innovative concept of behavior prediction for decision and control in cognitive autonomous systems. The objective is to coordinate human–machine collaboration such that human operators can assess and enable autonomous systems to utilize their experiential and unmodeled domain knowledge and perception for mission execution. The concept of quantum probability is proposed to construct a unified mathematical framework for interfacing between models of human cognition and machine intelligence.
QUANTUM INSPIRED REINFORCEMENT LEARNING IN CHANGING ENVIRONMENT
Authors: FAKHARI PEGAH , RAJAGOPAL KARTHIKEYAN , BALAKRISHNAN S. N. , BUSEMEYER J. R.
Published: October 2013

Inspired by quantum theory and reinforcement learning, a new framework of learning in unknown probabilistic environment is proposed. Several simulated experiments are given; the results demonstrate the robustness of the new algorithm for some complex problems. Also we generalized the Grover algorithm to improve the rate of converging to an optimal path. In other words, the new generalized algorithm helps to increase the probability of selecting good actions with better weights' adjustments.
Quantification of glycated hemoglobin indicator HbA1c through near-infrared spectroscopy
Authors: Pan Tao , Li Minmiao , Chen Jiemei , Xue Haiyan
Published: October 2013

A new strategy for quantitative analysis of a major clinical biochemical indicator called glycated hemoglobin (HbA1c) was proposed. The technique was based on the simultaneous near-infrared (NIR) spectral determination of hemoglobin (Hb) and absolute HbA1c content (Hb • HbA1c) in human hemolysate samples. Wavelength selections were accomplished using the improved moving window partial least square (MWPLS) method for stability. Each model was established using an approach based on randomness, similarity, and stability to obtain objective, stable, and practical models. The optimal wavebands obtained using MWPLS were 958 to 1036 nm for Hb and 1492 to 1858 nm for Hb • HbA1c, which were within the NIR overtone region. The validation root mean square error and validation correlation coefficients of prediction (V-SEP, V-R P ) were 3.4 g L-1 and 0.967 for Hb, respectively, whereas the corresponding values for Hb • HbA1c were 0.63 g L-1 and 0.913. The corresponding V-SEP and V-R P were 0.40% and 0.829 for the relative percentage of HbA1c. The experimental results confirm the feasibility for the quantification of HbA1c based on simultaneous NIR spectroscopic analyses of Hb and Hb • HbA1c.
PSEUDO-DIFFERENTIAL OPERATORS ASSOCIATED TO A PAIR OF HANKEL–CLIFFORD TRANSFORMATIONS ON CERTAIN BEURLING TYPE FUNCTION SPACES
Authors: Prasad Akhilesh , Singh V. K.
Published: October 2013

A brief introduction to the Hankel–Clifford transformations and its basic properties is given. The spaces [Formula: see text] and [Formula: see text] generalizing the spaces Hμ(I) and S(I), respectively are defined. It is given that the pseudo-differential operators h1,μ,a and h2,μ,a are automorphism of [Formula: see text] and [Formula: see text], respectively. Product and convolution on [Formula: see text] and [Formula: see text] are investigated. Some other spaces related to [Formula: see text] and [Formula: see text] are introduced and studied the continuity of the pseudo-differential operators h1,μ,a and h2,μ,a, respectively.
STRONGLY TORSION FREE ACTS OVER MONOIDS
Authors: Zare Abas , Golchin Akbar , Mohammadzadeh Hossein
Published: October 2013

An act ASis called torsion free if for any a, b ∈ ASand for any right cancellable element c ∈ S the equality ac = bc implies a = b. In [M. Satyanarayana, Quasi- and weakly-injective S-system, Math. Nachr.71 (1976) 183–190], torsion freeness is considered in a much stronger sense which we call in this paper strong torsion freeness and will characterize monoids by this property of their (cyclic, monocyclic, Rees factor) acts.
Complex network-enabled robust wireless network-on-chip architectures
Authors: Wettin Paul , Vidapalapati Anuroop , Gangul Amlan , Pande Partha Pratim
Published: October 2013

The Network-on-Chip (NoC) paradigm has emerged as a scalable interconnection infrastructure for modern multicore chips. However, with growing levels of integration, the traditional NoCs suffer from high latency and energy dissipation in on-chip data transfer due to conventional multihop metal/dielectric-based interconnects. Three-dimensional integration, on-chip photonics, RF, and wireless links have been proposed as radical low-power and low-latency alternatives to the conventional planar wire-based designs. Wireless NoCs with Carbon NanoTube (CNT) antennas are shown to outperform traditional wire-based NoCs significantly in achievable data rate and energy dissipation. However, such emerging and transformative technologies will be prone to high levels of failures due to various issues related to manufacturing challenges and integration. On the other hand, several naturally occurring complex networks such as colonies of microbes and the World Wide Web are known to be inherently robust against high rates of failures and harsh environments. This article advocates adoption of such complex network-based architectures to minimize the effect of wireless link failures on the performance of the NoC. Through cycle-accurate simulations it is shown that the wireless NoC architectures inspired by natural complex networks perform better than their conventional wired counterparts even in the presence of high degrees of link failures. We demonstrate the robustness of the proposed wireless NoC architecture by incorporating both uniform and application-specific traffic patterns.
Design space exploration of FinFET cache
Authors: Tang Aoxiang , Jha Niraj K.
Published: October 2013

Integration of cache on-chip has significantly improved the performance of modern processors. The relentless demand for ever-increasing performance has led to the need to increase the cache capacity and number of cache levels. However, the performance improvement is accompanied by an increase in chip's power dissipation, requiring the use of more expensive cooling technologies to ensure chip reliability and long product life. The emergence of FinFETs as the technology of choice for high-performance computing poses new challenges to processor designers. With the introduction of new features in FinFETs, for example, independently controllable back gates, researchers have proposed several innovative memory cells that can reduce leakage power significantly, making the integration of a larger cache more practical.

In this article, we comprehensively evaluate and compare the performance, power consumption (both dynamic and leakage), area, and temperature of different FinFET SRAM caches by exploring common configurations with varying cache size, block size, associativity, and number of banks. We evaluate caches based on four well-known FinFET SRAM cells: Pass-Gate FeedBack (PGFB), Row-based Back-Gate Biasing (RBGB), 8T, and 4T. We show how the caches can be simulated at self-consistent temperatures (at which leakage and temperature are in equilibrium).

Drowsy and decay caches are two well-known leakage reduction techniques. We implement them in the context of FinFET caches to investigate their impact. We show that the RBGB cell-based cache is far superior in leakage and Power-Delay Product (PDP) to those based on the other three cells, sometimes by an order of magnitude. This superiority is maintained even when drowsy or decay leakage reduction techniques are applied to caches based on the other three cells, but not to the one based on the RBGB cell. This significantly diminishes the importance of drowsy or decay cache techniques, at least when the RBGB cell is used.
NBTI-aware circuit node criticality computation
Authors: Yang Shengqi , Wang Wenping , Hagan Mark , Zhang Wei , Gupta Pallav , Cao Yu
Published: October 2013

For sub-65nm technology nodes, Negative Bias Temperature Instability (NBTI) has become a primary limiting factor of circuit lifetime. During the past few years, researchers have spent considerable effort on accurate modeling and characterization of circuit delay degradation caused by NBTI at different design levels. The search for techniques and methodologies which can aid in effectively minimizing the NBTI effect on circuit delay is still underway. In this work, we present the usage of node criticality computation to drive NBTI-aware timing analysis and optimization. Circuits that have undergone this optimization flow show strong resistance to NBTI delay degradation. For the first time, this work proposes a node criticality computation algorithm under an NBTI-aware timing analysis and optimization framework. Our work provides answers to the following yet unaddressed questions: (a) what is the definition of node criticality in a circuit under the NBTI effect? (b) how do we identify the critical nodes that, once protected, will be immune to NBTI timing degradation? and (c) what are the NBTI effect attenuation approaches? Experimental results indicate that by protecting the critical nodes found by our proposed methodology, circuit delay degradation can be reduced by up to 50%. Combined with peak temperature reduction, the delay degradation can be be further improved.
Color image processing with multi-peak resonant tunneling diodes
Authors: Lee Woo Hyung , Mazumder Pinaki
Published: October 2013

The article introduces a novel approach to color image processing that utilizes multi-peak resonant tunneling diodes for encoding color information in quantized states of the diodes. The Multi-Peak Resonant Tunneling Diodes (MPRTDs) are organized as a two-dimensional array of vertical pillars which are locally connected by programmable passive and active elements with a view to realizing a wide variety of color image processing functions such as quantization, color extraction, image smoothing, edge detection, and line detection. In order to process color information in the input images, two different methods for color representation schemes have been used: one using color mapping and the other using direct RGB representation. Finally, the article uses HSPICE simulation methods for the nestlist of the proposed RTD-based nanoarchitecture in order to verify a candidate of image functions by using the afore-mentioned representation methods.
Cyp1B1 expression promotes angiogenesis by suppressing NF-κB activity
Authors: Palenski Tammy L. , Gurel Zafer , Sorenson Christine M. , Hankenson Kurt D. , Sheibani Nader
Published: October 2013

Nuclear factor-κB (NF-κB) is a master regulator of genes that control a large number of cellular processes, including angiogenesis and inflammation. We recently demonstrated that cytochrome P-450 1B1 (Cyp1B1) deficiency in endothelial cells (EC) and pericytes (PC) results in increased oxidative stress, alterations in migration, attenuation of capillary morphogenesis, sustained activation of NF-κB, and increased expression of thrombospondin-2 (TSP2), an endogenous inhibitor of angiogenesis. On the basis of a growing body of evidence that phenethyl isothiocyanate (PEITC) and pyrrolidine dithiocarbamate (PDTC) function as antioxidants and suppressors of NF-κB activation, we investigated their potential ability to restore a normal phenotype in Cyp1B1-deficient ( cyp1b1−/−) vascular cells. PEITC and PDTC inhibited NF-κB activity and expression in c yp1b1−/− EC and PC. We also observed restoration of migration and capillary morphogenesis of cyp1b1−/− EC and decreased cellular oxidative stress in cyp1b1−/− EC and PC without restoration to normal TSP2 levels. In addition, expression of a dominant-negative inhibitor κBα, a suppressor of NF-κB activation, decreased NF-κB activity without affecting TSP2 expression in these cells. In contrast, knockdown of TSP2 expression resulted in attenuation of NF-κB activity in cyp1b1−/− vascular cells. Furthermore, expression of TSP2 in wild-type ( cyp1b1+/+) cells resulted in increased NF-κB activity. Together, our results demonstrate an important role for TSP2 in modulation of NF-κB activity and attenuation of angiogenesis. Thus Cyp1B1 expression in vascular cells plays an important role in the regulation of vascular homeostasis through modulation of the cellular reductive state, TSP2 expression, and NF-κB activation.
AICAR stimulation metabolome widely mimics electrical contraction in isolated rat epitrochlearis muscle
Authors: Miyamoto Licht , Egawa Tatsuro , Oshima Rieko , Kurogi Eriko , Tomida Yosuke , Tsuchiya Koichiro , Hayashi Tatsuya
Published: October 2013

Physical exercise has potent therapeutic and preventive effects against metabolic disorders. A number of studies have suggested that 5′-AMP-activated protein kinase (AMPK) plays a pivotal role in regulating carbohydrate and lipid metabolism in contracting skeletal muscles, while several genetically manipulated animal models revealed the significance of AMPK-independent pathways. To elucidate significance of AMPK and AMPK-independent signals in contracting skeletal muscles, we conducted a metabolomic analysis that compared the metabolic effects of 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR) stimulation with the electrical contraction ex vivo in isolated rat epitrochlearis muscles, in which both α1- and α2-isoforms of AMPK and glucose uptake were equally activated. The metabolomic analysis using capillary electrophoresis time-of-flight mass spectrometry detected 184 peaks and successfully annotated 132 small molecules. AICAR stimulation exhibited high similarity to the electrical contraction in overall metabolites. Principal component analysis (PCA) demonstrated that the major principal component characterized common effects whereas the minor principal component distinguished the difference. PCA and a factor analysis suggested a substantial change in redox status as a result of AMPK activation. We also found a decrease in reduced glutathione levels in both AICAR-stimulated and contracting muscles. The muscle contraction-evoked influences related to the metabolism of amino acids, in particular, aspartate, alanine, or lysine, are supposed to be independent of AMPK activation. Our results substantiate the significance of AMPK activation in contracting skeletal muscles and provide novel evidence that AICAR stimulation closely mimics the metabolomic changes in the contracting skeletal muscles.
Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment
Authors: Markworth James F. , Vella Luke , Lingard Benjamin S. , Tull Dedreia L. , Rupasinghe Thusitha W. , Sinclair Andrew J. , Maddipati Krishna Rao , Cameron-Smith David
Published: October 2013

Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0–3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2α, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1and RvE1), and protectins (PD1isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a biological active inflammatory resolution program, regulated by proresolving lipid mediators during postexercise recovery.
Sudden decrease in physical activity evokes adipocyte hyperplasia in 70- to 77-day-old rats but not 49- to 56-day-old rats
Authors: Company Joseph M. , Roberts Michael D. , Toedebusch Ryan G. , Cruthirds Clayton L. , Booth Frank W.
Published: October 2013

The cessation of physical activity in rodents and humans initiates obesogenic mechanisms. The overall purpose of the current study was to determine how the cessation of daily physical activity in rats at 49–56 days of age and at 70–77 days of age via wheel lock (WL) affects adipose tissue characteristics. Male Wistar rats began voluntary running at 28 days old and were either killed at 49–56 days old or at 70–77 days old. Two cohorts of rats always had wheel access (RUN), a second two cohorts of rats had wheel access restricted during the last 7 days (7d-WL), and a third two cohorts of rats did not have access to a voluntary running wheel after the first 6 days of (SED). We observed more robust changes with WL in the 70- to 77-day-old rats. Compared with RUN rats, 7d-WL rats exhibited greater rates of gain in fat mass and percent body fat, increased adipocyte number, higher percentage of small adipocytes, and greater cyclin A1 mRNA in epididymal and perirenal adipose tissue. In contrast, 49- to 56-day-old rats had no change in most of the same characteristics. There was no increase in inflammatory mRNA expression in either cohort with WL. These findings suggest that adipose tissue in 70- to 77-day-old rats is more protected from WL than 49- to 56-day-old rats and responds by expansion via hyperplasia.
High-saturated fat-sucrose feeding affects lactation energetics in control mice and mice selectively bred for high wheel-running behavior
Authors: Guidotti Stefano , Jónás Izabella , Schubert Kristin A. , Garland Theodore , Meijer Harro A. J. , Scheurink Anton J. W. , van Dijk Gertjan
Published: October 2013

Feeding a diet high in fat and sucrose (HFS) during pregnancy and lactation is known to increase susceptibility to develop metabolic derangements later in life. A trait for increased behavioral activity may oppose these effects, since this would drain energy from milk produced to be made available to the offspring. To investigate these interactions, we assessed several components of behavioral energetics during lactation in control mice (C) and in mice of two lines selectively bred for high wheel-running activity (S1, S2) subjected to a HFS diet or a low-fat (LF) diet. Energy intake, litter growth, and milk energy output at peak lactation (MEO; assessed by subtracting maternal metabolic rate from energy intake) were elevated in HFS-feeding dams across all lines compared with the LF condition, an effect that was particularly evident in the S dams. This effect was not preceded by improved lactation behaviors assessed between postnatal days 1 and 7 (PND 1–7). In fact, S1 dams had less high-quality nursing, and S2 dams showed poorer pup retrieval than C dams during PND 1–7, and S dams had generally higher levels of physical activity at peak lactation. These data demonstrate that HFS feeding increases MEO underlying increased litter and pup growth, particularly in mice with a trait for increased behavioral physical activity.
Role of ceruloplasmin in nitric oxide metabolism in plasma of humans and sheep: a comparison of adults and fetuses
Authors: Vrancken Kurt , Schroeder Hobe J. , Longo Lawrence D. , Power Gordon G. , Blood Arlin B.
Published: October 2013

Nitric oxide (NO) is metabolized in plasma, in part by the ferroxidase ceruloplasmin (Cp), to form nitrite and nitrosothiols (SNOs), which are proposed to mediate protective responses to hypoxia and ischemia. We hypothesized that NO metabolism would be attenuated in fetal plasma due to low Cp activity. We measured Cp concentrations and activity in plasma samples collected from adults and fetuses of humans and sheep. We then added NO ([NO]: 1.5 or 100 μM) to plasma and aqueous buffer and measured rates of NO disappearance and the production of nitrite and SNO. Cp concentrations in fetal plasma were <15% of adult levels. In aqueous buffer, 1.5 μM NO disappeared with a half-life of 347 ± 64 s (means ± SE) but in plasma of humans the half-life was 19 ± 2 s (adult) and 11 ± 1 s (fetus, P = 0.004) and in sheep it was 31 ± 3 s (adult) and 43 ± 5 s (fetus, P = 0.04). Cp activity was not correlated with the overall elimination half-life of NO or with the amount of SNO ([NO]: 100 μM) or nitrite ([NO]: 1.5 or 100 μM) produced but correlated with SNO yields at 1.5 μM [NO] ( r = 0.92, P = 0.04). Our data demonstrate that Cp is not essential to the increased rate of metabolism of NO in plasma relative to aqueous buffers and that it is not essential to the production of nitrite from NO. Cp may be involved in the conversion of NO to SNO in plasma under near-physiological concentrations of NO.
Prenatal hypoxia programs changes in β-adrenergic signaling and postnatal cardiac contractile dysfunction
Authors: Lindgren I. , Altimiras J.
Published: October 2013

Prenatal hypoxia leads to an increased risk of adult cardiovascular disease. We have previously demonstrated a programming effect of prenatal hypoxia on the cardiac β-adrenergic (βAR) response. The aim of this study was to determine 1) whether the decrease in βAR sensitivity in prenatally hypoxic 5-wk old chicken hearts is linked to changes in β1AR/β2ARs, Gαi expression and cAMP accumulation and 2) whether prenatal hypoxia has an effect on heart function in vivo. We incubated eggs in normoxia (N, 21% O2) or hypoxia from day 0 (H, 14% O2) and raised the posthatchlings to 5 wk of age. Cardiac β1AR/β2ARs were assessed through competitive binding of [3H]CGP-12177 with specific β1AR or β2AR blockers. Gαs and Gαi proteins were assessed by Western blot and cAMP accumulation by ELISA. Echocardiograms were recorded in anesthetized birds to evaluate diastolic/systolic diameter and heart rate and tissue sections were stained for collagen. We found an increase in relative heart mass, β1ARs, and Gαs in prenatally hypoxic hearts. cAMP levels after isoproterenol stimulation and collagen content was not changed in H compared with N, but in vivo echocardiograms showed systolic contractile dysfunction. The changes in βAR and G protein subtypes may be indicative of an early compensatory stage in the progression of cardiac dysfunction, further supported by the cardiac hypertrophy and systolic contractile dysfunction. We suggest that it is not the changes in the proximal part of the βAR system that causes the decreased cardiac contractility, but Ca2+ handling mechanisms further downstream in the βAR signaling cascade.
Synergistic effects of C-peptide and insulin on low O2-induced ATP release from human erythrocytes
Authors: Richards Jennifer P. , Stephenson Alan H. , Ellsworth Mary L. , Sprague Randy S.
Published: October 2013

Erythrocytes participate in the matching of oxygen (O2) delivery with local need in skeletal muscle via the release of O2and the vasodilator, ATP. It was reported that a concentration of insulin found in humans with insulin resistance inhibits low O2-induced ATP release. However, in vivo, insulin is coreleased with connecting peptide (C-peptide) at equimolar concentrations, but because of the shorter insulin half-life, the peptides circulate at ratios of C-peptide to insulin ranging from 1:1 to 6:1. Here, we investigate the hypothesis that C-peptide and insulin work synergistically to maintain low O2-induced ATP release from human erythrocytes. Using a thin-film tonometer to alter O2tension, we determined that either C-peptide or insulin alone inhibits low O2-induced ATP release in a concentration-dependent manner; however, coadministration of the peptides at a 1:1 ratio does not ( n = 5; P < 0.05). Because this ratio of C-peptide to insulin is not present in vivo for extended periods, we also investigated the effect of additional physiological ratios on ATP release. In the presence of insulin concentrations that would be found in fasting humans (0.05 nM), C-peptide to insulin ratios of 4:1 and 6:1 did not adversely affect low O2-induced ATP release. However, at a concentration of insulin found in the peripheral circulation of humans under postprandial conditions (0.5 nM), a ratio of C-peptide to insulin of 6:1 inhibited low O2-induced ATP release ( n = 5). These findings demonstrate a heretofore unrecognized synergism between C-peptide and insulin that could have physiological importance in the regulation of perfusion distribution in skeletal muscle.
Elucidation of the distal convoluted tubule transcriptome identifies new candidate genes involved in renal Mg2+ handling
Authors: de Baaij Jeroen H. F. , Groot Koerkamp Marian J. , Lavrijsen Marla , van Zeeland Femke , Meijer Hans , Holstege Frank C. P. , Bindels René J. M. , Hoenderop Joost G. J.
Published: October 2013

The kidney plays a key role in the maintenance of Mg2+ homeostasis. Specifically, the distal convoluted tubule (DCT) is instrumental in the fine-tuning of renal Mg2+ handling. In recent years, hereditary Mg2+ transport disorders have helped to identify important players in DCT Mg2+ homeostasis. Nevertheless, several proteins involved in DCT-mediated Mg2+ reabsorption remain to be discovered, and a full expression profile of this complex nephron segment may facilitate the discovery of new Mg2+-related genes. Here, we report Mg2+-sensitive expression of the DCT transcriptome. To this end, transgenic mice expressing enhanced green fluorescent protein under a DCT-specific parvalbumin promoter were subjected to Mg2+-deficient or Mg2+-enriched diets. Subsequently, the Complex Object Parametric Analyzer and Sorter allowed, for the first time, isolation of enhanced green fluorescent protein-positive DCT cells. RNA extracts thereof were analyzed by DNA microarrays comparing high versus low Mg2+ to identify Mg2+ regulatory genes. Based on statistical significance and a fold change of at least 2, 46 genes showed differential expression. Several known magnesiotropic genes, such as transient receptor potential cation channel, subfamily M, member 6 ( Trpm6), and Parvalbumin, were upregulated under low dietary Mg2+. Moreover, new genes were identified that are potentially involved in renal Mg2+ handling. To confirm that the selected candidate genes were regulated by dietary Mg2+ availability, the expression levels of solute carrier family 41, member 3 ( Slc41a3), pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1α ( Pcbd1), TBC1 domain family, member 4 ( Tbc1d4), and uromodulin ( Umod) were determined by RT-PCR analysis. Indeed, all four genes show significant upregulation in the DCT of mice fed a Mg2+-deficient diet. By elucidating the Mg2+-sensitive DCT transcriptome, new candidate genes in renal Mg2+ handling have been identified.