bluuebunny/crossref_metadata_2025 huggingface dataset:
RNA Polymerase I Transcription Silences Noncoding RNAs at the Ribosomal DNA Locus in Saccharomyces cerevisiae
Authors: Cesarini Elisa , Mariotti Francesca Romana , Cioci Francesco , Camilloni Giorgio
Published: December 2009

In
Saccharomyces cerevisiae
the repeated units of the ribosomal locus, transcribed by RNA polymerase I (Pol I), are interrupted by nontranscribed spacers (NTSs). These NTS regions are transcribed by RNA polymerase III to synthesize 5S RNA and by RNA polymerase II (Pol II) to synthesize, at low levels, noncoding RNAs (ncRNAs). While transcription of both RNA polymerase I and III is highly characterized, at the ribosomal DNA (rDNA) locus only a few studies have been performed on Pol II, whose repression correlates with the
SIR2
-dependent silencing. The involvement of both chromatin organization and Pol I transcription has been proposed, and peculiar chromatin structures might justify “ribosomal” Pol II silencing. Reporter genes inserted within the rDNA units have been employed for these studies. We studied, in the natural context, yeast mutants differing in Pol I transcription in order to find whether correlations exist between Pol I transcription and Pol II ncRNA production. Here, we demonstrate that silencing at the rDNA locus represses ncRNAs with a strength inversely proportional to Pol I transcription. Moreover, localized regions of histone hyperacetylation appear in cryptic promoter elements when Pol II is active and in the coding region when Pol I is functional; in addition, DNA topoisomerase I site-specific activity follows RNA polymerase I transcription. The repression of ncRNAs at the rDNA locus, in response to RNA polymerase I transcription, could represent a physiological circuit control whose mechanism involves modification of histone acetylation.
Global Gene Expression Analysis during Sporulation of the Aquatic Fungus Blastocladiella emersonii
Authors: Vieira André L. G. , Gomes Suely L.
Published: December 2009

The
Blastocladiella emersonii
life cycle presents a number of drastic biochemical and morphological changes, mainly during two cell differentiation stages: germination and sporulation. To investigate the transcriptional changes taking place during the sporulation phase, which culminates with the production of the zoospores, motile cells responsible for the dispersal of the fungus, microarray experiments were performed. Among the 3,773 distinct genes investigated, a total of 1,207 were classified as differentially expressed, relative to time zero of sporulation, at at least one of the time points analyzed. These results indicate that accurate transcriptional control takes place during sporulation, as well as indicating the necessity for distinct molecular functions throughout this differentiation process. The main functional categories overrepresented among upregulated genes were those involving the microtubule, the cytoskeleton, signal transduction involving Ca
2+
, and chromosome organization. On the other hand, protein biosynthesis, central carbon metabolism, and protein degradation were the most represented functional categories among downregulated genes. Gene expression changes were also analyzed in cells sporulating in the presence of subinhibitory concentrations of glucose or tryptophan. Data obtained revealed overexpression of microtubule and cytoskeleton transcripts in the presence of glucose, probably causing the shape and motility problems observed in the zoospores produced under this condition. In contrast, the presence of tryptophan during sporulation led to upregulation of genes involved in oxidative stress, proteolysis, and protein folding. These results indicate that distinct physiological pathways are involved in the inhibition of sporulation due to these two classes of nutrient sources.
Associations between Mucosal Innate and Adaptive Immune Responses and Resolution of Diarrheal Pathogen Infections
Authors: Long Kurt Z. , Rosado Jorge L. , Santos José Ignacio , Haas Meredith , Al Mamun Abdullah , DuPont Herbert L. , Nanthakumar Nanda N. , Estrada-Garcia Teresa
Published: December 2009

The identification of immune response mechanisms that contribute to the control of diarrheal disease in developing countries remains an important priority. We addressed the role of fecal chemokines and cytokines in the resolution of diarrhealEscherichia coliandGiardia lambliainfections. Stools collected from 127 Mexican children 5 to 15 months of age enrolled in a randomized, double-blind, placebo-controlled, vitamin A supplementation trial were screened for enteropathogenicEscherichia coli(EPEC), enterotoxigenicE. coli(ETEC), andGiardia lamblia. Fecal concentrations of tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-4 (IL-4), IL-5, IL-6, IL-8, IL-10, and interferon-γ (IFN-γ) were determined. Hazard models incorporating cytokine variables were fit to durations of asymptomatic and symptomatic pathogen infections, controlling for treatment group. Increased levels of TNF-α and IL-6 were associated with decreased durations of EPEC infection and increased ETEC durations. Increased IL-4 and IFN-γ levels were associated with decreased and increased durations, respectively, of both EPEC and ETEC infections. Increased IL-10 levels were associated with increased and decreased durations of asymptomatic and symptomatic EPEC infections, respectively, and increased durations of both asymptomatic and symptomatic ETEC infections. Increased levels of MCP-1, IFN-γ, IL-4, and IL-5 were associated with increasedG. lambliainfection duration, while increased IL-8 levels were associated with decreased durations. Differences in proinflammatory and Treg cytokine levels are associated with differences in the resolution of inflammatory and noninflammatory pathogen infections.
Activation of Human and Chicken Toll-Like Receptors by
Campylobacter
spp
Authors: de Zoete Marcel R. , Keestra A. Marijke , Roszczenko Paula , van Putten Jos P. M.
Published: December 2009

Campylobacter
infection in humans is accompanied by severe inflammation of the intestinal mucosa, in contrast to colonization of chicken. The basis for the differential host response is unknown. Toll-like receptors (TLRs) sense and respond to microbes in the body and participate in the induction of an inflammatory response. Thus far, the interaction of
Campylobacter
with chicken TLRs has not been studied. Here, we investigated the potential of four
Campylobacter
strains to activate human TLR1/2/6, TLR4, TLR5, and TLR9 and chicken TLR2t2/16, TLR4, TLR5, and TLR21. Live bacteria showed no or very limited potential to activate TLR2, TLR4, and TLR5 of both the human and chicken species, with minor but significant differences between
Campylobacter
strains. In contrast, lysed bacteria induced strong NF-κB activation through human TLR1/2/6 and TLR4 and chicken TLR2t2/16 and TLR4 but not via TLR5 of either species. Interestingly,
C. jejuni
induced TLR4-mediated beta interferon in human but not chicken cells. Furthermore, isolated chromosomal
Campylobacter
DNA was unable to activate human TLR9 in our system, whereas chicken TLR21 was activated by DNA from all of the campylobacters tested. Our data are the first comparison of TLR-induced immune responses in humans and chickens. The results suggest that differences in bacterial cell wall integrity and in TLR responses to
Campylobacter
LOS and/or DNA may contribute to the distinct clinical manifestation between the species.
Cell Sorting-Assisted Microarray Profiling of Host Cell Response to
Cryptosporidium parvum
Infection
Authors: Yang Yi-Lin , Buck Gregory A. , Widmer Giovanni
Published: December 2009

To study the transcriptional response of mammalian cells to infection with the intracellular apicomplexan parasite
Cryptosporidium parvum
, infected and uninfected cells were recovered from
C. parvum
-infected cell monolayers. This approach, which contrasts with a more conventional experimental design that compares infected to uninfected cell monolayers, enabled the identification of functional categories of genes that are differentially transcribed as a direct consequence of the presence of intracellular parasites. Among several categories of upregulated genes, glycoprotein metabolism was significantly overrepresented. To investigate whether these transcriptional changes affected the composition of the surface of infected cells, cells were probed with fluorescently labeled lectins. Among a panel of seven lectins, soybean agglutinin, which recognizes
N
-acetyl-
d
-galactosamine, generated the largest difference in fluorescence between infected and uninfected cells. The origin of the fluorescent signal emitted by infected cells was further investigated and attributed to the overexpression of glycoprotein on the surface of infected cells, as well as the presence of glycoprotein located in the proximity of intracellular parasites.
The
Streptococcus mutans
IrvR Repressor Is a CI-Like Regulator That Functions through Autocleavage and Clp-Dependent Proteolysis
Authors: Niu Guoqing , Okinaga Toshinori , Qi Fengxia , Merritt Justin
Published: December 2009

Previous work has shown that
irvR
is required for the proper regulation of genetic competence and dextran-dependent aggregation due to its ability to repress the transcription regulator
irvA
. In this study, we determined the mechanism used to relieve the repression of
irvA
. We demonstrate that IrvR is a “LexA-like” protein with four conserved amino acid residues likely required for IrvR autocleavage activity. Furthermore, recombinant IrvR protein purified from
Escherichia coli
was competent to undergo autocleavage
in vitro
. Using several truncated IrvR constructs, we show that the amino acids adjacent to the autocleavage site are essential for relieving
irvA
repression and engaging the
irvA-
dependent regulatory pathway primarily through the ClpXP and ClpCP proteases. By extending the IrvR C terminus with an epitope derived from the autocleavage site, we were also able to create a constitutive Clp-dependent degradation of the full-length IrvR protein. This suggests that the derepression of
irvA
occurs through a two-step mechanism involving the initial autocleavage of IrvR and exposure of a proteolytic degradation sequence followed by Clp-dependent degradation of the IrvR DNA binding domain. Thus,
irvA
derepression is highly analogous to the genetic switch mechanism used to regulate lysogeny in bacteriophages.
Roles of RubisCO and the RubisCO-Like Protein in 5-Methylthioadenosine Metabolism in the Nonsulfur Purple Bacterium
Rhodospirillum rubrum
Authors: Singh Jaya , Tabita F. Robert
Published: December 2009

Ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) catalyzes the assimilation of atmospheric CO
2
into organic matter and is thus central to the existence of life on earth. The beginning of the 2000s was marked by the discovery of a new family of proteins, the RubisCO-like proteins (RLPs), which are structural homologs of RubisCO. RLPs are unable to catalyze CO
2
fixation. The RLPs from
Chlorobaculum tepidum
,
Bacillus subtilis
,
Geobacillus kaustophilus
, and
Microcystis aeruginosa
have been shown to participate in sulfur metabolism. Whereas the precise function of
C. tepidum
RLP is unknown, the
B. subtilis
,
G. kaustophilus
, and
M. aeruginosa
RLPs function as tautomerases/enolases in a methionine salvage pathway (MSP). Here, we show that the form II RubisCO enzyme from the nonsulfur purple bacterium
Rhodospirillum rubrum
is also able to function as an enolase
in vivo
as part of an MSP, but only under anaerobic conditions. However, unlike
B. subtilis
RLP,
R
.
rubrum
RLP does not catalyze the enolization of 2,3-diketo-5-methylthiopentyl-1-phosphate. Instead, under aerobic growth conditions,
R. rubrum
RLP employs another intermediate of the MSP, 5-methylthioribulose-1-phosphate, as a substrate, resulting in the formation of different products. To further determine the interrelationship between RubisCOs and RLPs (and the potential integration of cellular carbon and sulfur metabolism), the functional roles of both RubisCO and RLP have been examined
in vivo
via the use of specific knockout strains and complementation studies of
R. rubrum
. The presence of functional, yet separate, MSPs in
R. rubrum
under both aerobic (chemoheterotrophic) and anaerobic (photoheterotrophic) growth conditions has not been observed previously in any organism. Moreover, the aerobic and anaerobic sulfur salvage pathways appear to be differentially controlled, with novel and previously undescribed steps apparent for sulfur salvage in this organism.
Multidrug Efflux Pump MdtBC of
Escherichia coli
Is Active Only as a B
2
C Heterotrimer
Authors: Kim Hong-Suk , Nagore Daniel , Nikaido Hiroshi
Published: December 2009

RND (resistance-nodulation-division) family transporters in Gram-negative bacteria frequently pump out a wide range of inhibitors and often contribute to multidrug resistance to antibiotics and biocides. An archetypal RND pump of
Escherichia coli
, AcrB, is known to exist as a homotrimer, and this construction is essential for drug pumping through the functionally rotating mechanism. MdtBC, however, appears different because two pump genes coexist within a single operon, and genetic deletion data suggest that both pumps must be expressed in order for the drug efflux to occur. We have expressed the corresponding genes, with one of them in a His-tagged form. Copurification of MdtB and MdtC under these conditions showed that they form a complex, with an average stoichiometry of 2:1. Unequivocal evidence that only the trimer containing two B protomers and one C protomer is active was obtained by expressing all possible combinations of B and C in covalently linked forms. Finally, conversion into alanine of the residues, known to form a proton translocation pathway in AcrB, inactivated transport only when made in MdtB, not when made in MdtC, a result suggesting that MdtC plays a different role not directly involved in drug binding and extrusion.
Flavobacterium johnsoniae gldN
and
gldO
Are Partially Redundant Genes Required for Gliding Motility and Surface Localization of SprB
Authors: Rhodes Ryan G. , Samarasam Mudiarasan Napoleon , Shrivastava Abhishek , van Baaren Jessica M. , Pochiraju Soumya , Bollampalli Sreelekha , McBride Mark J.
Published: December 2009

Cells of the gliding bacterium
Flavobacterium johnsoniae
move rapidly over surfaces. Mutations in
gldN
cause a partial defect in gliding. A novel bacteriophage selection strategy was used to aid construction of a strain with a deletion spanning
gldN
and the closely related gene
gldO
in an otherwise wild-type
F. johnsoniae
UW101 background. Bacteriophage transduction was used to move a
gldN
mutation into
F. johnsoniae
UW101 to allow phenotypic comparison with the
gldNO
deletion mutant. Cells of the
gldN
mutant formed nonspreading colonies on agar but retained some ability to glide in wet mounts. In contrast, cells of the
gldNO
deletion mutant were completely nonmotile, indicating that cells require GldN, or the GldN-like protein GldO, to glide. Recent results suggest that
Porphyromonas gingivalis
PorN, which is similar in sequence to GldN, has a role in protein secretion across the outer membrane. Cells of the
F. johnsoniae gldNO
deletion mutant were defective in localization of the motility protein SprB to the cell surface, suggesting that GldN may be involved in secretion of components of the motility machinery. Cells of the
gldNO
deletion mutant were also deficient in chitin utilization and were resistant to infection by bacteriophages, phenotypes that may also be related to defects in protein secretion.
IMPOSSIBILITY OF ASYMPTOTIC SYNCHRONIZATION FOR PULSE-COUPLED OSCILLATORS WITH DELAYED EXCITATORY COUPLING
Authors: WU WEI , CHEN TIANPING
Published: December 2009

Fireflies, as one of the most spectacular examples of synchronization in nature, have been investigated widely. In 1990, Mirollo and Strogatz proposed a pulse-coupled oscillator model to explain the synchronization of South East Asian fireflies (Pteroptyx malaccae). However, transmission delays were not considered in their model. In fact, when transmission delays are introduced, the dynamic behaviors of pulse-coupled networks change a lot. In this paper, pulse-coupled oscillator networks with delayed excitatory coupling are studied. A concept of synchronization, named weak asymptotic synchronization, which is weaker than asymptotic synchronization, is proposed. We prove that for pulse-coupled oscillator networks with delayed excitatory coupling, weak asymptotic synchronization cannot occur.
GLOBAL EXPONENTIAL STABILITY OF FUZZY INTERVAL DELAYED NEURAL NETWORKS WITH IMPULSES ON TIME SCALES
Authors: LI YONGKUN , ZHANG TIANWEI
Published: December 2009

In this paper, we investigate the existence and uniqueness of equilibrium point for fuzzy interval delayed neural networks with impulses on time scales. And we give the criteria of the global exponential stability of the unique equilibrium point for the neural networks under consideration using Lyapunov method. Finally, we present an example to illustrate that our results are effective.
IMPLICATIONS OF $D^0$--$\overline{D^0}$ ON THE RARE TOP QUARK DECAYS t → uγ AND t → ug
Authors: ARANDA J. I. , CORDERO-CID A. , RAMÍREZ-ZAVALETA F. , TOSCANO J. J. , TUTUTI E. S.
Published: December 2009

The recently observed mass difference of the [Formula: see text] mixing is used to predict the branching ratios of the rare top quark decays t → uγ and t → ug in a model-independent way using the effective Lagrangian approach. It is found that Br (t → uγ) < 4 × 10-4 and Br (t → ug) < 2 × 10-3, which may still be within reach of the LHC collider.
RELATIVISTIC HARMONIC OSCILLATOR MODEL FOR QUARK STARS
Authors: BANNUR VISHNU M.
Published: December 2009

The relativistic harmonic oscillator (RHO) model of hadrons is used to study quark stars. The mass–radius relationship is obtained and compared with bag model of quark star, using Tolman–Oppenheimer–Volkoff equation. In this model, the outward degenerate pressure due to discrete Landau levels and Landau degeneracy balances the inward gravitational pressure. Where as in bag model the degenerate pressure is due to the standard continuum levels which balances the combined inward pressure due to gravitation and bag pressure. So in RHO model, the confinement effect is included in the degenerate pressure. We found a qualitative similarity, but quantitative differences in mass–radius relationship of quark stars in these two models. Masses and radii are relatively larger and the central energy densities, required for stable quark stars, are lower in RHO model than that of bag model.
CHERN–SIMONS THEORY, EXACTLY SOLVABLE MODELS AND FREE FERMIONS AT FINITE TEMPERATURE
Authors: TIERZ MIGUEL
Published: December 2009

We show that matrix models in Chern–Simons theory admit an interpretation as 1D exactly solvable models, paralleling the relationship between the Gaussian model and the Calogero model. We compute the corresponding Hamiltonians, ground-state wave functions and ground-state energies and point out that the models can be interpreted as quasi-1D Coulomb plasmas. We also study the relationship between Chern–Simons theory on S3 and a system of N one-dimensional fermions at finite temperature with harmonic confinement. In particular, we show that the Chern–Simons partition function can be described by the density matrix of the free fermions in a very particular, crystalline, configuration. For this, we both use the Brownian motion and the matrix model description of Chern–Simons theory and find several common features with c = 1 theory at finite temperature. Finally, using the exactly solvable model result, we show that the finite temperature effect can be described with a specific two-body interaction term in the Hamiltonian, with 1D Coulombic behavior at large separations.
ESTIMATING THE ANNIHILATION DECAY Bs → ργ WITH FACTORIZATION
Authors: AHMADY M. R. , MAHMOUDI F.
Published: December 2009

The branching ratio for the rare two-body Bs → ργ decay is calculated using the factorization assumption. This transition is dominated by the annihilation diagrams and, in principle, prone to receiving substantial contributions from new physics. We estimate Br (Bs → ργ) ≈ 1.6 ×10-9 within the Standard Model and investigate the sensitivity of this decay mode to the effects of two new physics scenarios: vector quark model and supersymmetry. Our results indicate that the shift in branching ratio is at most around 10% with the addition of vector quarks and is negligibly small in the constrained minimal supersymmetric extension of the Standard Model.
Effect of Chronic Hypoxic Hypercapnia on the Expression of Bcl-2 and Bax Genes and Apoptosis in Rat Hippocampal Neurons
Authors: Shao Sheng-min , Chen Song-fang , Li Yong , Wang Xiao-tong
Published: December 2009

The objective of this paper is to explore the effect of chronic hypoxic hypercapnia on the apoptosis of rat neural cells in the hippocampus, as well as the relationship between apoptosis and Bcl-2 and Bax gene expression. In this study, 50 male Sprague-Dawley rats were randomly divided into 5 groups: a normal control group, and 4 hypoxic hypercapnia groups which received hypoxic hypercapnia treatment for 1, 2 , 3 and 4 weeks. The in situ apoptosis in the hippocampus was detected by TUNEL staining. The expression of bcl-2 and bax mRNA in the hippocampus was examined by RT-PCR. Results showed that the apoptosis index (AI) and expression of Bax mRNA increased with the duration of hypoxic hypercapnia, and that the expression of Bcl-2 mRNA increased at the beginning but then declined. There was a significant positive correlation between AI and the expression of Bax mRNA (r = 0.814, p < 0.01), and there was a significant negative correlation between AI and the ratio of Bcl-2 mRNA/Bax mRNA (r = –0.405, p < 0.01). The results suggest that apoptosis can be induced by chronic hypoxic hypercapnia in the rat hippocampus. The ratio of Bcl-2/Bax declined gradually, which accelerates the occurrence of apoptosis.
Variations in Compliance with Recommendations and Types of Meat/Seafood/Eggs according to Sociodemographic and Socioeconomic Categories
Authors: Touvier Mathilde , Kesse-Guyot Emmanuelle , Méjean Caroline , Estaquio Carla , Péneau Sandrine , Hercberg Serge , Castetbon Katia
Published: December 2009

Background/Aims: Strategic goals for meat/seafood/egg consumption include variety and adherence to recommendations while avoiding excessive intake. The aim of this study was to investigate their association with sociodemographic and -economic characteristics in a general population of French adults. Methods: Dietary intake was assessed using at least six 24-hour dietary records collected during a 2-year period from 4,574 subjects aged 45–60 years who participated in the SU.VI.MAX cohort study from 1995 to 1997. Compliance with the meat/seafood/egg (1–2 servings/day) and the specific seafood (≧2 servings/week) recommendations, variety and daily costs were compared across sociodemographic and -economic categories using logistic regression and covariance analyses. Results: Compliance with the sea- food recommendation was associated with older age (ptrend< 0.0001), higher education level (ptrend = 0.0002) and higher occupational category (p = 0.007). The variety of meat/seafood/egg intake was positively correlated with higher occupational category (p = 0.02) and not living alone (p = 0.01). The meat/seafood/egg budget spent on white meat was higher for younger subjects (ptrend = 0.007) with a lower education level (ptrend = 0.001) and occupational category (p = 0.0006). In contrast, fish costs increased with age (ptrend = 0.002) and education level (ptrend = 0.0002), while red meat costs were positively correlated with higher occupational category (p = 0.02). Conclusions: Compliance with recommendations, variety and types of meat/seafood/eggs differed across sociodemographic and -economic categories.
Educating Underserved Latino Communities about Family Health History Using Lay Health Advisors
Authors: Kaphingst K.A. , Lachance C.R. , Gepp A. , Hoyt D’Anna L. , Rios-Ellis B.
Published: December 2009

Background: Family health history (FHH) is a tool used to inform individuals about inherited disease risk. Due to their disproportionate morbidity and mortality from some common chronic diseases, U.S. Latinos are an important audience for FHH information. This study examined the effects of a culturally-tailored intervention led by lay health advisors (LHAs) in delivering information about FHH on participants’ intentions, self-efficacy, and conceptual knowledge. Methods: 474 Spanish-speaking Latino participants were enrolled in the study. Individuals in the intervention group participated in a single group educational session using discussion and interactive activities to build skills for discussing FHH with one’s family members and doctor, while individuals in the comparison group had a brochure read aloud to them. Pre- and post-test questionnaires were verbally administered. Results: Primary dependent variables were intentions and self-efficacy to discuss FHH with family members and doctors; these increased in both groups. Multivariate analyses demonstrated that the intervention led to a significantly greater increase in self-efficacy to discuss FHH with family members (p = 0.03). LHA participants were also more than twice as likely (OR = 2.6, 95% CI = 1.3–5.0) to correctly understand the purpose of a FHH and found FHH information more useful (p < 0.0001). Conclusions: A communication intervention delivered by LHAs shows promise as an effective means of educating underserved Spanish-speaking Latinos about the importance of FHH for disease prevention. Such community-based approaches can help to close knowledge and skills gaps about FHH and increase confidence in using this information to improve the health of those most at risk.
Interleukin 10 Gene Polymorphisms and Development of Post Kala-Azar Dermal Leishmaniasis in a Selected Sudanese Population
Authors: Farouk S. , Salih M.A. , Musa A.M. , Blackwell J.M. , Miller E.N. , Khalil E.A. , ElHassan A.M. , Ibrahim M.E. , Mohamed H.S.
Published: December 2009

Background: Post kala-azar dermal leishmaniasis (PKDL) is a cutaneous form of disease that develops at variable times after individuals have received treatment for clinical visceral leishmaniasis (VL). The study aimed to investigate the possible role of interleukin 10 (IL-10) and development of PKDL. Methods: 77 families composed of 41 complete case-parent trios and 36 case-parent pairs from the Masalit ethnic group were genotyped for 3 IL10 promoter polymorphisms: -1082A/G, -819C/T and -592C/A. Results: Single point analysis using the transmission disequilibrium test showed no evidence of association between any of these IL10 promoter single nucleotide polymorphisms (SNPs) and development of PKDL. Haplotype analysis performed using TRANSMIT showed borderline significance between PKDL and the haplotype AA across -592C/A and -1082A/G (p = 0.053). Haplotypes GCC (0.33) and ATA (0.30) were the common haplotypes in this Sudanese population. Allele frequencies for the 3 SNPs differed significantly in Sudan compared to other African (Gambian, Malawian, YRI) populations. Conclusion: There is no evidence for an association between 3 SNPs in the IL10 gene promoter and susceptibility to PKDL in the Masalit ethnic group in Sudan, although some evidence for haplotype association was observed.
Translational Research in Cancer Genetics: The Road Less Traveled
Authors: Schully S.D. , Benedicto C.B. , Gillanders E.M. , Wang S.S. , Khoury M.J.
Published: December 2009

Gene discoveries in cancer have the potential for clinical and public health applications. To take advantage of such discoveries, a translational research agenda is needed to take discoveries from the bench to population health impact. To assess the current status of translational research in cancer genetics, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Year 2007, as well as the cancer genetic research articles published in 2007. We classified both funded grants and publications as follows: T0 as discovery research; T1 as research to develop a candidate health application (e.g., test or therapy); T2 as research that evaluates a candidate application and develops evidence-based recommendations; T3 as research that assesses how to integrate an evidence-based recommendation into cancer care and prevention; and T4 as research that assesses health outcomes and population impact. We found that 1.8% of the grant portfolio and 0.6% of the published literature was T2 research or beyond. In addition to discovery research in cancer genetics, a translational research infrastructure is urgently needed to methodically evaluate and translate gene discoveries for cancer care and prevention.
Guiding Policy Decisions for Genetic Screening: Developing a Systematic and Transparent Approach
Authors: Andermann A. , Blancquaert I. , Beauchamp S. , Costea I.
Published: December 2009

With the ever-widening gap between what is technologically possible and services available, jurisdictions around the world are faced with complex decisions regarding the introduction and expansion of genetic screening programs. A series of literature reviews and consultations with stakeholders and experts led to the development of a decision support guide for genetic screening policy-making. This involved establishing a preliminary list of core criteria synthesized from the growing literature on genetic screening, which was then transformed through a series of consultations into a more elaborate decision guide. Although certain perennial challenges in genetic screening policy-making remain, the decision support guide aims to promote a fair and evidence-informed process that makes explicit the ethical dilemmas often inherent to such policy decisions.
Impact of Body Mass Index and the Metabolic Syndrome on the Risk of Cardiovascular Disease and Death in Middle-Aged Men
Authors: Ärnlöv Johan , Ingelsson Erik , Sundström Johan , Lind Lars
Published: December 2009

Background—

The purpose of this study was to investigate associations between combinations of body mass index (BMI) categories and metabolic syndrome (MetS) and the risk of cardiovascular disease and death in middle-aged men.

Methods and Results—

At age 50 years, cardiovascular risk factors were assessed in 1758 participants without diabetes in the community-based Uppsala Longitudinal Study of Adult Men (ULSAM). According to BMI-MetS status, they were categorized as normal weight (BMI <25 kg/m
2
) without MetS (National Cholesterol Education Program criteria; n=891), normal weight with MetS (n=64), overweight (BMI 25 to 30 kg/m
2
) without MetS (n=582), overweight with MetS (n=125), obese (BMI >30 kg/m
2
) without MetS (n=30), or obese with MetS (n=66). During follow-up (median 30 years), 788 participants died, and 681 developed cardiovascular disease (composite of cardiovascular death or hospitalization for myocardial infarction, stroke, or heart failure). In Cox proportional-hazards models that adjusted for age, smoking, and low-density lipoprotein cholesterol, an increased risk for cardiovascular disease was observed in normal-weight participants with MetS (hazard ratio 1.63, 95% confidence interval 1.11 to 2.37), overweight participants without MetS (hazard ratio 1.52, 95% confidence interval 1.28 to 1.80), overweight participants with MetS (hazard ratio 1.74, 95% confidence interval 1.32 to 2.30), obese participants without MetS (hazard ratio 1.95, 95% confidence interval 1.14 to 3.34), and obese participants with MetS (hazard ratio 2.55, 95% confidence interval 1.81 to 3.58) compared with normal-weight individuals without MetS. These BMI-MetS categories significantly predicted total mortality rate in a similar pattern.

Conclusions—

Middle-aged men with MetS had increased risk for cardiovascular events and total death regardless of BMI status during more than 30 years of follow-up. In contrast to previous reports, overweight and obese individuals without MetS also had an increased risk. The present data refute the notion that overweight and obesity without MetS are benign conditions.
Anthracycline Cardiomyopathy Is Mediated by Depletion of the Cardiac Stem Cell Pool and Is Rescued by Restoration of Progenitor Cell Function
Authors: De Angelis Antonella , Piegari Elena , Cappetta Donato , Marino Laura , Filippelli Amelia , Berrino Liberato , Ferreira-Martins João , Zheng Hanqiao , Hosoda Toru , Rota Marcello , Urbanek Konrad , Kajstura Jan , Leri Annarosa , Rossi Francesco , Anversa Piero
Published: December 2009

Background—

Anthracyclines are the most effective drugs available in the treatment of neoplastic diseases; however, they have profound consequences on the structure and function of the heart, which over time cause a cardiomyopathy that leads to congestive heart failure.

Methods and Results—

Administration of doxorubicin in rats led to a dilated myopathy, heart failure, and death. To test whether the effects of doxorubicin on cardiac anatomy and function were mediated by alterations in cardiac progenitor cells (CPCs), these cells were exposed to the anthracycline, which increased the formation of reactive oxygen species and caused increases in DNA damage, expression of p53, telomere attrition, and apoptosis. Additionally, doxorubicin resulted in cell-cycle arrest at the G2/M transition, which led to a significant decrease in CPC growth. Doxorubicin elicited multiple molecular adaptations; the massive apoptotic death that occurred in CPCs in the presence of anthracycline imposed on the surviving CPC pool the activation of several pathways aimed at preservation of the primitive state, cell division, lineage differentiation, and repair of damaged DNA. To establish whether delivery of syngeneic progenitor cells opposed the progression of doxorubicin cardiotoxicity, enhanced green fluorescent protein–labeled CPCs were injected in the failing myocardium; this treatment promoted regeneration of cardiomyocytes and vascular structures, which improved ventricular performance and rate of animal survival.

Conclusions—

Our results raise the possibility that autologous CPCs can be obtained before antineoplastic drugs are given to cancer patients and subsequently administered to individuals who are particularly sensitive to the cardiotoxicity of these agents for prevention or management of heart failure.
Peak C-Reactive Protein Level Predicts Long-Term Outcomes in Type B Acute Aortic Dissection
Authors: Sakakura Kenichi , Kubo Norifumi , Ako Junya , Wada Hiroshi , Fujiwara Naoki , Funayama Hiroshi , Ikeda Nahoko , Nakamura Tomohiro , Sugawara Yoshitaka , Yasu Takanori , Kawakami Masanobu , Momomura Shin-ichi
Published: December 2009

Acute aortic dissection (AAD) is associated with an inflammatory reaction, as evidenced by elevated inflammatory markers, including C-reactive protein (CRP). The association between the peak CRP level and long-term outcomes in type B AAD has not been systematically investigated. The purpose of this study was to investigate whether the peak CRP level during admission predicts long-term outcomes in type B AAD. We conducted a clinical follow-up study of type B AAD. We divided the study population into 4 groups according to the tertiles of peak CRP levels (T1: 0.60 to 9.37 mg/dL; T2: 9.61 to 14.87 mg/dL; T3: 14.90 to 32.60 mg/dL; and unavailable peak CRP group). Multivariate Cox regression analysis was applied to investigate whether the tertiles of peak CRP predict adverse events even after adjusting for other variables. A total of 232 type B AAD patients were included in this analysis. The median follow-up period was 50 months. CRP reached its peak on day 4.5±1.7. Mean peak CRP values in T1, T2, and T3 were 6.4±2.4, 12.0±1.5, and 19.5±4.0 mg/dL, respectively. There were 65 events (39 deaths and 26 aortic events) during the follow-up. T3 and T2 (versus T1) were strong predictors of adverse events (T3: hazard ratio: 6.02 [95% CI: 2.44 to 14.87],
P
=0.0001; T2: hazard ratio: 3.25 [95% CI: 1.37 to 7.71],
P
=0.01) after controlling for all of the confounding factors. In conclusion, peak CRP is a strong predictor for adverse long-term events in patients with type B AAD.
Tumor Necrosis Factor-α Antagonists Improve Aortic Stiffness in Patients With Inflammatory Arthropathies
Authors: Angel Kristin , Provan Sella Aarrestad , Gulseth Hanne Løvdahl , Mowinckel Petter , Kvien Tore Kristian , Atar Dan
Published: December 2009

The chronic inflammatory state of rheumatoid arthritis and other inflammatory arthropathies, such as ankylosing spondylitis and psoriatic arthritis, contributes to the accelerated atherosclerosis associated with these conditions. This study evaluates the effect of treatment with tumor necrosis factor (TNF)-α antagonists on arterial stiffness in patients with inflammatory arthropathies. A total of 60 patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and clinical indication for anti–TNF-α therapy were included. Thirty-five patients started with anti–TNF-α therapy and were compared with a nontreatment group of 25 patients. Aortic stiffness (aortic pulse wave velocity), augmentation index, and disease activity were assessed at baseline and after 3 months. Aortic pulse wave velocity (mean±SD) was reduced in the treatment group but not in the control group (−0.50±0.78 m/s versus 0.05±0.54 m/s, respectively;
P
=0.002). Concomitantly, C-reactive protein and the disease activity score were reduced in the treatment group (−9.3±20.2 mg/L [
P
<0.001] and −0.74±0.91 [
P
=0.004]). Augmentation index remained unchanged in both groups (0.1±7.1% versus −1.0±5.8%, respectively;
P
=0.53). In a multivariate linear regression model, only treatment with TNF-α antagonist and change in mean arterial pressure predicted alterations in aortic pulse wave velocity. In summary, anti–TNF-α therapy improved aortic stiffness in patients with inflammatory arthropathies. These findings support the idea that anti-inflammatory treatment has a favorable effect on cardiovascular risk in patients with inflammatory arthropathies.
Adrenic Acid Metabolites as Endogenous Endothelium-Derived and Zona Glomerulosa-Derived Hyperpolarizing Factors
Authors: Kopf Phillip G. , Zhang David X. , Gauthier Kathryn M. , Nithipatikom Kasem , Yi Xiu-Yu , Falck John R. , Campbell William B.
Published: December 2009

Adrenic acid (docosatetraenoic acid), an abundant fatty acid in the adrenal gland, is identical to arachidonic acid except for 2 additional carbons on the carboxyl end. Adrenic acid is metabolized by cyclooxygenases, cytochrome P450s, and lipoxygenases; however, little is known regarding the role of adrenic acid and its metabolites in vascular tone. Because of its abundance in the adrenal gland, we investigated the role of adrenic acid in vascular tone of bovine adrenal cortical arteries and its metabolism by bovine adrenal zona glomerulosa cells. In adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations, which were inhibited by the epoxyeicosatrienoic acid antagonist 14,15-epoxyeicosa-5(Z)-enoic acid and the cytochrome P450 inhibitor SKF-525A. The large-conductance calcium-activated potassium channel blocker iberiotoxin or removal of the endothelium abolished these relaxations. Reverse-phase high-pressure liquid chromatography and liquid chromatography/mass spectrometry isolated and identified numerous adrenic acid metabolites from zona glomerulosa cells, including dihomo-epoxyeicosatrienoic acids and dihomo-prostaglandins. In denuded adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations in the presence of zona glomerulosa cells but not in their absence. These relaxations were inhibited by SKF-525A, 14,15-epoxyeicosa-5(Z)-enoic acid, and iberiotoxin. Dihomo-16,17-epoxyeicosatrienoic acid caused concentration-dependent relaxations of adrenal cortical arteries, which were inhibited by 14,15-epoxyeicosa-5(Z)-enoic acid and high potassium. Our results suggest that adrenic acid relaxations of bovine adrenal cortical arteries are mediated by endothelial and zona glomerulosa cell cytochrome P450 metabolites. Thus, adrenic acid metabolites could function as endogenous endothelium-derived and zona glomerulosa-derived hyperpolarizing factors in the adrenal cortex and contribute to the regulation of adrenal blood flow.
Resting Heart Rate Pattern During Follow-Up and Mortality in Hypertensive Patients
Authors: Paul Laura , Hastie Claire E. , Li Weiling S. , Harrow Craig , Muir Scott , Connell John M.C. , Dominiczak Anna F. , McInnes Gordon T. , Padmanabhan Sandosh
Published: December 2009

There is a linear relationship between resting heart rate (HR) and mortality in normotensive and untreated hypertensive individuals. However, it is not clear whether HR is a marker of increased risk in hypertensive patients on treatment. We investigated the relationship between HR and mortality in patients with hypertension. We analyzed baseline HR, final HR, and HR change during follow-up in patients attending the Glasgow Blood Pressure Clinic. Using a threshold of 80 bpm, we classified patients into those who had a consistently high (high-high) or low (low-low) HR or patients whose HR increased (low-high) or decreased (high-low) over time. Survival analysis was carried out using Cox proportional hazards models adjusted for age, sex, body mass index, smoking, rate-limiting therapy, systolic blood pressure, and serum cholesterol. For each beat of HR change there was a 1% change in mortality risk. The highest risk of an all-cause event was associated with patients who had increased their HR by ≥5 bpm at the end of follow-up (1.51 [95% CI: 1.03 to 2.20];
P
=0.035). Compared with low-low patients, high-high patients had a 78% increase in the risk of all-cause mortality (HR: 1.78 [95% CI: 1.31 to 2.41];
P
<0.001). Cardiovascular mortality showed a similar pattern of results. Rate-limiting therapy did not have an independent effect on outcomes in this analysis. Change in HR achieved during follow-up of hypertensive patients is a better predictor of risk than baseline or final HR. After correction for rate-limiting therapy, HR remained a significant independent risk factor.
Interleukin 17 Promotes Angiotensin II–Induced Hypertension and Vascular Dysfunction
Authors: Madhur Meena S. , Lob Heinrich E. , McCann Louise A. , Iwakura Yoichiro , Blinder Yelena , Guzik Tomasz J. , Harrison David G.
Published: December 2009

We have shown previously that T cells are required for the full development of angiotensin II–induced hypertension. However, the specific subsets of T cells that are important in this process are unknown. T helper 17 cells represent a novel subset that produces the proinflammatory cytokine interleukin 17 (IL-17). We found that angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media. To determine the effect of IL-17 on blood pressure and vascular function, we studied IL-17
−/−
mice. The initial hypertensive response to angiotensin II infusion was similar in IL-17
−/−
and C57BL/6J mice. However, hypertension was not sustained in IL-17
−/−
mice, reaching levels 30-mm Hg lower than in wild-type mice by 4 weeks of angiotensin II infusion. Vessels from IL-17
−/−
mice displayed preserved vascular function, decreased superoxide production, and reduced T-cell infiltration in response to angiotensin II. Gene array analysis of cultured human aortic smooth muscle cells revealed that IL-17, in conjunction with tumor necrosis factor-α, modulated expression of >30 genes, including a number of inflammatory cytokines/chemokines. Examination of IL-17 in diabetic humans showed that serum levels of this cytokine were significantly increased in those with hypertension compared with normotensive subjects. We conclude that IL-17 is critical for the maintenance of angiotensin II–induced hypertension and vascular dysfunction and might be a therapeutic target for this widespread disease.
Increased Angiotensin II in the Mesometrial Triangle of a Transgenic Rat Model of Preeclampsia
Authors: Brosnihan K. Bridget , Hering Lydia , Dechend Ralf , Chappell Mark C. , Herse Florian
Published: December 2009

The pregnant female human angiotensinogen (
h
AGN) transgenic rat mated with the male
h
renin (
h
REN) transgenic rat is a model of preeclampsia with increased blood pressure, proteinuria, and placenta alterations of edema and necrosis. The reverse mating of female
h
REN×male
h
AGN does not show preeclamptic features. Because the placenta is well-recognized to be a key contributor to the preeclamptic syndrome, our hypothesis is that local angiotensin peptide concentrations found in the placenta and its associated mesometrial triangle of the preeclamptic transgenic rat differ from the reverse mating. We characterized the angiotensin peptide content and the mRNA expression of
h
REN and
h
AGN of the mesometrial triangle and the placenta. Three groups of pregnant rats from the matings (Sprague-Dawley×Sprague-Dawley, reverse mating, and female
h
AGN×male
h
REN) were studied on day 21 of gestation. In the
h
AGN×
h
REN transgenic rat, angiotensin II is significantly increased in the placenta and mesometrial triangle vs Sprague-Dawley (24.2±3.9 vs 8.6±1.5 pg/mg protein; 27.8±5.5 vs 5.6±1.3 pg/mg protein;
P
<0.05), whereas in the reverse mating angiotensin II is increased in the placenta (19.1±1.7 vs 5.6±1.3 pg/mg protein;
P
<0.05) but unchanged in the mesometrial triangle (4.2±0.2 vs 8.6±1.5 pg/mg protein). The marked contrast in the expression of angiotensin II in the mesometrial triangle of the preeclamptic model vs the reverse mating suggests that local angiotensin II generated from the maternal parts of the uteroplacental unit may play a critical role in preeclampsia.
Protein Kinase C-Dependent NAD(P)H Oxidase Activation Induced by Type 1 Diabetes in Renal Medullary Thick Ascending Limb
Authors: Yang Jing , Lane Pascale H. , Pollock Jennifer S. , Carmines Pamela K.
Published: December 2009

Type 1 diabetes provokes a protein kinase C (PKC)-dependent accumulation of superoxide anion in the renal medullary thick ascending limb (mTAL). We hypothesized that this phenomenon involves PKC-dependent NAD(P)H oxidase activation. The validity of this hypothesis was explored using mTAL suspensions prepared from rats with streptozotocin-induced diabetes and from sham (vehicle-treated) rats. Superoxide production was 5-fold higher in mTAL suspensions from diabetic rats compared with suspensions from sham rats. The NAD(P)H oxidase inhibitor apocynin caused an 80% decrease in superoxide production by mTAL from diabetic rats (
P
<0.05 vs untreated) without altering superoxide production by sham mTAL. NAD(P)H oxidase activity was >2-fold higher in mTAL from diabetic rats than in sham mTAL (
P
<0.05). Pretreatment with calphostin C (broad-spectrum PKC inhibitor) or rottlerin (PKCδ inhibitor) reduced NAD(P)H oxidase activity by ≈80% in both groups; however, PKCα/β or PKCβ inhibition did not alter NAD(P)H oxidase activity in either group. Protein levels of Nox2, Nox4, and p47phox were significantly higher in diabetic mTAL than in mTAL from sham rats. In summary, elevated superoxide production by mTAL from diabetic rats was normalized by NAD(P)H oxidase inhibition. PKC-dependent, PKCδ-dependent, and total NAD(P)H oxidase activity was greater in mTAL from diabetic rats compared with sham. Protein levels of Nox2, Nox4, and p47phox were increased in mTAL from diabetic rats. We conclude that increased superoxide production by the mTAL during diabetes involves a PKCδ-dependent increase in NAD(P)H oxidase activity in concert with increased protein levels of catalytic and regulatory subunits of the enzyme.