bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Analysis of the Tick-Borne Encephalitis Virus Cyclization ElementsIndicates Major Differences between Mosquito-Borne and Tick-Borne Flaviviruses
Authors: Kofler Regina M. , Hoenninger Verena M. , Thurner Caroline , Mandl Christian W.
Published: March 2006

The linear, positive-stranded RNA genome of flaviviruses is thought to
adopt a circularized conformation via interactions of short
complementary sequence elements located within its terminal regions.
This process of RNA cyclization is a crucial precondition for RNA
replication. In the case of mosquito-borne flaviviruses, highly
conserved cyclization sequences (CS) have been identified, and their
functionality has been experimentally confirmed. Here, we provide an
experimental identification of CS elements of tick-borne encephalitis
virus (TBEV). These elements, termed 5′-CS-A and
3′-CS-A, are conserved among various tick-borne flaviviruses,
but they are unrelated to the mosquito-borne CS elements and are
located at different genomic positions. The 5′-CS-A element is
situated upstream rather than downstream of the AUG start codon and, in
contrast to mosquito-borne flaviviruses, it was found that the entire
protein C coding region is not essential for TBEV replication. The
complementary 3′-CS-A element is located within the bottom stem
rather than upstream of the characteristic 3′-terminal
stem-loop structure, implying that this part of the proposed structure
cannot be formed when the genome is in its circularized conformation.
Finally, we demonstrate that the CS-A elements can also mediate their
function when the 5′-CS-A element is moved from its natural
position to one corresponding to the mosquito-borne CS. The recognition
of essential RNA elements and their differences between mosquito-borne
and tick-borne flaviviruses has practical implications for the design
of replicons in vaccine and vector development.
Expression of Baculovirus Late and Very Late Genes Depends on LEF-4, a Component of the Viral RNA Polymerase Whose Guanyltransferase Function Is Essential
Authors: Knebel-Mörsdorf Dagmar , Quadt Ilja , Li Yi , Montier Laura , Guarino Linda A.
Published: March 2006

Baculovirus
lef-4
encodes one subunit of the viral RNA polymerase. Here, we demonstrate the essential nature of LEF-4 by RNA interference and bacmid knockout technology. Silencing of LEF-4 in wild-type virus-infected cells suppressed expression of structural genes, while early expression was unaffected, demonstrating its essential role in late gene expression. After transfection of insect cells with
lef-4
mutant bacmid, no viral progeny was produced, further defining its central role in infection. Cotransfection with wild-type
lef-4
plasmid restored normal replication, but plasmid encoding a guanyltransferase-deficient version failed to rescue. These results emphasize the importance of the mRNA capping function of LEF-4.
Genomic Sequence of Rhesus Cytomegalovirus 180.92: Insights into the Coding Potential of Rhesus Cytomegalovirus
Authors: Rivailler Pierre , Kaur Amitinder , Johnson R. Paul , Wang Fred
Published: March 2006

A pathogenic isolate of rhesus cytomegalovirus (rhCMV 180.92) was cloned, sequenced, and annotated. Comparisons with the published rhCMV 68.1 genome revealed 8 open reading frames (ORFs) in isolate 180.92 that are absent in 68.1, 10 ORFs in 68.1 that are absent in 180.92, and 34 additional ORFs that were not previously annotated. Most of the differences appear to be due to genetic rearrangements in both isolates from a region that is frequently altered in human CMV (hCMV) during in vitro passage. These results indicate that the rhCMV ORF repertoire is larger than previously recognized. Like hCMV, understanding of the complete coding capacity of rhCMV is complicated by genomic instability and may require comparisons with additional isolates in vitro and in vivo.
Maternally Derived Recombinant Human Anti-Hantavirus Monoclonal Antibodies Are Transferred to Mouse Offspring during Lactation and Neutralize Virus In Vitro
Authors: Yu Shuyang , Liang Mifang , Fan BaoLiang , Xu Hongtao , Li Chuan , Zhang Quanfu , Li Dexin , Tang Bo , Li Shijie , Dai Yunping , Wang Meili , Zheng Min , Yan Bingxue , Zhu Qinghong , Li Ning
Published: March 2006

Transgenic mice expressing a recombinant human monoclonal antibody (rHMAb) against hantavirus were generated. These mice could be used as models to explore the possibilities of producing rHMAbs for therapeutic purposes. The highest concentration of the rHMAb in the milk of the transgenic females was 6.6 mg/ml. The rHMAb was also detected in the sera of pups fed by the transgenic females. Both the rHMAbs in the milk of transgenic mice and those in the sera of suckling pups were found to be active against hantaviruses, although the light chain of the antibody absorbed by the pups was modified by N-linked glycosylation.
Hepatitis B Virus Particle Formation in the Absence of Pregenomic RNA and Reverse Transcriptase
Authors: Schormann Wiebke , Kraft Anke , Ponsel Dirk , Bruss Volker
Published: March 2006

Cytoplasmic hepatitis B virus (HBV) capsids are not enveloped and secreted unless the packaged RNA pregenome is reverse transcribed. The expression of the capsid protein C, together with envelope proteins in the absence of pregenomic RNA, produced normal amounts of intracellular capsids, but the secretion of virion-like particles was greatly reduced. The I97L C protein mutant, allowing immature nucleocapsid envelopment in the background of an HBV genome, did not promote the envelopment of capsids lacking a pregenome, suggesting that this mutation is not sufficient to induce secretion competence independently of the pregenome.
Cellular Factors Required for Lassa Virus Budding
Authors: Urata Shuzo , Noda Takeshi , Kawaoka Yoshihiro , Yokosawa Hideyoshi , Yasuda Jiro
Published: March 2006

It is known that Lassa virus Z protein is sufficient for the release of virus-like particles (VLPs) and that it has two L domains, PTAP and PPPY, in its C terminus. However, little is known about the cellular factor for Lassa virus budding. We examined which cellular factors are used in Lassa virus Z budding. We demonstrated that Lassa Z protein efficiently produces VLPs and uses cellular factors, Vps4A, Vps4B, and Tsg101, in budding, suggesting that Lassa virus budding uses the multivesicular body pathway functionally. Our data may provide a clue to develop an effective antiviral strategy for Lassa virus.
Comparative genomic hybridisation in malignant deciduoid mesothelioma
Authors: Scattone A , Pennella A , Gentile M , Musti M , Nazzaro P , Buonadonna A L , Marzullo A , Cavone D , Pollice L , Serio G
Published: March 2006

Background:Malignant deciduoid mesothelioma is a rare variant of epithelioid mesothelioma. This tumour generally has poor prognosis, and can be asbestos related.

Aim:To identify peculiar genetic changes responsible for critical phases in pathogenesis of malignant deciduoid mesothelioma and their prognostic relevance.

Methods:Comparative genomic hybridisation was carried out in six cases of malignant pleural deciduoid mesothelioma, four sporadic and two familial. All cases were found to be asbestos related. Four patients died during follow-up and the mean survival was 29.5 (SD 14.2, range 12–43) months.

Results:Genetic abnormalities were found in all the tumour tissues, the most frequent being chromosomal gains at 1p, 12q, 17, 8q, 19 and 20 and losses at 13q, 6q and 9p. Survival was found to be longer in those patients who presented a smaller number of losses (⩽2) in the tumorous chromosomes.

Conclusions:Although numerous genetic changes are presented by deciduoid mesotheliomas, certain chromosomal regions are preferentially affected. The clinical outcome for this mesothelioma subtype is predicted by the number of losses.
TRADE GAINS: THE END OF THE ROAD?
Authors: KEMP MURRAY C.
Published: March 2006

In 1972, the potential gainfulness of free trade was established under fairly general assumptions — essentially those of Arrow and Debreu. Since then, the assumptions have been considerably weakened, notably by accommodating overlapping mortal generations and an infinite horizon. However, there remain several indispensable but implausible assumptions. Two of those assumptions are examined, in a preliminary way, in the present paper: (a) in finite trade models of Arrow–Debreu type, each individual is sufficiently ill-informed or irrational to believe that he/she has no market power; (b) in models of overlapping generations and infinite horizons, there are no intergenerational bequests or gifts inter vivos. Few clear generalizations are found. However, an attempt is made to describe circumstances under which assumptions (a) and (b) can be abandoned.
PRIVATE INVESTMENT IN INFRASTRUCTURE IN ASIA: THE IMPACT OF REGULATION
Authors: KIRKPATRICK COLIN , PARKER DAVID , ZHANG YIN-FANG
Published: March 2006

This paper provides an empirical analysis of the impact of economic regulation on the inflow of private foreign investment in the infrastructure sector in Asian economies over the period 1988 to 2002. The results confirm that foreign investment in infrastructure has responded positively to the establishment of an effective regulatory framework which provides regulatory credibility to the private sector. The main policy implication of the findings is the need to support capacity building and institutional strengthening for robust and independent regulation in the developing countries of Asia.
LONGEVITY INSURANCE: A MISSING MARKET
Authors: CREIGHTON ADAM , JIN HENRY HONGBO , PIGGOTT JOHN , VALDEZ EMILIANO A.
Published: March 2006

More than half of the world's old live in Asia, and around 35% in India and China alone. As demographic transition proceeds regionally and globally, the development of a robust and reliable longevity insurance market will become essential. Although the need for such insurance is most pressing in Asia, longevity risk is poorly managed practically everywhere. This paper reviews theory and practice relating to longevity risk and insurance, amid a rapidly changing demographic and policy landscape. It analyzes the reasons for the failure of longevity insurance markets, and examines possible innovations in both markets and public policy that may lead to a more vibrant market and a greater variety of longevity insurance products. These include risk sharing between the buyer and seller, "deductibles", reverse mortgages, and securitization.
ON THE LOWEST LYING 4++$q\bar{q}$ NONET AND GLUEBALL
Authors: LI DE-MIN , SHI ZHI-QIANG , YU HONG
Published: March 2006

In the framework of meson–meson mixing, in the presence of the a4(2040), [Formula: see text] and f4(2050) being the 13F4[Formula: see text] states, we suggest that the f′4, the ninth member of the 13F4meson nonet, has a mass of about 2084 MeV, and some predictions on the f4and f′4decaying into two photons and pseudoscalar mesons are presented. Also, the mass of the lowest lying 4++glueball is predicted to be about 3.15 GeV by using the meson-glueball mass relation derived from the glueball dominance picture, which is in agreement with 3.42 GeV, the average value of the recent predicted results was given by lattice QCD, potential model, semi-relativistic potential model and quasi-particle model.
THEORETICAL APPROACH USING EXTENDED HUCKEL TIGHT-BINDING METHOD OF THE ELECTRONIC STRUCTURE OF CeOs4Sb12 FILLED SKUTTERUDITE
Authors: GALVAN DONALD H. , SAMANIEGO J. C.
Published: March 2006

Based on band structure, total and projected density of states and Mulliken Population Analysis, the electronic properties of CeOs 4 Sb 12 were investigated. The calculated energy bands depict a semiconductor behavior with an energy gap (direct gap at H ) of the order of 0.45 eV. On the other hand, a strong hybridization occurs between Ce f-orbitals with Os d-, p-, and Sb p-orbitals, which convince us to believe that this hybridization, added to the existence of a mini gap, are responsible for the heavy Fermion behavior, as well as the possibility to consider it a candidate for thermoelectric applications.
INTEGRABLE COUPLINGS AND NEW EXACT SOLUTIONS FOR THE NONISOSPECTRAL AKNS EQUATION
Authors: SUN YE-PENG , CHEN DENG-YUAN
Published: March 2006

In this paper, we derive nonisospectral AKNS equations from the AKNS spectral problem. By using a new Loop algebra [Formula: see text], their integrable couplings are constructed. Moreover, bilinear forms of the nonisospectral AKNS equation are given. New exact solutions are obtained through the Hirota method. Some nonisospectral characteristics of the obtained solutions are discussed.
NUMERICAL ANALYSIS OF A COUPLED FINITE-INFINITE ELEMENT METHOD FOR EXTERIOR HELMHOLTZ PROBLEMS
Authors: AUTRIQUE JEAN-CHRISTOPHE , MAGOULÈS FRÉDÉRIC
Published: March 2006

Coupled finite-infinite element computations are very efficient for modeling large scale acoustics problems. Parallel algorithms, like sub-structuring and domain decomposition methods, have shown to be very efficient for solving huge linear systems arising from acoustics. In this paper, a coupled finite-infinite element method is described, formulated and analyzed for parallel computations purpose. New numerical results illustrate the efficiency of this method for academic test cases and industrial problems alike.
SOLVING NONLINEAR WAVE EQUATIONS IN THE GRID COMPUTING ENVIRONMENT: AN EXPERIMENTAL STUDY
Authors: BAHI JACQUES M. , COUTURIER RAPHAËL , VUILLEMIN PHILIPPE
Published: March 2006

In this paper we are interested in studying the development of parallel algorithms to solve nonlinear wave equations. Both synchronous and asynchronous algorithms contexts are considered. The solver is based on the multisplitting Newton method that provides a coarse-grained scheme. Experiments are carried out in both homogeneous and heterogeneous grid environments. According to the configuration environment, the behaviors of parallel synchronous and asynchronous algorithms are analyzed. Experiments allow us to draw some conclusions about the use of parallel iterative algorithms in grid computing environment.
PROPORTIONALITY AND NON-MANIPULABILITY IN BANKRUPTCY PROBLEMS
Authors: MORENO-TERNERO JUAN D.
Published: March 2006

We explore the relationship between proportionality and manipulation (via merging or splitting agents' claims) in bankruptcy problems. We provide an alternative proof to the well-known result that, in an unrestricted domain, immunity to manipulation is equivalent to requiring proportional division. We show that this result also holds for restricted (but sufficiently rich) domains, such as the domain of simple problems and the domain of zero-normalized problems. Finally, we characterize two adjustments of the proportional rule by combining non-manipulabilty on these domains and the usual axioms of independence of claims truncation and composition from minimal rights.
Cross-Layering for Performance Improvement in Multi-Hop Wireless Networks
Authors: GRANELLI FABRIZIO , KLIAZOVICH DZMITRY
Published: March 2006

Cross-layering represents a perspective design principle for adapting natively wired protocols to the wireless scenario and for improving their performance. The paper explores the possibilities of cross-layer design as a candidate tool for performance optimization, focusing on problems deriving from the usage of ARQ schemes in today's wireless networks and proposes a novel and general cross-layer interaction scheme between the transport and the link layers. Achieved results in the framework of a IEEE 802.11-based multi-hop wireless network demonstrate the value of the proposed framework, and allow to provide guidelines for future work on the topic.
INVESTIGATING A WIRELESS SENSOR NETWORK OPTIMAL LIFETIME SOLUTION FOR LINEAR TOPOLOGIES
Authors: Hellman Keith , Colagrosso Michael
Published: March 2006

We investigate a known optimal lifetime solution for a linear wireless sensor network through simulation, and propose alternative solutions where a known optimal solution does not exist. The network is heterogeneous in the sensors' energy distribution and also in the amount of data each sensor must communicate. As a basis for comparison, we analyze the lifetime of a network using a simple, nearest-neighbor routing algorithm, and an analytic solution to the optimal lifetime of networks meeting certain constraints. Alternative solutions considered range from those requiring global knowledge of the network to solutions using only next-neighbor knowledge. We compare the performance of all the routing algorithms in simulation.
PERFORMANCE MODELLING OF TRAFFIC CONGESTION IN WIRELESS NETWORKS
Authors: YAR ASFAND-E , AWAN I. U. , WOODWARD M. E.
Published: March 2006

Evolution in Wireless Technologies and Networks imposes a greater need for network support as current congestion control and avoidance techniques are mainly designed for wired networks. The current performance evaluation techniques proposed for wireless networks are not able to achieve optimal performance to guarantee desired Quality of Service (QoS) standards. Thus, the new schemes such as Active Queue Management (AQM) are needed to be adaptive to dynamic wireless networks and bursty traffic conditions to help in avoiding severe performance degradation in wireless environment. Thus, in this paper we developed and validated a novel approximate analytical performance model of a multiple threshold Random Early Detection (RED) congestion control mechanism based on the principle of Maximum Entropy (ME). It can be employed at the wireless gateways/base stations to regulate the buffer management and bandwidth allocation. Closed form expressions for the state and blocking probabilities have also been characterized. Numerical examples have been presented for aggregate and marginal QoS measures, which show the credibility of the ME solution and its validation against simulation.
DIRECT PREDICTION OF T-CELL EPITOPES USING SUPPORT VECTOR MACHINES WITH NOVEL SEQUENCE ENCODING SCHEMES
Authors: HUANG LEI , DAI YANG
Published: March 2006

New peptide encoding schemes are proposed to use with support vector machines for the direct recognition of T cell epitopes. The methods enable the presentation of information on (1) amino acid positions in peptides, (2) neighboring side chain interactions, and (3) the similarity between amino acids through a BLOSUM matrix. A procedure of feature selection is also introduced to strengthen the prediction. The computational results demonstrate competitive performance over previous techniques.
A NEW REGULATORY INTERACTION SUGGESTED BY SIMULATIONS FOR CIRCADIAN GENETIC CONTROL MECHANISM IN MAMMALS
Authors: MATSUNO HIROSHI , INOUYE SHIN-ICHI T. , OKITSU YASUKI , FUJII YASUSHI , MIYANO SATORU
Published: March 2006

Knowledge of molecular biological systems is increasing at an amazing pace. It is becoming harder to intuitively evaluate the significance of each interaction between the molecules of the complex biological systems. Hence, we need to develop an efficient computational method to explore the biological mechanisms. In this study, we employed a hybrid functional Petri net in order to analyze mammalian circadian genetic control mechanisms, which consists of feedback loops of clock genes and generates endogenous near 24 h rhythms in mammals. We constructed a computational model based on the available biological data, and by using Genomic Object Net, we performed computer simulations of the time courses of clock gene transcription and translation. Although the original model successfully reproduced most of the circadian genetic control mechanisms, two discrepancies remained despite a wide selection of the parameters. We found that addition of a hypothetical path into the original model result in successful simulation of time courses and phase relationships among clock genes. This also demonstrates the usefulness of the hybrid functional Petri net approach to biological systems.
DETECTING AND SORTING TARGETING PEPTIDES WITH NEURAL NETWORKS AND SUPPORT VECTOR MACHINES
Authors: HAWKINS JOHN , BODÉN MIKAEL
Published: March 2006

This paper presents a composite multi-layer classifier system for predicting the subcellular localization of proteins based on their amino acid sequence. The work is an extension of our previous predictor PProwler v1.1 which is itself built upon the series of predictors SignalP and TargetP. In this study we outline experiments conducted to improve the classifier design. The major improvement came from using Support Vector machines as a "smart gate" sorting the outputs of several different targeting peptide detection networks. Our final model (PProwler v1.2) gives MCC values of 0.873 for non-plant and 0.849 for plant proteins. The model improves upon the accuracy of our previous subcellular localization predictor (PProwler v1.1) by 2% for plant data (which represents 7.5% improvement upon TargetP).
HOW MANY QUESTIONS DO YOU NEED TO PROVE THAT UNASKED QUESTIONS HAVE NO ANSWERS?
Authors: CABELLO ADÁN
Published: March 2006

Suppose a quantum system is prepared in an arbitrary quantum state. How many yes-no questions about that system would you have to consider to prove that such questions have no predefined answers? Peres conjectured that the minimum number was 18, as in the case of the set found in 1995. Asher's conjecture has recently been proven correct: there are no sets with fewer than 18 questions. This is the end of a long story which began in 1967, when Kochen and Specker found a similar set requiring 117 questions.
ADDITIVITY FOR TRANSPOSE DEPOLARIZING CHANNELS
Authors: DATTA NILANJANA , HOLEVO ALEXANDER S. , SUHOV YURI
Published: March 2006

Additivity of the minimal output entropy for the family of transpose depolarizing channels introduced by Fannes et al.5 is considered. It is shown that using the method of Ref. 3 allows us to prove the additivity for the range of the parameter values for which the problem was left open in Ref. 5. Together with the result of Ref. 5, this covers the whole family of transpose depolarizing channels. In addition, the multiplicativity of the maximal p-norm for this family of channels is proved for all 1 ≤ p ≤ 2.
ANOTHER LOOK AT QUANTUM TELEPORTATION
Authors: VAIDMAN L. , EREZ N. , RETZKER A.
Published: March 2006

A dialog with Asher Peres regarding the meaning of quantum teleportation is briefly reviewed. The Braunstein–Kimble method for teleportation of light is analyzed in the language of quantum wave functions. A pictorial example of continuous variable teleportation is presented using computer simulation.
DISTINGUISHING UNENTANGLED STATES WITH AN UNENTANGLED MEASUREMENT
Authors: WOOTTERS WILLIAM K.
Published: March 2006

In a 1991 paper, Asher Peres and the author theoretically analyzed a set of unentangled bipartite quantum states that could apparently be distinguished better by a global measurement than by any sequence of local measurements on the individual subsystems. The present paper returns to the same example, and shows that the best result so far achieved can alternatively be attained by a measurement that, while still global, is "unentangled" in the sense that the operator associated with each measurement outcome is a tensor product.
Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y+
Authors: O’Kane Robyn L. , Viña Juan R. , Simpson Ian , Zaragozá Rosa , Mokashi Ashwini , Hawkins Richard A.
Published: March 2006

Cationic amino acid (CAA) transport is brought about by two families of proteins that are found in various tissues: Cat (CAA transporter), referred to as system y+, and Bat [broad-scope amino acid (AA) transporter], which comprises systems b0,+, B0,+, and y+L. CAA traverse the blood-brain barrier (BBB), but experiments done in vivo have only been able to examine the BBB from the luminal (blood-facing) side. In the present study, plasma membranes isolated from bovine brain microvessels were used to identify and characterize the CAA transporter(s) on both sides of the BBB. From these studies, it was concluded that system y+was the only transporter present, with a prevalence of activity on the abluminal membrane. System y+was voltage dependent and had a Kmof 470 ± 106 μM (SE) for lysine, a Kiof 34 μM for arginine, and a Kiof 290 μM for ornithine. In the presence of Na+, system y+was inhibited by several essential neutral AAs. The Kivalues were 3–10 times the plasma concentrations, suggesting that system y+was not as important a point of access for these AAs as system L1. Several small nonessential AAs (serine, glutamine, alanine,and glycine) inhibited system y+with Kivalues similar to their plasma concentrations, suggesting that system y+may account for the permeability of the BBB to these AAs. System y+may be important in the provision of arginine for NO synthesis. Real-time PCR and Western blotting techniques established the presence of the three known nitric oxide synthases in cerebral endothelial cells: NOS-1 (neuronal), NOS-2 (inducible), and NOS-3 (endothelial). These results confirm that system y+is the only CAA transporter in the BBB and suggest that NO can be produced in brain endothelial cells.
The vascular endothelial cell mediates insulin transport into skeletal muscle
Authors: Wang Hong , Liu Zhenqi , Li Guolian , Barrett Eugene J.
Published: March 2006

The pathways by which insulin exits the vasculature to muscle interstitium have not been characterized. In the present study, we infused FITC-labeled insulin to trace morphologically (using confocal immunohistochemical methods) insulin transport into rat skeletal muscle. We biopsied rectus muscle at 0, 10, 30, and 60 min after beginning a continuous (10 mU·min−1·kg−1), intravenous FITC-insulin infusion (with euglycemia maintained). The FITC-insulin distribution was compared with that of insulin receptors (IR), IGF-I receptors (IGF-IR), and caveolin-1 (a protein marker for caveolae) in skeletal muscle vasculature. We observed that muscle endothelium stained strongly for FITC-insulin within 10 min, and this persisted to 60 min. Endothelium stained more strongly for FITC-insulin than any other cellular elements in muscle. IR, IGF-IR, and caveolin-1 were also detected immunohistochemically in muscle endothelial cells. We further compared their intracellular distribution with that of FITC-insulin in cultured bovine aortic endothelial cells (bAECs). Considerable colocalization of IR or IGF-IR with FITC-insulin was noted. There was some but less overlap of IR or IGF-IR or FITC-insulin with caveolin-1. Immunoprecipitation of IR coprecipitated caveolin-1, and conversely the precipitation of caveolin-1 brought down IR. Furthermore, insulin increased the tyrosine phosphorylation of caveolin-1, and filipin (which inhibits caveolae formation) blocked insulin uptake. Finally, the ability of insulin, IGF-I, and IGF-I-blocking antibody to diminish insulin transport across bAECs grown on transwell plates suggested that IGF-IR, in addition to IR, can also mediate transendothelial insulin transit. We conclude that in vivo endothelial cells rapidly take up and concentrate insulin relative to plasma and muscle interstitium and that IGF-IR, like IR, may mediate insulin transit through endothelial cells in a process involving caveolae.
Integration of Evoked Responses in Supragranular Cortex Studied With Optical Recordings In Vivo
Authors: Civillico Eugene F. , Contreras Diego
Published: March 2006

Complex representations in sensory cortices rely on the integration of inputs that overlap temporally and spatially, particularly in supragranular layers, yet the spatiotemporal dynamics of this synaptic integration are largely unknown. The rodent somatosensory system offers an excellent opportunity to study these dynamics because of the overlapping functional representations of single-whisker inputs. We recorded responses in mouse primary somatosensory (barrel) cortex to single and paired whisker deflections using high-speed voltage-sensitive dye imaging. Responses to paired deflections at intervals of 0 and 10 ms summed sublinearly, producing a single transient smaller in amplitude than the sum of the component responses. At longer intervals of 50 and 100 ms, the response to the second deflection was reduced in amplitude and limited spatially relative to control. Between 100 and 200 ms, the response to the second deflection recovered and often showed areas of facilitation. With increasing interstimulus interval from 50 to 200 ms, recovery of the second response occurred from the second stimulated whisker’s barrel column outward. In contrast to results with paired-whisker stimulation, when a whisker deflection was preceded by a weak electrical stimulus applied to the neighboring cortex, the summation of evoked responses was predominantly linear at all intervals tested. Thus under our conditions, the linearity of response summation in cortex was not predicted by the amplitudes of the component responses on a column-by-column basis, but rather by the timing and nature of the inputs.
An Optimization Principle for Determining Movement Duration
Authors: Tanaka Hirokazu , Krakauer John W. , Qian Ning
Published: March 2006

Movement duration is an integral component of motor control, but nearly all extant optimization models of motor planning prefix duration instead of explaining it. Here we propose a new optimization principle that predicts movement duration. The model assumes that the brain attempts to minimize movement duration under the constraint of meeting an accuracy criterion. The criterion is task and context dependent but is fixed for a given task and context. The model determines a unique duration as a trade-off between speed (time optimality) and accuracy (acceptable endpoint scatter). We analyzed the model for a linear motor plant, and obtained a closed-form equation for determining movement duration. By solving the equation numerically with specific plant parameters for the eye and arm, we found that the model can reproduce saccade duration as a function of amplitude (the main sequence), and arm-movement duration as a function of the ratio of target distance to size (Fitts's law). In addition, it explains the dependency of peak saccadic speed on amplitude and the dependency of saccadic duration on initial eye position. Furthermore, for arm movements, the model predicts a scaling relationship between peak velocity and distance and a reduction in movement duration with a moderate increase in viscosity. Finally, for a linear plant, our model predicts a neural control signal identical to that of the minimum-variance model set to the same movement duration. This control signal is a smooth function of time (except at the endpoint), in contrast to the discontinuous bang–bang control found in the time-optimal control literature. We suggest that one aspect of movement planning, as revealed by movement duration, may be to assign an endpoint accuracy criterion for a given task and context.
Purine and folate metabolism as a potential target of sex-specific nutrient allocation in Drosophila and its implication for lifespan-reproduction tradeoff
Authors: Bauer Matthias , Katzenberger Jörg D. , Hamm Anne C. , Bonaus Melanie , Zinke Ingo , Jaekel Jens , Pankratz Michael J.
Published: March 2006

The reallocation of metabolic resources is important for survival during periods of limited nutrient intake. This has an influence on diverse physiological processes, including reproduction, repair, and aging. One important aspect of resource allocation is the difference between males and females in response to nutrient stress. We identified several groups of genes that are regulated in a sex-biased manner under complete or protein starvation. These range from expected differences in genes involved in reproductive physiology to those involved in amino acid utilization, sensory perception, immune response, and growth control. A striking difference was observed in purine and the tightly interconnected folate metabolism upon protein starvation. From these results, we conclude that the purine and folate metabolic pathway is a major point of transcriptional regulation during resource allocation and may have relevance for understanding the physiological basis for the observed tradeoff between reproduction and longevity.
Genetic segregation of airway disease traits despite redundancy of calcium-activated chloride channel family members
Authors: Patel Anand C. , Morton Jeffrey D. , Kim Edy Y. , Alevy Yael , Swanson Suzanne , Tucker Jennifer , Huang Guaming , Agapov Eugene , Phillips Thomas E. , Fuentes Maria E. , Iglesias Antonio , Aud Dee , Allard John D. , Dabbagh Karim , Peltz Gary , Holtzman Michael J.
Published: March 2006

Complex airway diseases such as asthma and chronic obstructive pulmonary disease exhibit stereotyped traits (especially airway hyperreactivity and mucous cell metaplasia) that are variably expressed in each patient. Here, we used a mouse model for virus-induced long-term expression of these traits to determine whether individual traits can be genetically segregated and thereby linked to separate determinants. We showed that an F2 intercross population derived from susceptible and nonsusceptible mouse strains can manifest individual phenotypic extremes that exhibit one or the other disease trait. Functional genomic analysis of these extremes further indicated that a member of the calcium-activated chloride channel ( CLCA) gene family designated mClca3 was inducible with mucous cell metaplasia but not airway hyperreactivity. In confirmation of this finding, we found that mClca3 gene transfer to mouse airway epithelium was sufficient to induce mucous cell metaplasia but not airway hyperreactivity. However, newly developed mClca3−/−mice exhibited the same degree of mucous cell metaplasia and airway hyperreactivity as wild-type mice. Bioinformatic analysis of the Clca locus led to the identification of mClca5, and gene transfer indicated that mClca5 also selectively drives mucous cell metaplasia. Thus, in addition to the capacity of CLCA family members to exhibit diverse functional activities, there is also preserved function so that more than one family member mediates mucous cell metaplasia. Nonetheless, Clca expression appears to be a selective determinant of mucous cell metaplasia so that shared homologies between CLCA family members may still represent a useful target for focused therapeutic intervention in hypersecretory airway disease.
New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome
Authors: Smith A.C. , Rubin T. , Shuman C. , Estabrooks L. , Aylsworth A.S. , McDonald M.T. , Steele L. , Ray P.N. , Weksberg R.
Published: March 2006

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.
Antibodies for Targeted Cancer Therapy – Technical Aspects and Clinical Perspectives
Authors: Zangemeister-Wittke Uwe
Published: March 2006

The efficacy of traditional anti-cancer agents comes with the price of toxicity to normal cells, which limits the success of therapy. In the past 2 decades, greater understanding of the molecular differences between malignant and normal cells has led to the development of therapies that more specifically target human tumors. These include new anti-cancer agents directed against intracellular targets associated with malignant alterations, such as increased proliferation, impaired apoptosis or angiogenesis. In addition, antibodies have been developed that are directed towards tumor-associated antigens and provide tailor-made effector functions by inhibiting cell growth, inducing apoptosis or constituting cytotoxic drug delivery systems. Since the targeted approach of anti-cancer therapies increases the exposure of malignant cells and at the same time reduces the exposure of normal tissues, it offers the promise of enhanced efficacy and lower side effects. Antibodies, immunoconjugates and liposomal drug delivery systems derived thereof are now mainstream cancer therapeutics, and by the end of 2003 17 marketed antibody-based products generated several billion in combined annual sales. This study highlights the most recent breakthroughs in antibody technology and summarizes major achievements in antibody-based cancer therapy in oncology trials.
Anti-Interleukin-5 Antibody Therapy in Eosinophilic Diseases
Authors: Simon Dagmar , Braathen Lasse R. , Simon Hans-Uwe
Published: March 2006

Eosinophilia in atopic diseases and hypereosinophilic syndrome is often associated with a high expression of interleukin-5 (IL-5). IL-5 plays an important role in regulating the production, differentiation, recruitment, activation, and survival of eosinophils. Therefore, neutralizing IL-5 with an antibody is a promising therapeutic strategy in eosinophilic diseases. In patients with hypereosinophilic syndrome and eosinophilic esophagitis, anti-IL-5 antibody therapy resulted in an improvement of symptoms. In patients with bronchial asthma, no effect on the late phase reaction and on airway hyperresponsiveness has been observed. Moreover, patients with atopic dermatitis demonstrated only a moderate improvement of their skin lesions and pruritus. Anti-IL-5 therapy was followed by a rapid and sustained decrease of peripheral blood eosinophil numbers. The decrease of tissue eosinophils was, however, less dramatic. Investigating the effects of anti-IL-5 therapy will improve our understanding of the pathogenic roles of both IL-5 and eosinophils in eosinophilic inflammatory responses.
Environment as a Critical Factor for the Pathogenesis and Outcome of Gastrointestinal Disease: Experimental and Human Inflammatory Bowel Disease and Helicobacter-Induced Gastritis
Authors: Bleich A. , Mähler M.
Published: March 2006

Environmental factors play an important role in the manifestation, course, and prognosis of diseases of the gastrointestinal tract such as inflammatory bowel disease (IBD) and Helicobacter pylori-induced gastritis. These two disease complexes were chosen for a discussion of the contribution of environmental factors to the disease outcome in humans and animal models. Dissecting complex diseases like IBD and Helicobacter-induced gastritis has shown that the outcome of disease depends on the allelic constellation of a host and the microbial and physical environments. Host alleles predisposing to a disease in one genomic and/or environmental milieu may not be deleterious in other constellations; on the other hand, microbes can have different effects in different hosts and under different environmental conditions. The impact of the complex interaction between host genetics and environmental factors, particularly microflora, also underlines the importance of a defined genetic background and defined environments in animal studies and is indicative of the difficulties in analyzing complex diseases in humans.
Expression of RUNX3 Protein in Human Esophageal Mucosa and Squamous Cell Carcinoma
Authors: Hiramatsu Toshiki , Osaki Mitsuhiko , Ito Yuka , Tanji Yoshiyuki , Tokuyasu Naruo , Ito Hisao
Published: March 2006

Runt-related transcriptional factor gene 3 (RUNX3) belongs to the runt domain family of transcriptional factors that plays an important role during normal tissue development and in tumorigenesis in several organs. This study examined the expression of RUNX3 protein in human esophageal mucosa and squamous cell carcinoma in comparison with clinicopathological profiles. Western blot analysis and RT-PCR revealed that both RUNX3/P44 and P27, but not P46, were expressed in all three human esophageal squamous cell carcinoma (SCC) cell lines, as well as in three pairs of esophageal SCC cell lines and the corresponding nontumoral mucosa specimens. RUNX3 expression was shown in prickle and functional cell layer cells in normal esophageal mucosa. On the other hand, immunoreactivity was seen only in carcinoma cells around the cancer pearls. RUNX3 expression was significantly higher in the 19 well-differentiated SCCs than in the 56 moderately or 69 poorly differentiated SCCs (p < 0.01). The 3-year survival rate was significantly lower in the 29 patients with lower RUNX3 expression than in the 37 patients with higher expression (p = 0.0003). These results indicated that RUNX3 protein might play an important role in cellular differentiation in both esophageal mucosa and SCC. The expression correlated with the patients’ prolonged survival, implying a tumor suppressive effect in esophageal SCCs.
The Antiatherogenic Effect of Allicin: Possible Mode of Action
Authors: Gonen Ayelet , Harats Dror , Rabinkov Aharon , Miron Talia , Mirelman David , Wilchek Meir , Weiner Lev , Ulman Esfir , Levkovitz Hana , Ben-Shushan Dikla , Shaish Aviv
Published: March 2006

Objective: Garlic (Allium sativum) has been suggested to affect several cardiovascular risk factors. Its antiatherosclerotic properties are mainly attributed to allicin that is produced upon crushing of the garlic clove. Most previous studies used various garlic preparations in which allicin levels were not well defined. In the present study, we evaluated the effects of pure allicin on atherogenesis in experimental mouse models. Methods and Results: Daily dietary supplement of allicin, 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9 and 56.8% in apolipoprotein E-deficient and low-density lipoprotein (LDL) receptor knockout mice, respectively, as compared with control mice. LDL isolated from allicin-treated groups was more resistant to CuSO4-induced oxidation ex vivo than LDL isolated from control mice. Incubation of mouse plasma with 3H-labeled allicin showed binding of allicin to lipoproteins. By using electron spin resonance, we demonstrated reduced Cu2+ binding to LDL following allicin treatment. LDL treatment with allicin significantly inhibited both native LDL and oxidized LDL degradation by isolated mouse macrophages. Conclusions: By using a pure allicin preparation, we were able to show that allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages.
Importance of Genetic Diagnosis of DAX-1 Deficiency: Example from a Large, Multigenerational Family
Authors: Ostermann Sandrine , Salvi Roberto , Lang-Muritano Mariarosaria , Voirol Marie-Jeanne , Puttinger Rudolf , Gaillard Rolf C. , Schoenle Eugen , Pralong François P.
Published: March 2006

Background: Inactivating mutations of DAX-1 give rise to the X-linked form of adrenal hypoplasia congenita (AHC). Affected fetuses are at risk of early postnatal Addisonian crisis, but the variable phenotypic expression of DAX-1 insufficiency renders this diagnosis challenging. Methods: We describe the familial transmission of AHC over several generations. The proband was diagnosed with adrenal insufficiency at age 3.5 years: molecular analysis revealed a novel, 373-bp deletion including the second exon of DAX-1. Given the familial history of several unexplained deaths in male infants related to the proband via his maternal great-grandmother, we hypothesized that all these boys had been affected with AHC. Another female member of the family being pregnant with a male fetus at the time, we performed DAX-1 analysis on the mother and the newborn. The mother was heterozygous for the deletion, and the newborn hemizygous: he presented an adrenal crisis at 10 days of life, and is now doing well on hormone replacement therapy. Conclusion: The unfortunate deaths of male infants at each generation of this family underlie the importance of early and precise diagnosis of this rare condition, stressing the value of genetic diagnosis in six potential female carriers of this family entering their reproductive years.
Complications in Children with Long-Term Cochlear Implants
Authors: Lin Yung-Song , Lee Fei-Peng , Peng Shu-Chen
Published: March 2006

Objectives: To evaluate the complications in children who underwent cochlear implantation between 1991 and 2002 at Chi Mei Medical Center, Taipei Medical University. Method: The medical records of 169 cases of pediatric cochlear implants from 1991 to 2002 with a follow-up period of 3–11 years were reviewed for demographics and complications. A follow-up phone call and clinical visits were performed to determine the long-term results. Results: The medical-surgical complications were facial nerve stimulation, transient dizziness, flap breakdown, minor change of taste, cholesteatoma, otitis media with effusion and mastoiditis. The device-related complications included 4 device failures and 1 device breakage in a traffic accident. Conclusion: Chronic otitis media and cholesteatoma developed in children as long-term complications and surgical challenges. Nevertheless, cochlear implantation surgery in children is a reliable and safe procedure with a low percentage of severe complications. To prevent cholesteatoma formation, parents are advised to schedule a regular ENT consultation at least yearly for early identification and treatment in the stages of acute otitis media or drum retraction.
Should We Use Ossicular Remnants in Ossicular Reconstruction following Cholesteatoma Removal?
Authors: Ferekidis E. , Nikolopoulos T.P. , Yiotakis J. , Ferekidou E. , Korres S. , Manolopoulos L. , Kandiloros D.
Published: March 2006

The remnants of the acoustic ossicles have been used in ossicular reconstruction during mastoid surgery for many decades. The present study assessed the status of the acoustic ossicles in 114 patients (57 with cholesteatoma and 57 without) during surgery for chronic otitis media using the operating microscope. In 52 cases, the ossicles (malleus and/or incus) were assessed using both the surgical and scanning electron microscope in order to reveal any erosions and compare the findings. From the 57 operated ears with cholesteatoma, 45 (79%) had ossicular erosion whereas 12 (21%) did not. In the group of 57 operated ears with chronic otitis media without cholesteatoma, 33 (58%) had ossicular erosion whereas 24 (42%) did not. This difference was statistically significant (p = 0.02). With regard to the 52 operated cases who were studied with both microscopes, in the cholesteatoma patients the surgical microscope was not able to reveal any ossicular erosions in 39% of the cases, whereas the scanning electron microscope revealed moderate or severe erosions in the same ears. This suggests that the operating microscope is not reliable enough to determine if ossicular remnants can be used in ossicular reconstruction following cholesteatoma surgery. There is a considerable risk that epithelia or other cholesteatoma particles remain in the areas of erosions that cannot be seen with the operating microscope. The use of such ossicular remnants may lead to cholesteatoma recurrence and failures in mastoid surgery. Therefore, autoclaving or alternative prosthesis may be considered in such cases.