bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric Research Regulations under Legal Scrutiny: Grimes Narrows Their Interpretation
Authors: Kopelman Loretta M.
Published: January 2007

In Grimes v. Kennedy Krieger Institute, the Maryland Court of Appeals (Maryland’s highest court) considered whether it is possible for investigators or research entities to have a special relationship with subjects, thereby creating a duty of care that could, if breached, give rise to an action in negligence. The research under review, the Lead Abatement and Repair & Maintenance Study, was conducted from 1993 to 1996 by investigators at the Kennedy Krieger Institute (KKI), an affiliate of Johns Hopkins University.

After briefly discussing the case at the center of this ruling, I consider how ambiguities within the federal research regulations at 45 C.F.R. § 46 contribute to disagreements among reasonable and informed people of good will about what studies should be approved. I argue that Grimes may be understood as placing restrictions on how these regulations may be interpreted and used.
Untreated Addiction Imposes an Ethical Bar to Recruiting Addicts for Non-Therapeutic Studies of Addictive Drugs
Authors: Cohen Peter J.
Published: January 2007

The mental illness of substance dependence or addiction is responsible for major economic, social, and personal costs. If we are to elucidate its etiology, understand its mechanisms, and eventually bring it under control, scientific investigation is essential. Research in animals and humans has enhanced our understanding of this disease through examination of genetic, neurophysiological, biochemical, and behavioral factors. But because animals cannot verbalize their subjective responses to drugs and because significant symptoms of addiction (e.g., craving, impaired control, and compulsive use) cannot be observed in non-drug-dependent humans, it is not surprising that certain investigations of substance dependence have required the participation of addicted or substance-dependent humans.
Why the Netherlands?
Authors: Cohen-Almagor Raphael
Published: January 2007

The Dutch experience has influenced the debate on euthanasia and death with dignity around the globe, especially with regard to whether physician-assisted suicide and euthanasia should be legitimized or legalized. Review of the literature reveals complex and often contradictory views about the Dutch experience. Some claim that the Netherlands offers a model for the world to follow; others believe that the Netherlands represents danger, rather than promise, and that the Dutch experience is the definitive answer regarding why we shouldnotmake active euthanasia and physician-assisted suicide part of our lives.

Having investigated the Dutch experience for a number of years, in the summer of 1999 I went to the Netherlands to visit the major centers of medical ethics as well as some research hospitals, and to speak with leading figures in euthanasia policy and practice. This essay commences by providing some background information on the practice of euthanasia and on the legal framework, and then reports the main answers to my first question: Why the Netherlands?
The Role of IRBs in Research Involving Commerical Biobanks
Authors: Rothstein Mark A.
Published: January 2007

In the post-genome world of biomedical research, an increasingly common research strategy is to focus on large repositories of biological specimens. There are now several well-known efforts to compile vast collections of biological materials, reanalyze extant samples, collect new ones, and link the samples to medical records. The significant issues of law, ethics, and policy raised by these research activities usually are heightened when commercial enterprises play a leading role in accumulating and distributing the samples. Emerging companies are not only compiling repositories for their own use, but some companies are positioning themselves to act as intermediaries, developing vast biobanks for sale to a wide range of other researchers.
Influence of Exposure to Light on the Sensorial Quality of Minimally Processed Cauliflower
Authors: Sanz Cervera Susana , Olarte Carmen , Echávarri J. Federico , Ayala Fernando
Published: January 2007

ABSTRACT:  The impact of lighting on minimally processed cauliflower packaged in 4 different film types (PVC and 3 P‐Plus) has been measured and quantified. The effect on the sensorial quality of storage at 4 °C in darkness and partial or continuous lighting was evaluated. The gas concentrations in the packages and the weight losses were also determined. Atmosphere composition inside the packages depended on both the permeability of the film used for the packaging and exposure to light. Samples stored with lighting maintained the gaseous exchange between plant tissue and the atmosphere inside the packages for longer periods than in samples kept in darkness. This prompted a greater loss of water vapor as well as the development of atmospheres with low levels of O2 and high levels of CO2 in the samples packed with less permeable films. The most important aspect in sensory evaluation was color. In instrumental color evaluation, coordinates h* and L* were the main means for estimating color evolution. The presence of light accelerated browning in the cut zones. The development of abnormal coloring in these areas marked the end of shelf life for minimally processed cauliflower. Among the sensory attributes studied, color was the most affected by exposure to light. Samples packed in P‐Plus 120 film displayed the lowest level of color deterioration in the cut zones. However, under lit conditions, the low permeability of this film caused atmospheres with very low O2 contents and high CO2 contents. These atmospheres produced a loss of texture and the development of off‐odors.
Iron‐Binding Properties, Amino Acid Composition, and Structure of Muscle Tissue Peptides from in vitro Digestion of Different Meat Sources
Authors: Storcksdieck S. , Bonsmann Genannt , Hurrell R. F.
Published: January 2007

ABSTRACT:  Background: The enhancing effect of meat on nonheme iron bioavailability in humans is thought to be due to the release of low‐molecular‐weight (LMW) iron‐binding peptides during digestion. Objective: To better characterize the LMW iron‐binding peptides from meat digests. Methods: Cooked beef, chicken, cod, lamb, and pork myofibrillar or sarcoplasmic protein extracts, casein, and egg albumin were digested in vitro with pepsin or pepsin/pancreatin. Ultrafiltrates were analyzed for N and iron and further characterized by gel filtration with added 59Fe, amino acid analysis, and LC‐MS. Results: 84% to 98% of total iron in enzymic digests was associated with soluble LMW peptides (< 10 kDa) of the myofibrillar proteins compared to only 2% to 20% in the corresponding sarcoplasmic protein digests. Pepsin digestion alone of the myobrillar proteins generated > 80% soluble LMW iron, compared to < 5% with casein and egg albumin. Iron‐binding peptides from myofibrillar protein with an estimated 2 kDa molecular mass were separated by gel filtration. Peptides in this fraction were enriched in aspartic and glutamic acid residues and included potential peptide fragments of myosin. Conclusion: LMW (< 10 kDa) peptides in enzyme digests of myofibrillar proteins were the major facilitators of iron solubility. Unlike with casein, egg albumin, and most sarcoplasmic proteins, these LMW peptides were generated on pepsin digestion. One group of iron‐binding peptides had a mass of approximately 2 kDa and was enriched in glutamic and aspartic acids. Such early generation of a multitude of LMW iron‐binding peptides could explain the enhancing effect of muscle tissue on iron absorption.
Processed and Prepared Corn Products As Sources of Lutein and Zeaxanthin: Compositional Variation in the Food Chain
Authors: De Oliveira Giovanna P. R. , Rodriguez‐Amaya Delia B.
Published: January 2007

ABSTRACT:  Widely consumed by populations of all socioeconomic classes worldwide, corn is one of the few food sources of lutein and zeaxanthin. However, data on these carotenoids in processed corn and corn as eaten are lacking. Thus, the major carotenoids in the principal brands of processed corn (canned corn, corn meal, corn flour, corn flake) and in typical corn dishes (farofa, boiled corn, pamonha, curau, fried and boiled polenta) were determined. There was marked variation between processed products and between brands of the same product, but variation between lots of the same brand was small. Canned corn had the highest zeaxanthin (11.91 to 18.06 μg/g), β‐cryptoxanthin (2.32 to 3.77 μg/g), and β‐carotene (1.79 to 2.75 μg/g) contents. The corn flake breakfast cereal had the second highest amount of zeaxanthin (9.08 to 12.77 μg/g). Corn meal had the highest lutein (4.02 to 7.62 μg/g) level and also had good zeaxanthin content (6.13 to 11.39 μg/g), but drastic reduction of all carotenoids, especially zeaxanthin, occurred when it was toasted to farofa. Boiled corn also had lower carotenoid levels compared to the raw corn. The wide variations in carotenoid concentrations appeared to be due mainly to varietal differences in the carotenoid composition of raw materials and to losses during processing and preparation for consumption.
Stability and Consumer Acceptance of Long‐Chain Omega‐3 Fatty Acids (Eicosapentaenoic Acid, 20:5, n‐3 and Docosahexaenoic Acid, 22:6, n‐3) in Cream‐Filled Sandwich Cookies
Authors: Borneo R. , Kocer D. , Ghai G. , Tepper B. J. , Karwe M. V.
Published: January 2007

ABSTRACT:  We formulated a filling for sandwich cookies containing 400 mg of eicosapentaenoic acid, 20:5, n‐3 (EPA) + docosahexaenoic acid, 22:6, n‐3 (DHA) encapsulated in a matrix of starch and gelatin. Cookies were stored at 2 different temperatures (18 °C and 35 °C) and under 2 different packaging conditions (atmospheric and vacuum packed) for 28 d. At regular intervals, cookies were analyzed for moisture, water activity, and concentrations of EPA, DHA, and dienes. Results showed that there were no significant losses of EPA and DHA during storage under the conditions of study. A maximum loss of 5% was observed after 28 d of storage. The concentration of dienes obtained under different conditions were low (< 25 mmol/kg) as compared to a salmon oil sample with appreciable signs of oxidation (600 mmol/kg). Sensory evaluation of cookies by an untrained panel of healthy consumers and ulcerative colitis patients revealed no aftertaste and high acceptability of the cookies. Our results demonstrated that it is possible to make shelf‐stable fortified foods with high levels of long‐chain ω3FA.
Recombination and the Nature of Bacterial Speciation
Authors: Fraser Christophe , Hanage William P. , Spratt Brian G.
Published: January 2007

Genetic surveys reveal the diversity of bacteria and lead to the questioning of species concepts used to categorize bacteria. One difficulty in defining bacterial species arises from the high rates of recombination that results in the transfer of DNA between relatively distantly related bacteria. Barriers to this process, which could be used to define species naturally, are not apparent. Here, we review conceptual models of bacterial speciation and describe our computer simulations of speciation. Our findings suggest that the rate of recombination and its relation to genetic divergence have a strong influence on outcomes. We propose that a distinction be made between clonal divergence and sexual speciation. Hence, to make sense of bacterial diversity, we need data not only from genetic surveys but also from experimental determination of selection pressures and recombination rates and from theoretical models.
Strong Relationship Between DMS and the Solar Radiation Dose over the Global Surface Ocean
Authors: Vallina Sergio M. , Simó Rafel
Published: January 2007

Marine biogenic dimethylsulfide (DMS) is the main natural source of tropospheric sulfur, which may play a key role in cloud formation and albedo over the remote ocean. Through a global data analysis, we found that DMS concentrations are highly positively correlated with the solar radiation dose in the upper mixed layer of the open ocean, irrespective of latitude, plankton biomass, or temperature. This is a necessary condition for the feasibility of a negative feedback in which light-attenuating DMS emissions are in turn driven by the light dose received by the pelagic ecosystem.
The Neural Basis of Loss Aversion in Decision-Making Under Risk
Authors: Tom Sabrina M. , Fox Craig R. , Trepel Christopher , Poldrack Russell A.
Published: January 2007

People typically exhibit greater sensitivity to losses than to equivalent gains when making decisions. We investigated neural correlates of loss aversion while individuals decided whether to accept or reject gambles that offered a 50/50 chance of gaining or losing money. A broad set of areas (including midbrain dopaminergic regions and their targets) showed increasing activity as potential gains increased. Potential losses were represented by decreasing activity in several of these same gain-sensitive areas. Finally, individual differences in behavioral loss aversion were predicted by a measure of neural loss aversion in several regions, including the ventral striatum and prefrontal cortex.
Asymmetric Inheritance of Mother Versus Daughter Centrosome in Stem Cell Division
Authors: Yamashita Yukiko M. , Mahowald Anthony P. , Perlin Julie R. , Fuller Margaret T.
Published: January 2007

Adult stem cells often divide asymmetrically to produce one self-renewed stem cell and one differentiating cell, thus maintaining both populations. The asymmetric outcome of stem cell divisions can be specified by an oriented spindle and local self-renewal signals from the stem cell niche. Here we show that developmentally programmed asymmetric behavior and inheritance of mother and daughter centrosomes underlies the stereotyped spindle orientation and asymmetric outcome of stem cell divisions in the
Drosophila
male germ line. The mother centrosome remains anchored near the niche while the daughter centrosome migrates to the opposite side of the cell before spindle formation.
Damage to the Insula Disrupts Addiction to Cigarette Smoking
Authors: Naqvi Nasir H. , Rudrauf David , Damasio Hanna , Bechara Antoine
Published: January 2007

A number of brain systems have been implicated in addictive behavior, but none have yet been shown to be necessary for maintaining the addiction to cigarette smoking. We found that smokers with brain damage involving the insula, a region implicated in conscious urges, were more likely than smokers with brain damage not involving the insula to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking.
Comment on "Evolutionary Paths Underlying Flower Color Variation inAntirrhinum"
Authors: Rausher Mark D.
Published: January 2007

Although Whibleyet al. (Reports, 18 August 2006, p. 963) argue for the presence of high-fitness ridges in theAntirrhinumfloral-color adaptive landscape, their data are equally compatible with adaptive landscapes having a single peak and no ridges. Their demonstration of divergent selection across a hybrid zone argues against the presence of adaptive ridges.
Riffs on Numerical Themes
Authors: Bohannon John
Published: January 2007

Codebook
.
Rudresh Mahanthappa Quartet ()
. Pi Recordings, New York, 2006. CD. $14.

A jazz quartet presents compositions that reflect number theory.
Necrotizing Fasciitis fromVibrio vulnificusin a Patient with Undiagnosed Hepatitis and Cirrhosis
Authors: Muldrew Kenneth L. , Miller Russell R. , Kressin Megan , Tang Yi-Wei , Stratton Charles
Published: January 2007

Necrotizing fasciitis due toVibrio vulnificusmay result in overwhelming sepsis, leading to death in some patients. Significant risk factors for severe disease include preexisting liver disease. We report a case ofVibrio vulnificusnecrotizing fasciitis in a patient with previously undiagnosed chronic hepatitis and cirrhosis.
Molecular and Spatial Epidemiology of Cryptosporidiosis in Children in a Semiurban Community in South India
Authors: Ajjampur Sitara Swarna Rao , Gladstone Beryl Primrose , Selvapandian David , Muliyil Jaya Prakash , Ward Honorine , Kang Gagandeep
Published: January 2007

Cryptosporidium
spp. are a leading cause of diarrhea in Indian children, but there are no data for prevalent species or subgenotypes. Genetic characterization of
Cryptosporidium
spp. by PCR-restriction fragment length polymorphism and spatial analysis of cases using Geographical Information Systems technology was carried out for 53 children with cryptosporidial diarrhea in an urban slum. The two most common species were
C. hominis
(81%) and
C. parvum
(12%). Other species identified were
C. felis
and
C. parvum
(mouse genotype). Five subgenotypes were identified at the
Cpgp40/15
locus. Subgenotype Ia predominated among
C. hominis
isolates, and all
C. parvum
isolates were subgenotype Ic.
C. hominis
infection was associated with a greater severity of diarrhea. Sequencing of the
Cpgp40/15
alleles of
C. felis
and
C. parvum
(mouse genotype) revealed similarities to subgenotype IIa and
C. meleagridis
, respectively. Space-time analysis revealed two clusters of infection due to
C. hominis
Ia, with a peak in February 2005. This is the first study to demonstrate space-time clustering of a single subgenotype of
C. hominis
in a setting where cryptosporidiosis is endemic. Molecular characterization and spatial analysis have the potential to further the understanding of disease and transmission in the community.
Multicenter Beta Trial of the GeneXpert Enterovirus Assay
Authors: Kost Christine B. , Rogers Beverly , Oberste M. Steven , Robinson Christine , Eaves Brenda L. , Leos Kristi , Danielson Susan , Satya Malini , Weir Fred , Nolte Frederick S.
Published: January 2007

The GeneXpert Dx system (Cepheid, Sunnyvale, CA) is a fully integrated and automated nucleic acid sample preparation, amplification, and real-time detection system. It consists of an instrument, a personal computer, and disposable fluidic cartridges. The analytical sensitivity and specificity of the GeneXpert enterovirus assay (GXEA) were determined with a panel of 63 different enterovirus serotypes and 24 other microorganisms, respectively. The potential for blood, hemoglobin, white blood cells, and excess protein to interfere with the assay was also assessed. The performance parameters of the GXEA were determined at three sites with 102 cerebrospinal fluid (CSF) samples obtained from patients with suspected meningitis. All samples were tested for enterovirus RNA with locally developed reverse transcription-PCR (RT-PCR) assays at the trial sites and with a seminested RT-PCR and an analyte-specific reagent (Cepheid) at a reference laboratory. The 5′ nontranslated region was the target for all of the PCR assays except the seminested RT-PCR, which amplified a VP1 sequence. The VP1 amplicon was sequenced to identify the enterovirus types. Consensus reference laboratory RT-PCR results were used to classify cases of enteroviral meningitis. The GXEA detected all of the enterovirus serotypes and none of the other microorganisms tested except rhinovirus 16. The assay was unaffected by moderate amounts of blood or blood components. Thirty-six (35%) of the CSF samples tested had at least one positive PCR result. Eleven different enterovirus serotypes were identified in the positive samples. The GXEA had a sensitivity of 97.1% (95% confidence interval [CI], 84.7 to 99.9%) and a specificity of 100% (95% CI, 94.6 to 100%) for the diagnosis of enteroviral meningitis.
Isolation of
Mycoplasma genitalium
from First-Void Urine Specimens by Coculture with Vero Cells
Authors: Hamasuna Ryoichi , Osada Yukio , Jensen Jørgen Skov
Published: January 2007

Isolation of
Mycoplasma genitalium
from clinical specimens remains difficult. We describe an improvement of the Vero cell coculture method in which the growth of
M. genitalium
was monitored by quantitative real-time PCR. Four new
M. genitalium
strains were isolated from six first-void urine specimens of male Japanese patients with urethritis. In two of them, only
M. genitalium
was detected: one also contained
Ureaplasma urealyticum
, and one contained
Chlamydia trachomatis
,
Neisseria gonorrhoeae
,
U. urealyticum
, and
Ureaplasma parvum
. In the specimens yielding isolates of
M. genitalium
, growth was documented by quantitative PCR after two to five passages in Vero cells. The complete isolation procedure from the initial inoculation to completion of single-colony cloning took about 1 year. Isolation of
M. genitalium
from urine specimens proved to be more difficult than from swab specimens. Due to the cytotoxic effect of urine, a procedure involving washing of the urinary sediment was introduced. Furthermore, prolonged storage of the urine specimens before culture was shown to be detrimental to the success of isolation, as shown by the lack of success in attempts to isolate
M. genitalium
from mailed urine specimens as well as by simulation experiments. High concentrations of penicillin G and amphotericin B were surprisingly inhibitory to the growth of wild-type
M. genitalium
strains, but penicillin G at 200 IU/ml and polymyxin B at 500 μg/ml could be used as selective antibiotics to avoid bacterial overgrowth in the Vero cell cultures.
Identification of Variable-Number Tandem-Repeat (VNTR) Sequences in
Legionella pneumophila
and Development of an Optimized Multiple-Locus VNTR Analysis Typing Scheme
Authors: Pourcel Christine , Visca Paolo , Afshar Baharak , D'Arezzo Silvia , Vergnaud Gilles , Fry Norman K.
Published: January 2007

The utility of a genotypic typing assay for
Legionella pneumophila
was investigated. A multiple-locus variable number of tandem repeats (VNTR) analysis (MLVA) scheme using PCR and agarose gel electrophoresis is proposed based on eight minisatellite markers. Panels of well-characterized strains were examined in a multicenter analysis to validate the assay and to compare its performance to that of other genotyping assays. Excellent typeability, reproducibility, stability, and epidemiological concordance were observed. The MLVA type or profile is composed of a string of allele numbers, corresponding to the number of repeats at each VNTR locus, separated by commas, in a predetermined order. A database containing information from 99
L. pneumophila
serogroup 1 strains and four strains of other serogroups and their MLVA profiles, which can be queried online, is available from
http://bacterial-genotyping.igmors.u-psud.fr/
.
Staphylococcus aureus
Strains Isolated from Bloodstream Infections Changed Significantly in 2006
Authors: van der Mee-Marquet Nathalie , Epinette Christophe , Loyau Jeremy , Arnault Laurence , Domelier Anne-Sophie , Losfelt Barbara , Girard Nicole , Quentin Roland ,   and the Bloodstream Infection Study Group of the Relais d'Hygiène du Centre
Published: January 2007

We studied 358
Staphylococcus aureus
strains isolated from bloodstream infections (BSI) observed during an epidemiological study covering 2,007,681 days of hospitalization in 32 healthcare institutions (HCIs) between 2004 and 2006. The strains were tested for antibiotic susceptibility and characterized genetically. The incidence of
S. aureus
BSI declined regularly through 2004 and 2005 and then significantly increased in 2006 (+80%). This was largely due to an increase in BSI involving methicillin-sensitive
S. aureus
(MSSA) strains and nonmultiresistant methicillin-resistant
S. aureus
(NORSA) strains. Ninety-six percent of the NORSA strains were resistant only to methicillin and fluoroquinolones. Most of the MSSA strains belonged to a small number of pulsed-field gel electrophoresis (PFGE) divisions and were associated with epidemic phenomena in HCIs. The NORSA strains also clustered into a limited number of PFGE divisions but could not be related to any local outbreak in HCIs. In 2006, there was a significant increase in the incidence of BSI associated with
tst
gene-positive MSSA strains (+275%) and the first three BSI associated with
tst
gene-positive MRSA were observed. PFGE data revealed a limited heterogeneity among the
tst
gene-positive strains without any outbreak in the HCIs. Our study underlines the need for infection control teams to focus efforts on preventing both MRSA and MSSA BSI. As recently demonstrated in vitro, fluoroquinolones may enhance horizontal transfer of virulence and antibiotic resistance genes. These antibiotics are widely used in France, so our findings raise the issue of whether their use has contributed to the acquisition of
mecA
and
tst
genes by
S. aureus
strains.
Lymphogranuloma Venereum in Australia: AnorectalChlamydia trachomatisSerovar L2b in Men Who Have Sex with Men
Authors: Stark D. , van Hal S. , Hillman R. , Harkness J. , Marriott D.
Published: January 2007

Lymphogranuloma venereum (LGV) is a sexually transmitted infection that is causing an ongoing epidemic in men who have sex with men (MSM) in Europe, the United Kingdom, and North America. Twenty-nine rectal swabs positive forChlamydia trachomatiswere analyzed by real-time PCR for the presence of LGV serovars. Genotyping revealed an identical L2b serovar from four specimens. All patients were MSM and human immunodeficiency virus infected. Three of the four presented with severe ulcerative proctitis. We report a cluster of rectal LGV serovar L2b infections in Sydney, Australia.
Virus-Like Particle Vaccine Induces Protective Immunity against Homologous and Heterologous Strains of Influenza Virus
Authors: Quan Fu-Shi , Huang Chunzi , Compans Richard W. , Kang Sang-Moo
Published: January 2007

Recurrent outbreaks of highly pathogenic avian influenza virus pose the threat of pandemic spread of lethal disease and make it a priority to develop safe and effective vaccines. Influenza virus-like particles (VLPs) have been suggested to be a promising vaccine approach. However, VLP-induced immune responses, and their roles in inducing memory immune responses and cross-protective immunity have not been investigated. In this study, we developed VLPs containing influenza virus A/PR8/34 (H1N1) hemagglutinin (HA) and matrix (M1) proteins and investigated their immunogenicity, long-term cross-protective efficacy, and effects on lung proinflammatory cytokines in mice. Intranasal immunization with VLPs containing HA induced high serum and mucosal antibody titers and neutralizing activity against PR8 and A/WSN/33 (H1N1) viruses. Mice immunized with VLPs containing HA showed little or no proinflammatory lung cytokines and were protected from a lethal challenge with mouse-adapted PR8 or WSN viruses even 5 months postimmunization. Influenza VLPs induced mucosal immunoglobulin G and cellular immune responses, which were reactivated rapidly upon virus challenge. Long-lived antibody-secreting cells were detected in the bone marrow of immunized mice. Immune sera administered intranasally were able to confer 100% protection from a lethal challenge with PR8 or WSN, which provides further evidence that anti-HA antibodies are primarily responsible for preventing infection. Taken together, these results indicate that nonreplicating influenza VLPs represent a promising strategy for the development of a safe and effective vaccine to control the spread of lethal influenza viruses.
Vaccine-Induced T Cells Control Reversion of AIDS Virus Immune Escape Mutants
Authors: Fernandez Caroline S. , Smith Miranda Z. , Batten C. Jane , De Rose Robert , Reece Jeanette C. , Rollman Erik , Venturi Vanessa , Davenport Miles P. , Kent Stephen J.
Published: January 2007

Many current-generation human immunodeficiency virus (HIV) vaccines induce specific T cells to control acute viremia, but their utility following infection with escape mutant virus is unclear. We studied reversion to wild type of an escape mutant simian-HIV in major histocompatibility complex-matched vaccinated pigtail macaques. High levels of vaccine-induced CD8
+
T cells strongly correlated with maintenance of escape mutant virus during acute infection. Interestingly, in animals with lower CD8
+
T-cell levels, transient reversion to wild-type virus resulted in better postacute control of viremia. Killing of wild-type virus facilitated by transient reversion outweighs the benefit of a larger CD8
+
T-cell response that only maintains the less fit escape mutant virus. These findings have important implications for the further development of T-cell-based HIV vaccines where exposure to escape mutant viruses is common.
Spindles of an Entomopoxvirus Facilitate Its Infection of the Host Insect by Disrupting the Peritrophic Membrane
Authors: Mitsuhashi Wataru , Kawakita Hiromu , Murakami Ritsuko , Takemoto Yutaka , Saiki Tomoaki , Miyamoto Kazuhisa , Wada Sanae
Published: January 2007

The mode of action by which entomopoxvirus (EPV) spindles, proteinaceous crystalline bodies produced by EPVs, enhance EPV infection has not been clarified. We fed
Anomala cuprea
EPV (AcEPV) spindles to host insects; subsequent scanning electron microscopy revealed the disruption of the peritrophic membranes (PMs) of these insects. The PM is reportedly a barrier against the infection of some insects by viruses. Quantitative PCR of AcEPV DNA in the ectoperitrophic area revealed that PM disruption facilitated the passage of EPVs through the PM toward the initial infection site, the midgut epithelium. These results indicate that EPV spindles enhance infection by EPVs by disrupting the PM in the host insects. Fusolin is almost exclusively the constituent protein of the spindles and is the enhancing factor of the infectivity of nucleopolyhedroviruses (NPVs) and possibly that of EPVs. Spheroid is another type of proteinaceous crystalline structure produced by EPVs.
Pseudaletia separata
EPV (PsEPV) spheroids reportedly contain considerable amounts of fusolin and enhance NPV infection. We assessed the ability of AcEPV spheroids to enhance EPV infectivity and their effect on the PM and carried out immunological experiments; these experiments showed that AcEPV spheroids contain little or no fusolin and are biologically inactive, in contrasts to the situation in PsEPV.
Respiratory Syncytial Virus NS1 Protein Degrades STAT2 by Using the Elongin-Cullin E3 Ligase
Authors: Elliott Joanne , Lynch Oonagh T. , Suessmuth Yvonne , Qian Ping , Boyd Caroline R. , Burrows James F. , Buick Richard , Stevenson Nigel J. , Touzelet Olivier , Gadina Massimo , Power Ultan F. , Johnston James A.
Published: January 2007

Respiratory syncytial virus (RSV) infection causes bronchiolitis and pneumonia in infants. RSV has a linear single-stranded RNA genome encoding 11 proteins, 2 of which are nonstructural (NS1 and NS2). RSV specifically downregulates STAT2 protein expression, thus enabling the virus to evade the host type I interferon response. Degradation of STAT2 requires proteasomal activity and is dependent on the expression of RSV NS1 and NS2 (NS1/2). Here we investigate whether RSV NS proteins can assemble ubiquitin ligase (E3) enzymes to target STAT2 to the proteasome. We demonstrate that NS1 contains elongin C and cullin 2 binding consensus sequences and can interact with elongin C and cullin 2 in vitro; therefore, NS1 has the potential to act as an E3 ligase. By knocking down expression of specific endogenous E3 ligase components using small interfering RNA, NS1/2, or RSV-induced STAT2, degradation is prevented. These results indicate that E3 ligase activity is crucial for the ability of RSV to degrade STAT2. These data may provide the basis for therapeutic intervention against RSV and/or logically designed live attenuated RSV vaccines.
Control of Human Immunodeficiency Virus Type 1 Is Associated with HLA-B*13 and Targeting of Multiple Gag-Specific CD8+T-Cell Epitopes
Authors: Honeyborne Isobella , Prendergast Andrew , Pereyra Florencia , Leslie Alasdair , Crawford Hayley , Payne Rebecca , Reddy Shabashini , Bishop Karen , Moodley Eshia , Nair Kriebashnie , van der Stok Mary , McCarthy Noel , Rousseau Christine M. , Addo Marylyn , Mullins James I. , Brander Christian , Kiepiela Photini , Walker Bruce D. , Goulder Philip J. R.
Published: January 2007

To better understand relationships between CD8+T-cell specificity and the immune control of human immunodeficiency virus type 1 (HIV-1), we analyzed the role of HLA-B*13, an allele associated with low viremia, in a cohort of 578 C clade-infected individuals in Durban, South Africa. Six novel B*13-restricted cytotoxic T lymphocyte epitopes were defined from analyses of 37 B*13-positive subjects, including three Gag epitopes. These B*13-restricted epitopes contribute to a broad Gag-specific CD8+response that is associated with the control of viremia. These data are consistent with data from studies of other HLA-class I alleles associated with HIV control that have shown that the targeting of multiple Gag epitopes is associated with relative suppression of viremia.
BOSE–EINSTEIN CONDENSATES IN THE LOWEST LANDAU LEVEL: HAMILTONIAN DYNAMICS
Authors: NIER F.
Published: January 2007

In a previous article with A. Aftalion and X. Blanc, it was shown that the hypercontractivity property of the dilation semigroup in spaces of entire functions was a key ingredient in the study of the Lowest Landau Level model for fast rotating Bose–Einstein condensates. That former work was concerned with the stationary constrained variational problem. This article is about the nonlinear Hamiltonian dynamics and the spectral stability of the constrained minima with motivations arising from the description of Tkatchenko modes of Bose–Einstein condensates. Again the hypercontractivity property provides a very strong control of the nonlinear term in the dynamical analysis.
NONCOMMUTATIVE HOMOTOPY ALGEBRAS ASSOCIATED WITH OPEN STRINGS
Authors: KAJIURA HIROSHIGE
Published: January 2007

We discuss general properties of A∞-algebras and their applications to the theory of open strings. The properties of cyclicity for A∞-algebras are examined in detail. We prove the decomposition theorem, which is a stronger version of the minimal model theorem, for A∞-algebras and cyclic A∞-algebras and discuss various consequences of it. In particular, it is applied to classical open string field theories and it is shown that all classical open string field theories on a fixed conformal background are cyclic A∞-isomorphic to each other. The same results hold for classical closed string field theories, whose algebraic structure is governed by cyclic L∞-algebras.
THE DYNAMICS OF GAMES OF INNOVATION
Authors: MILLER ROGER , OLLEROS XAVIER
Published: January 2007

Many executives see innovation as an unmanageable process, riddled with risks. The research we conducted with the Industrial Research Institute, interviewing over 200 vice-presidents of research and development and chief technical officers in many sectors around the world, yields a more nuanced view. Innovation becomes manageable once managers move away from normative prescriptions that view the process as uniform and recognise that different rules and practices apply to different circumstances.

Our argument is that clusters of interdependent firms contributing to the building of a set of interacting products and services tend to self-organise themselves into distinct and relatively persistent "games of innovation". Such games operate at a meso level of analysis, grouping together many complementary agents, such as competitors, suppliers, public regulators, universities, innovation-support agencies, and venture capitalists. Six games of innovation, each with a distinct set of rules for innovating, have been identified around value-creation exchanges between buyers and sellers. Three games focus on market creation: "patent-driven discovery", "systems integration" and "platform orchestration". Market maintenance games are "cost-based competition", "systems extension and engineering" and "customised mass production".

The perspective proposed in this paper recognises that heterogeneous innovation patterns and strategies can coexist within a single industrial sector and that the same game can be played in many sectors. Specific conditions call for distinct rules and practices. Customer expectations, for example, are central in some games but almost irrelevant in others. Rules for managing innovation are neither generic best practices that can be applied universally nor narrow industry recipes. They are game- and role-specific ways to create and capture market value.
GAMES OF INNOVATION: THE ROLES OF NONPROFIT ORGANISATIONS
Authors: DALZIEL MARGARET
Published: January 2007

Games of innovation involve four types of organisational players: firms, governments, universities, and nonprofit organisations. Of the four, nonprofit organisations are the least well understood. To capture the contributions of all types of organisational players, I adopt the perspective of a focal firm and consider the roles that other organisations play with respect to its ability to innovate. I introduce the roles of institutional enabler and institutional balancer, in which another organisation increases or decreases, respectively, the focal firm's ability to innovate by shaping the networks and markets in which it participates. I then develop propositions regarding the importance of the institutional enabler and balancer roles, and the roles of nonprofit organisations, in games of innovation.
Reversible and irreversible interactions of DIDS with the human electrogenic Na/HCO3 cotransporter NBCe1-A: role of lysines in the KKMIK motif of TM5
Authors: Lu Jing , Boron Walter F.
Published: January 2007

Others have shown that H2DIDS reversibly and covalently binds to the first lysine (K) in the SKLIK motif at the extracellular end of transmembrane segment 5 of the Cl-HCO3 exchanger AE1. Here we mutated K558, K559, and/or K562 in the homologous KKMIK motif of human NBCe1-A. We expressed constructs in Xenopus oocytes, and used a two-electrode voltage clamp to test the sensitivity of the NBC current (−160 to +20 mV) to DIDS. A 30-s DIDS exposure decreased the current at 0 mV, and a subsequent albumin wash returned the current to the initial value (less any irreversible DIDS inhibition), permitting the determination of a complete dose-response curve on a single oocyte. For all constructs, the reversible DIDS inhibition of the NBC current decreased at more negative voltages. The apparent inhibitory constant for reversible DIDS binding increased in the sequence RRMIR < KKMIK ( wt, ∼40 μM) < NKMIK ≅ NKMIN ≅ KKMIN < KNMIN ≅ KNMIK < NNMIK < NNMIN (∼400 μM) < DDMID < EEMIE (∼800 μM). Thus the second K is the most important for reversible DIDS blockade. Nevertheless, these mutations had relatively little effect on slope conductance in the absence of DIDS. For KKMIK, RRMIR, NKMIK, KKMIN, KNMIK, and NNMIN, the rates of irreversible inhibition by DIDS roughly parallel the apparent affinities for reversible DIDS binding. The rate was extremely low for DDMID. The fitted maximal inhibitions were 80–91% for the first five constructs, and 66% for NNMIN. Thus DIDS probably reversibly binds before irreversibly reacting with NBCe1-A. Finally, tenidap blocks not only KKMIK, but also NNMIN and EEMIE.
Glucocorticoids stimulate ENaC upregulation in bovine mammary epithelium
Authors: Quesnell Rebecca R. , Han Xiaobin , Schultz Bruce D.
Published: January 2007

Mammary epithelia produce an isotonic, low-Na+ fluid that is rich in nutrients. Mechanisms that account for the low electrolyte concentration have not been elucidated, although amiloride-sensitive ion transport has been reported in some situations. We hypothesized that corticosteroid exposure modulates epithelial Na+ channel (ENaC) expression and/or activity in bovine mammary epithelial cells. BME-UV cells were grown to confluent monolayers on permeable supports with a standard basolateral medium and apical medium of low-electrolyte, high-lactose composition that resembles the ionic composition of milk. Ion transport was assessed in modified Ussing flux chambers. Exposure to glucocorticoids (dexamethasone, cortisol, or prednisolone), but not aldosterone, increased short-circuit current ( Isc), a sensitive measure of net ion transport, whereas apical exposure to amiloride or benzamil reduced corticosteroid-induced Isc close to basal levels. Quantitative RT-PCR indicated a glucocorticoid-induced increase in mRNA for β- and γ-ENaC, whereas α-ENaC mRNA expression was only mildly affected. Exposure to mifepristone (a glucocorticoid receptor antagonist), but not spironolactone (a mineralocorticoid receptor antagonist), precluded both the corticosteroid-induced elevation in amiloride-sensitive Isc and the induced changes in β- and γ-ENaC mRNA. We conclude that Na+ movement across mammary epithelia is modulated by corticosteroids via a glucocorticoid receptor-mediated mechanism that regulates the expression of the β- and γ-subunits of ENaC. ENaC expression and activity could account for the low Na+ concentration that is typical of milk.
Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice
Authors: Laschke Matthias W. , Menger Michael D. , Wang Yusheng , Lindell Gert , Jeppsson Bengt , Thorlacius Henrik
Published: January 2007

Cholestasis is a major complication in sepsis although the underlying mechanisms remain elusive. The aim of this study was to evaluate the role of P-selectin and leukocyte recruitment in endotoxemia-associated cholestasis. C57BL/6 mice were challenged intraperitoneally with endotoxin (0.4 mg/kg), and 6 h later the common bile duct was cannulated for determination of bile flow and biliary excretion of bromosulfophthalein. Mice were pretreated with an anti-P-selectin antibody or an isotype-matched control antibody. Leukocyte infiltration was determined by measuring hepatic levels of myeloperoxidase. Tumor necrosis factor-α and CXC chemokines in the liver was determined by ELISA. Liver damage was monitored by measuring serum levels of alanine aminotransferase and aspartate aminotransferase. Apoptosis was quantified morphologically by nuclear condensation and fragmentation using Hoechst 33342 staining. Endotoxin induced a significant inflammatory response with increased TNF-α and CXC chemokine concentrations, leukocyte infiltration, liver enzyme release, and apoptotic cell death. This response was associated with pronounced cholestasis indicated by a >70% decrease of bile flow and biliary excretion of bromosulfophthalein. Immunoneutralization of P-selectin significantly attenuated endotoxin-induced leukocyte infiltration reflected by a >60% reduction of hepatic myeloperoxidase levels. Interference with P-selectin decreased endotoxin-mediated hepatocellular apoptosis and necrosis, but did not affect hepatic levels of tumor necrosis factor-α and CXC chemokines. Of interest, inhibition of P-selectin restored bile flow and biliary excretion of bromosulfophthalein to normal levels in endotoxin-challenged animals. Our study demonstrates for the first time that P-selectin-mediated recruitment of leukocytes, but not the local production of proinflammatory mediators, is the primary cause of cholestasis in septic liver injury.
Giant Spontaneous Depolarizing Potentials in the Developing Thalamic Reticular Nucleus
Authors: Pangratz-Fuehrer Susanne , Rudolph Uwe , Huguenard John R.
Published: January 2007

The thalamic reticular nucleus (nRt) provides a major source of inhibition in the thalamo-cortical circuit and is critically involved in the generation of spindle oscillations. Here we describe the properties of thalamic giant depolarizing potentials (tGDPs) that were observed in nRt during early development. tGDPs persisted in presence of ionotropic glutamate antagonists but were completely abolished by GABAAR antagonist SR 35591. tGDPs occurred primarily between p3 and p8 (in 30–50% of cells) and occasionally up until p15. tGDPs lasted 0.4–3 s with peak conductances of 2–13 nS and occurred at frequencies between 0.02 and 0.06 Hz. We used mice with a benzodiazepine-insensitive α3 subunit [α3(H126R)] to probe for the identity of the GABA receptors responsible for tGDP generation. Benzodiazepine enhancement of tGDP amplitude and duration persisted in nRt neurons in α3(H126R) mice, indicating that the GABAARs containing α3 are not critical for tGDP generation and suggesting that tGDPs are mediated by GABAARs containing the α5 subunit, which is transiently expressed in nRt neurons in early postnatal development. Furthermore we found that exogenous GABA application depolarized nRt neurons younger than p8, indicating elevated [Cl−]i at this developmental stage. Taken together, these data suggest that in immature nRt, long-lasting depolarizing responses mediated by GABA receptors could trigger Ca2+ entry and play a role in functional development of the spindle-generating circuitry.
Properties of Shape Tuning of Macaque Inferior Temporal Neurons Examined Using Rapid Serial Visual Presentation
Authors: De Baene Wouter , Premereur Elsie , Vogels Rufin
Published: January 2007

We used rapid serial visual presentation (RSVP) to examine the tuning of macaque inferior temporal cortical (IT) neurons to five sets of 25 shapes each that varied systematically along predefined shape dimensions. A comparison of the RSVP technique using 100-ms presentations with that using a longer duration showed that shape preference can be determined with RSVP. Using relatively complex shapes that vary along relatively simple shape dimensions, we found that the large majority of neurons preferred extremes of the shape configuration, extending the results of a previous study using simpler shapes and a standard testing paradigm. A population analysis of the neuronal responses demonstrated that, in general, IT neurons can represent the similarities among the shapes at an ordinal level, extending a previous study that used a smaller number of shapes and a categorization task. However, the same analysis showed that IT neurons do not faithfully represent the physical similarities among the shapes. The responses to the two-part shapes could be predicted, virtually perfectly, from the average of the responses to the respective two parts presented in isolation. We also showed that IT neurons adapt to the stimulus distribution statistics. The neural shape discrimination improved when a shape set with a narrower stimulus range was presented, suggesting that the tuning of IT neurons is not static but adapts to the stimulus distribution statistics, at least when stimulated at a high rate with a restricted set of stimuli.
Contextual Interaction of GABAergic Circuitry With Dynamic Synapses
Authors: Khanbabaie Reza , Mahani Alireza S. , Wessel Ralf
Published: January 2007

Visual context shapes human perception, yet our understanding of this phenomenon in terms of synaptic circuitry is still rudimentary. Our in vitro experiments with avian tectum reveal two distinct GABAergic pathways that mediate the spatiotemporal tectal interaction of retinal inputs. One pathway mediates postsynaptic lateral inhibition. The other pathway interacts with the synaptic depression of retinotectal synapses. Simulations of an experimentally constrained model including the two pathways reproduce the observed avian tectum wide-field neuron's sensitivity to small and moving stimuli, while being insensitive to whole-field motion.