bluuebunny/crossref_metadata_2025 huggingface dataset:
Detailed
In Vivo
Analysis of the Role of
Helicobacter pylori
Fur in Colonization and Disease
Authors: Miles Shana , Piazuelo M. Blanca , Semino-Mora Cristina , Washington Mary Kay , Dubois Andre , Peek Richard M. , Correa Pelayo , Merrell D. Scott
Published: April 2010

Helicobacter pylori
persistently colonizes the harsh and dynamic environment of the stomach in over one-half of the world's population and has been identified as a causal agent in a spectrum of pathologies that range from gastritis to invasive adenocarcinoma. The ferric uptake regulator (Fur) is one of the few regulatory proteins that has been identified in
H. pylori
. Fur regulates genes important for acid acclimation and oxidative stress and has been shown to be important for colonization of
H. pylori
in both murine and Mongolian gerbil models of infection. To more thoroughly define the role of Fur
in vivo
, we conducted an extensive temporal analysis of the location of, competitive ability of, and resultant pathology induced by a Δ
fur
strain in the Mongolian gerbil model of infection and compared the results to results for its wild-type parent. We found that at the earliest time points postinfection, significantly more Δ
fur
bacteria than wild-type bacteria were recovered. However, this trend was reversed by day 3, when there was significantly increased recovery of the wild-type strain. The increased recovery of the Δ
fur
strain at 1 day postinfection reflected increased recovery from both the corpus and the antrum of the stomach. When the wild-type strain was allowed to colonize first, the Δ
fur
strain was unable to compete for colonization at any time postinfection. However, when the Δ
fur
strain was allowed to colonize first, the wild type efficiently outcompeted the Δ
fur
strain only at early times postinfection. Finally, we demonstrated that there was a delay in the development and severity of inflammation and pathology of the Δ
fur
strain in the gastric mucosa even after comparable levels of colonization occurred. Together, these data indicate that
H. pylori
Fur is most important at early stages of infection and illustrate the importance of the ability of
H. pylori
to adapt to its constantly fluctuating environment when it is establishing infection, inflammation, and disease.
Three Paralogous LysR-Type Transcriptional Regulators Control Sulfur Amino Acid Supply in
Streptococcus mutans
Authors: Sperandio Brice , Gautier Céline , Pons Nicolas , Ehrlich Dusko S. , Renault Pierre , Guédon Eric
Published: April 2010

The genome of
Streptococcus mutans
encodes 4 LysR-type transcriptional regulators (LTTRs), three of which, MetR, CysR (
cys
teine synthesis
r
egulator), and HomR (
hom
ocysteine synthesis
r
egulator), are phylogenetically related. MetR was previously shown to control methionine metabolic gene expression. Functional analysis of CysR and HomR was carried out by phenotypical studies and transcriptional analysis. CysR is required to activate the transcription of
cysK
encoding the cysteine biosynthesis enzyme,
tcyABC
and
gshT
genes encoding cysteine and glutathione transporter systems, and
homR
. HomR activates the transcription of
metBC
encoding methionine biosynthesis enzymes,
tcyDEFGH
involved in cysteine transport, and still uncharacterized thiosulfate assimilation genes. Control of HomR by CysR provides evidence of a cascade regulation for sulfur amino acid metabolism in
S. mutans
. Two conserved motifs were found in the promoter regions of CysR and HomR target genes, suggesting their role in the regulator binding recognition site. Both CysR and HomR require
O
-acetylserine to activate transcription. A global sulfur amino acid supply gene regulatory pathway is proposed for
S. mutans
, including the cascade regulation consequent to transcriptional activation of HomR by CysR. Phylogenetic study of MetR, CysR, and HomR homologues and comparison of their potential regulatory patterns among the
Streptococcaceae
suggest their rapid evolution.
The Virulence of aDickeya dadantii3937 Mutant Devoid of Osmoregulated Periplasmic Glucans Is Restored by Inactivation of the RcsCD-RcsB Phosphorelay
Authors: Bouchart Franck , Boussemart Gilles , Prouvost Anne-France , Cogez Virginie , Madec Edwige , Vidal Olivier , Delrue Brigitte , Bohin Jean-Pierre , Lacroix Jean-Marie
Published: April 2010

Dickeya dadantiiis a pectinolytic phytopathogen enterobacterium that causes soft rot disease on a wide range of plant species. The virulence ofD. dadantiiinvolves several factors, including the osmoregulated periplasmic glucans (OPGs) that are general constituents of the envelope of proteobacteria. In addition to the loss of virulence,opg-negative mutants display a pleiotropic phenotype, including decreased motility and increased exopolysaccharide synthesis. A nitrosoguanidine-induced mutagenesis was performed on theopgGstrain, and restoration of motility was used as a screen. The phenotype of theopgmutant echoes that of the Rcs system: high level activation of the RcsCD-RcsB phosphorelay is needed to activate exopolysaccharide synthesis and to repress motility, while low level activation is required for virulence in enterobacteria. Here, we show that mutations in the RcsCDB phosphorelay system restored virulence and motility in aD. dadantii opg-negative strain, indicating a relationship between the Rcs phosphorelay and OPGs.
Methanococci Use the Diaminopimelate Aminotransferase (DapL) Pathway for Lysine Biosynthesis
Authors: Liu Yuchen , White Robert H. , Whitman William B.
Published: April 2010

The pathway of lysine biosynthesis in the methanococci has not been identified previously. A variant of the diaminopimelic acid (DAP) pathway uses diaminopimelate aminotransferase (DapL) to catalyze the direct conversion of tetrahydrodipicolinate (THDPA) to
ll
-DAP. Recently, the enzyme DapL (MTH52) was identified in
Methanothermobacter thermautotrophicus
and shown to belong to the DapL1 group. Although the
Methanococcus maripaludis
genome lacks a gene that can be unambiguously assigned a DapL function based on sequence similarity, the open reading frame MMP1527 product shares 30% amino acid sequence identity with MTH52. A Δ
mmp1527
deletion mutant was constructed and found to be a lysine auxotroph, suggesting that this DapL homolog in methanococci is required for lysine biosynthesis. In cell extracts of the
M. maripaludis
wild-type strain, the specific activity of DapL using
ll
-DAP and α-ketoglutarate as substrates was 24.3 ± 2.0 nmol min
−1
mg of protein
−1
. The gene encoding the DapL homolog in
Methanocaldococcus jannaschii
(MJ1391) was cloned and expressed in
Escherichia coli
, and the protein was purified. The maximum activity of MJ1391 was observed at 70°C and pH 8.0 to 9.0. The apparent

K
m

s of MJ1391 for
ll
-DAP and α-ketoglutarate were 82.8 ± 10 μM and 0.42 ± 0.02 mM, respectively. MJ1391 was not able to use succinyl-DAP or acetyl-DAP as a substrate. Phylogenetic analyses suggested that two lateral gene transfers occurred in the DapL genes, one from the archaea to the bacteria in the DapL2 group and one from the bacteria to the archaea in the DapL1 group. These results demonstrated that the DapL pathway is present in marine methanogens belonging to the
Methanococcales
.
Repression of
recA
Induction by RecX Is Independent of the RecA Protein in
Deinococcus radiodurans
Authors: Sheng Duohong , Li Mingfeng , Jiao Jiandong , Sheng Xiehuang , Deng Wenqiang , Hua Yuejin
Published: April 2010

Besides inhibiting RecA activity at the protein level,
Deinococcus radiodurans
RecX can suppress RecA induction at the transcriptional level. The regulation of RecX on
recA
induction is independent of RecA activity, and its N terminus is involved in this process.
Multiple Signals Direct the Assembly and Function of a Type 1 Secretion System
Authors: Masi Muriel , Wandersman Cécile
Published: April 2010

Type 1 secretion systems (T1SS) are present in a wide range of Gram-negative bacteria and are involved in the secretion of diverse substrates such as proteases, lipases, and hemophores. T1SS consist of three proteins: an inner membrane ABC (ATP binding cassette) protein, a periplasmic adaptor, and an outer membrane channel of the TolC family. Assembly of the tripartite complex is transient and induced upon binding of the substrate to the ABC protein. It is generally accepted that T1SS-secreted proteins have a C-terminal secretion signal required for secretion and that this signal interacts with the ABC protein. However, we have previously shown that for the
Serratia marcescens
hemophore HasA, interactions with the ABC protein and subsequent T1SS assembly require additional regions. In this work, we characterize these regions and demonstrate that they are numerous, distributed throughout the HasA polypeptide, and most likely linear. Together with the C-terminal signal, these elements maximize the secretion of HasA. The data also show that the C-terminal signal of HasA triggers HasD-driven ATP hydrolysis, leading to disassembly of the complex. These data support a model of type 1 secretion involving a multistep interaction between the substrate and the ABC protein that stabilizes the assembled secretion system until the C terminus is presented. This model also supports tight coupling between synthesis and secretion.
Initiation of Decay of
Bacillus subtilis rpsO
mRNA by Endoribonuclease RNase Y
Authors: Yao Shiyi , Bechhofer David H.
Published: April 2010

rpsO
mRNA, a small monocistronic mRNA that encodes ribosomal protein S15, was used to study aspects of mRNA decay initiation in
Bacillus subtilis
. Decay of
rpsO
mRNA in a panel of 3′-to-5′ exoribonuclease mutants was analyzed using a 5′-proximal oligonucleotide probe and a series of oligonucleotide probes that were complementary to overlapping sequences starting at the 3′ end. The results provided strong evidence that endonuclease cleavage in the body of the message, rather than degradation from the native 3′ end, is the rate-determining step for mRNA decay. Subsequent to endonuclease cleavage, the upstream products were degraded by polynucleotide phosphorylase (PNPase), and the downstream products were degraded by the 5′ exonuclease activity of RNase J1. The
rpsO
mRNA half-life was unchanged in a strain that had decreased RNase J1 activity and no RNase J2 activity, but it was 2.3-fold higher in a strain with decreased activity of RNase Y, a recently discovered RNase of
B. subtilis
encoded by the
ymdA
gene. Accumulation of full-length
rpsO
mRNA and its decay intermediates was analyzed using a construct in which the
rpsO
transcription unit was under control of a bacitracin-inducible promoter. The results were consistent with RNase Y-mediated initiation of decay. This is the first report of a specific mRNA whose stability is determined by RNase Y.
Complete Genome Sequence of the Photosynthetic Purple Nonsulfur Bacterium
Rhodobacter capsulatus
SB 1003
Authors: Strnad Hynek , Lapidus Alla , Paces Jan , Ulbrich Pavel , Vlcek Cestmir , Paces Vaclav , Haselkorn Robert
Published: April 2010

Rhodobacter capsulatus
SB 1003 belongs to the group of purple nonsulfur bacteria. Its genome consists of a 3.7-Mb chromosome and a 133-kb plasmid. The genome encodes genes for photosynthesis, nitrogen fixation, utilization of xenobiotic organic substrates, and synthesis of polyhydroxyalkanoates. These features made it a favorite research tool for studying these processes. Here we report its complete genome sequence.
Genome Sequences of
Oceanicola granulosus
HTCC2516
T
and
O
ceanicola batsensis
HTCC2597
T
Authors: Thrash J. Cameron , Cho Jang-Cheon , Vergin Kevin L. , Giovannoni Stephen J.
Published: April 2010

Genome sequences from the prolific
Roseobacter
clade in the
Alphaproteobacteria
are beginning to reveal the genetic basis for the diverse lifestyles of these organisms. Here we present the genome sequences of
Oceanicola granulosus
HTCC2516
T
and
O
ceanicola batsensis
HTCC2597
T
, two marine
Roseobacter
species isolated from the Sargasso Sea using dilution-to-extinction culturing, whose genomes encode for significant differences in metabolic potential.
YieJ (CbrC) Mediates CreBC-Dependent Colicin E2 Tolerance in
Escherichia coli
Authors: Cariss S. James L. , Constantinidou Chrystala , Patel Mala D. , Takebayashi Yuiko , Hobman Jon L. , Penn Charles W. , Avison Matthew B.
Published: April 2010

Colicin E2-tolerant (known as Cet2)
Escherichia coli
K-12 mutants overproduce an inner membrane protein, CreD, which is believed to cause the Cet2 phenotype. Here, we show that overproduction of CreD in a Cet2 strain results from hyperactivation of the CreBC two-component regulator, but CreD overproduction is not responsible for the Cet2 phenotype. Through microarray analysis and gene knockout and overexpression studies, we show that overexpression of another CreBC-regulated gene,
yieJ
(also known as
cbrC
), causes the Cet2 phenotype.
Functional Organization of the Inverted Repeats of IS30
Authors: Szabó Mónika , Kiss János , Olasz Ferenc
Published: April 2010

The mobile element IS30has 26-bp imperfect terminal inverted repeats (IRs) that are indispensable for transposition. We have analyzed the effects of IR mutations on both major transposition steps, the circle formation and integration of the abutted ends, characteristic for IS30. Several mutants show strikingly different phenotypes if the mutations are present at one or both ends and differentially influence the transposition steps. The two IRs are equivalent in the recombination reactions and contain several functional regions. We have determined that positions 20 to 26 are responsible for binding of the N-terminal domain of the transposase and the formation of a correct 2-bp spacer between the abutted ends. However, integration is efficient without this region, suggesting that a second binding site for the transposase may exist, possibly within the region from 4 to 11 bp. Several mutations at this part of the IRs, which are highly conserved in the IS30family, considerably affected both major transposition steps. In addition, positions 16 and 17 seem to be responsible for distinguishing the IRs of related insertion sequences by providing specificity for the transposase to recognize its cognate ends. Finally, we show bothin vivoandin vitrothat position 3 has a determining role in the donor function of the ends, especially in DNA cleavage adjacent to the IRs. Taken together, the present work provides evidence for a more complex organization of the IS30IRs than was previously suggested.
Vp1659 Is a
Vibrio parahaemolyticus
Type III Secretion System 1 Protein That Contributes to Translocation of Effector Proteins Needed To Induce Cytolysis, Autophagy, and Disruption of Actin Structure in HeLa Cells
Authors: Zhou Xiaohui , Konkel Michael E. , Call Douglas R.
Published: April 2010

Vibrio parahaemolyticus
harbors two type III secretion systems (T3SSs; T3SS1 and T3SS2), of which T3SS1 is involved in host cell cytotoxicity. T3SS1 expression is positively regulated by ExsA, and it is negatively regulated by ExsD. We compared the secretion profiles of a wild-type strain (NY-4) of
V. parahaemolyticus
with those of an ExsD deletion mutant (Δ
exsD
) and with a strain of NY-4 that overexpresses T3SS1 (NY-4:p
exsA
). From this comparison, we detected a previously uncharacterized protein, Vp1659, which shares some sequence homology with LcrV from
Yersinia
. We show that
vp1659
expression is positively regulated by ExsA and is negatively regulated by ExsD. Vp1659 is specifically secreted by T3SS1 of
V. parahaemolyticus
, and Vp1659 is not required for the successful extracellular secretion of another T3SS1 protein, Vp1656. Mechanical fractionation showed that Vp1659 is translocated into HeLa cells in a T3SS1-dependent manner and that deletion of Vp1659 does not prevent VopS from being translocated into HeLa cells during infection. Deletion of
vp1659
significantly reduces cytotoxicity when HeLa cells are infected by
V. parahaemolyticus
, while complementation of the Δ
vp1659
strain restores cytotoxicity. Differential staining showed that Vp1659 is required to induce membrane permeability in HeLa cells. We also show evidence that Vp1659 is required for actin rearrangement and the induction of autophagy. On the basis of these data, we conclude that Vp1659 is a T3SS1-associated protein that is a component of the secretion apparatus and that it is necessary for the efficient translocation of effector proteins into epithelial cells.
Isolation of the Fungus
Geosmithia argillacea
in Sputum of People with Cystic Fibrosis
Authors: Barton R. C. , Borman A. M. , Johnson E. M. , Houbraken J. , Hobson R. P. , Denton M. , Conway S. P. , Brownlee K. G. , Peckham D. , Lee T. W. R.
Published: April 2010

We report the repeated isolation of the fungus
Geosmithia argillacea
from sputum samples of people with cystic fibrosis. Identification was based on morphology and DNA sequence analysis. Isolation of
G. argillacea
did not appear to be associated with clinical deterioration. The pathogenic potential of
G. argillacea
is discussed.
Does Bleach Processing Increase the Accuracy of Sputum Smear Microscopy for Diagnosing Pulmonary Tuberculosis?
Authors: Cattamanchi A. , Davis J. L. , Pai M. , Huang L. , Hopewell P. C. , Steingart K. R.
Published: April 2010

Bleach digestion of sputum prior to smear preparation has been reported to increase the yield of microscopy for diagnosing pulmonary tuberculosis, even in high-HIV-prevalence settings. To determine the diagnostic accuracy of bleach microscopy, we updated a systematic review published in 2006 and applied the Grading of Recommendations Assessment, Development, and Evaluation framework to rate the overall quality of the evidence. We searched multiple databases (as of January 2009) for primary studies in all languages comparing bleach and direct microscopy. We assessed study quality using a validated tool and heterogeneity by standard methods. We used hierarchical summary receiver operating characteristic (HSROC) analysis to calculate summary estimates of diagnostic accuracy and random-effects meta-analysis to pool sensitivity and specificity differences. Of 14 studies (11 papers) included, 9 evaluated bleach centrifugation and 5 evaluated bleach sedimentation. Overall, examination of bleach-processed versus direct smears led to small increases in sensitivity (for bleach centrifugation, 6% [95% confidence interval {CI} = 3 to 10%,
P
= 0.001]; for bleach sedimentation, 9% [95% CI = 4 to 14%,
P
= 0.001]) and small decreases in specificity (for bleach centrifugation, −3% [95% CI = −4% to −1%,
P
= 0.004]; for bleach sedimentation, −2% [95% CI = −5% to 0%,
P
= 0.05]). Similarly, analysis of HSROC curves suggested little or no improvement in diagnostic accuracy. The quality of evidence was rated very low for both bleach centrifugation and bleach sedimentation. This updated systematic review suggests that the benefits of bleach processing are less than those described previously. Further research should focus on alternative approaches to optimizing smear microscopy, such as light-emitting diode fluorescence microscopy and same-day sputum collection strategies.
Development and Evaluation of a Simple Assay for Marburg Virus Detection Using a Reverse Transcription-Loop-Mediated Isothermal Amplification Method
Authors: Kurosaki Yohei , Grolla Allen , Fukuma Aiko , Feldmann Heinz , Yasuda Jiro
Published: April 2010

Marburg virus (MARV) causes a severe hemorrhagic fever in humans with a high mortality rate. The rapid and accurate identification of the virus is required to appropriately provide infection control and outbreak management. Here, we developed and evaluated a one-step reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay for the rapid and simple detection of MARV. By combining two sets of primers specific for the Musoke and Ravn genetic lineages, a multiple RT-LAMP assay detected MARV strains of both lineages, and no cross-reactivity with other hemorrhagic fever viruses (Ebola virus and Lassa virus) was observed. The assay could detect 10
2
copies of the viral RNA per tube within 40 min by real-time monitoring of the turbidities of the reaction mixtures. The assay was further evaluated using viral RNA extracted from clinical specimens collected in the 2005 Marburg hemorrhagic fever outbreak in Angola and yielded positive results for samples containing MARV at greater than 10
4
50% tissue culture infective doses/ml, exhibiting 78% (14 of 18 samples positive) consistency with the results of a reverse transcription-PCR assay carried out in the field laboratory. The results obtained by both agarose gel electrophoresis and naked-eye judgment indicated that the RT-LAMP assay developed in this study is an effective tool for the molecular detection of MARV. Furthermore, it seems suitable for use for field diagnostics or in laboratories in areas where MARV is endemic.
Mupirocin Resistance Related to Increasing Mupirocin Use in Clinical Isolates of Methicillin-Resistant
Staphylococcus aureus
in a Pediatric Population
Authors: Hogue Jacob S. , Buttke Patricia , Braun LoRanee E. , Fairchok Mary P.
Published: April 2010

We investigated the proportion of methicillin-resistant
Staphylococcus aureus
(MRSA) isolates from pediatric patients demonstrating mupirocin resistance related to mupirocin use at our institution. No mupirocin resistance was found in 98% of isolates, whereas mupirocin prescriptions increased by 110%. Resistance rates remained low despite the increasing use of mupirocin.
Simple PCR-Based DNA Microarray System To Identify Human Pathogenic Fungi in Skin
Authors: Sato Tomotaka , Takayanagi Atsushi , Nagao Keisuke , Tomatsu Nobuhiro , Fukui Toshifumi , Kawaguchi Masahiro , Kudoh Jun , Amagai Masayuki , Yamamoto Nobuko , Shimizu Nobuyoshi
Published: April 2010

Fungal diseases in immunocompromised hosts pose significant threats to their prognoses. An accurate diagnosis and identification of the fungal pathogens causing the infection are critical to determine the proper therapeutic interventions, but these are often not achieved, due to difficulties with isolation and morphological identification. In an effort to ultimately carry out the simultaneous detection of all human pathogenic microbes, we developed a simple system to identify 26 clinically important fungi by using a combination of PCR amplification and DNA microarray assay (designated PCR-DM), in which PCR-amplified DNA from the internal transcribed spacer region of the rRNA gene was hybridized to a DNA microarray fabricated with species-specific probes sets using the Bubble Jet technology. PCR-DM reliably identified all 26 reference strains; hence, we applied it to cases of onychomycosis, taking advantage of the accessibility of tissue from skin. PCR-DM detected fungal DNA and identified pathogens in 92% of 106 microscopy-confirmed onychomycosis specimens. In contrast, culture was successful for only 36 specimens (34%), 3 of which had results inconsistent with the results of PCR-DM, but sequence analysis of the isolates proved that the PCR-DM result was correct. Thus, PCR-DM provides a powerful method to identify pathogenic fungi with high sensitivity and speed directly from tissue specimens, and this concept could be applied to other fungal or nonfungal infectious human diseases in less accessible anatomical sites.
HER-2/NEU overexpression in vulvar Paget disease: the Yale experience
Authors: Richter Christine E , Hui Pei , Buza Natalia , Silasi Dan-Arin , Azodi Masoud , Santin Alessandro D , Schwartz Peter E , Rutherford Thomas J
Published: April 2010

Aims

To determine the level of HER-2/neu overexpression in vulvar Paget disease (PD) in order to assess the possibility of using HER-2/neu as a target for the treatment of Paget disease.

Methods

A medical record search identified 39 patients with a histologically confirmed diagnosis of vulvar PD between 1986 and 2009. A tissue microarray containing all 39 tumour samples was created, and corresponding sections were stained immunohistochemically with an anti-HER-2/neu-antibody (HercepTest). Staining results were reported on a scale from 0 to 3+. 2+ and 3+ were considered as HER-2/neu overexpression. The HER-2/neu expression was correlated with clinical, pathological and outcome data.

Results

Negative staining for HER-2/neu was noticed in four patients (12%), 1+ in 10 patients (30%), 2+ in 11 patients (33%) and 3+ in eight patients (25%), resulting in 19 patients with HER-2/neu overexpression (2+ and 3+, 58%) and 14 patients without HER-2/neu overexpression (0 and 1+, 42%). The proportion of HER-2/neu overexpression was higher in the patients with invasive than with non-invasive PD (71%, n=5/7 invasive PD vs 54%, n=14/26 non-invasive PD). There was no significant correlation between HER-2/neu staining results and clinical, pathological or outcome data.

Conclusions

Surgical treatment of vulvar Paget disease is associated with a high recurrence rate and extensive reconstructive procedures. In this study, over 50% of the patients with vulvar Paget disease overexpress HER-2/neu. Anti-HER-2/neu-antibodies like trastuzumab may therefore be an interesting treatment option for HER-2/neu-positive vulvar Paget disease. Clinical trials are needed to evaluate the efficacy of trastuzumab in this disease.
Optimal distance bounds for fast search on compressed time-series query logs
Authors: Vlachos Michail , Kozat Suleyman S. , Yu Philip S.
Published: April 2010

Consider a database of time-series, where each datapoint in the series records the total number of users who asked for a specific query at an internet search engine. Storage and analysis of such logs can be very beneficial for a search company from multiple perspectives. First, from a data organization perspective, because query Weblogs capture important trends and statistics, they can help enhance and optimize the search experience (keyword recommendation, discovery of news events). Second, Weblog data can provide an important polling mechanism for the microeconomic aspects of a search engine, since they can facilitate and promote the advertising facet of the search engine (understand what users request and when they request it).

Due to the sheer amount of time-series Weblogs, manipulation of the logs in a compressed form is an impeding necessity for fast data processing and compact storage requirements. Here, we explicate how to compute the lower and upper distance bounds on the time-series logs when working directly on their compressed form. Optimal distance estimation means tighter bounds, leading to better candidate selection/elimination and ultimately faster search performance. Our derivation of the optimal distance bounds is based on the careful analysis of the problem using optimization principles. The experimental evaluation suggests a clear performance advantage of the proposed method, compared to previous compression/search techniques. The presented method results in a 10--30% improvement on distance estimations, which in turn leads to 25--80% improvement on the search performance.
In the Virtual Extension
Authors: CACM Staff
Published: April 2010

Communications
' Virtual Extension brings more quality articles to ACM members. These articles are now available in the ACM Digital Library.
Cloud computing and developing nations
Authors: Greengard Samuel
Published: April 2010

For a growing number of organizations worldwide, cloud computing offers a quick and affordable way to tap into IT infrastructure as an Internet service. But obstacles and challenges remain.
Is mobile email addiction overlooked?
Authors: Turel Ofir , Serenko Alexander
Published: April 2010

Studying the prevalence of mobile email addiction and the associated possible implications for organizations.
Consistency without concurrency control in large, dynamic systems
Authors: Letia Mihai , Preguiça Nuno , Shapiro Marc
Published: April 2010

Replicas of a commutative replicated data type (CRDT) eventually converge without any complex concurrency control. We validate the design of a non-trivial CRDT, a replicated sequence, with performance measurements in the context of Wikipedia. Furthermore, we discuss how to eliminate a remaining scalability bottleneck: Whereas garbage collection previously required a system-wide consensus, here we propose a flexible two-tier architecture and a protocol for migrating between tiers. We also discuss how the CRDT concept can be generalised, and its limitations.
A case for the accountable cloud
Authors: Haeberlen Andreas
Published: April 2010

For many companies, clouds are becoming an interesting alternative to a dedicated IT infrastructure. However, cloud computing also carries certain risks for both the customer and the cloud provider. The customer places his computation and data on machines he cannot directly control; the provider agrees to run a service whose details he does not know. If something goes wrong - for example, data leaks to a competitor, or the computation returns incorrect results - it can be difficult for customer and provider to determinewhich of themhas caused the problem, and, in the absence of solid evidence, it is nearly impossible for them to hold each other responsible for the problem if a dispute arises.

In this paper, we propose that the cloud should be made accountable to both the customer and the provider. Both parties should be able to check whether the cloud is running the service as agreed. If a problem appears, they should be able to determine which of them is responsible, and to prove the presence of the problem to a third party, such as an arbitrator or a judge. We outline the technical requirements for an accountable cloud, and we describe several challenges that are not yet met by current accountability techniques.
QUeST 2009 Workshop Report
Authors: Kröger Peer , Renz Matthias
Published: April 2010

Querying and mining uncertain data has received a lot of attention from the research community in recent years due to the enormous increase of geographically referenced data occasioned by developments in IT, digital mapping and remote sensing. The global expansion of Geo Information Systems emphasizes the importance of developing data driven inductive approaches to geographical analysis and modeling. An important problem is that collected data often is inherently imprecise and may contain incomplete, inaccurate or outdated information. Such data arises particular in dynamic environments. Traditional querying and mining approaches are often inapplicable or may extract misleading or plain wrong information when applied to uncertain data.
Alterations in membrane type-1 matrix metalloproteinase abundance after the induction of thoracic aortic aneurysm in a murine model
Authors: Jones Jeffrey A. , Ruddy Jean Marie , Bouges Shenikqua , Zavadzkas Juozas A. , Brinsa Theresa A. , Stroud Robert E. , Mukherjee Rupak , Spinale Francis G. , Ikonomidis John S.
Published: April 2010

Thoracic aortic aneurysms (TAAs) develop as a result of dysregulated extracellular matrix remodeling mediated by several matrix metalloproteinases (MMPs). Membrane type-1 MMP (MT1-MMP) is the prototypical member of a unique family of membrane-bound MMPs, possessing multiple substrates and functions. The present study tested the hypothesis that MT1-MMP expression, abundance, and activity would be elevated during TAA development and that this protease is produced primarily by mesenchymal cells within the thoracic aorta. Descending thoracic aortas were harvested from C57BL/6J mice at multiple time points (2, 4, 8, and 16 wk, n = 15 each) post-TAA induction (0.5M CaCl2, 15 min) and compared with reference controls ( n = 15). The expression and abundance of MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase (TIMP)-2 were assessed by quantitative PCR and immunoblot analysis. MT1-MMP activity was determined by fluorescent peptide assay. MT1-MMP was localized within the aortic wall by immunohistochemistry. MT1-MMP abundance and localization in live animals (8 wk post-TAA induction vs. control) was determined by microultrasound imaging with an MT1-MMP-targeted microbubble contrast agent. Aortic diameter was increased 172 ± 7% at 16 wk post-TAA induction ( P < 0.05). MT1-MMP and MMP-2 mRNA levels were elevated at 2 wk post-TAA induction ( P < 0.05). MT1-MMP protein abundance increased progressively to a maximum of 178 ± 26% at 16 wk post-TAA induction, whereas MMP-2 and TIMP-2 peaked at 2 wk post-TAA induction (526 ± 93% and 376 ± 48%, respectively, P < 0.05). MT1-MMP colocalized with fibroblasts, and MT1-MMP-targeted contrast binding was elevated in 8-wk TAA-induced mice versus control mice (217 ± 53% vs. 81 ± 8%, P < 0.05). In conclusion, these novel results suggest that MT1-MMP plays a dynamic multifunctional role in TAA development and, therefore, may provide a significant target for therapeutic strategies.
Chronic femoral artery occlusion augments exercise pressor reflex in decerebrated rats
Authors: Tsuchimochi Hirotsugu , McCord Jennifer L. , Hayes Shawn G. , Koba Satoshi , Kaufman Marc P.
Published: April 2010

In decerebrated rats, we determined the pressor and cardioaccelerator reflex responses to static contraction of hindlimb muscles whose femoral arteries were either occluded 72 h before contraction, occluded 3 min before contraction, or freely perfused. We found that the pressor reflex arising from the limb whose femoral artery was occluded for 72 h before contraction (32 ± 5 mmHg, n = 16) was significantly higher than the pressor reflex arising from the contralateral freely perfused limb (15 ± 3 mmHg, n = 16, P < 0.001) or than that arising from the contralateral limb whose femoral artery was occluded for only 3 min (17 ± 4 mmHg, n = 16, P < 0.001). Moreover, the pressor reflex arising from the limb whose femoral artery was occluded for 3 min before the start of contraction was not significantly different than that arising from the contralateral freely perfused limb ( n = 16, P = 0.819). The pressor component of the reflex arising from the limb whose femoral artery was occluded for 72 h was not changed by transient receptor potential vanilloid (TRPV) 1 receptor blockade with iodo-resiniferatoxin ( n = 15, P = 0.272), although the cardioaccelerator component was significantly reduced ( P = 0.005). In addition, the pressor response evoked by capsaicin injection in the femoral artery of the 72-h occluded limb was more than double that evoked from the freely perfused limb ( P = 0.026). We conclude that chronic (i.e., 72 h) but not acute (3 min), femoral arterial occlusion augments pressor reflex arising from contraction of hindlimb muscles and that TRPV1 receptors play little role in this augmentation.
Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection
Authors: Ionova Irina A. , Vásquez-Vivar Jeannette , Cooley Brian C. , Khanna Ashwani K. , Whitsett Jennifer , Herrnreiter Anja , Migrino Raymond Q. , Ge Zhi-Dong , Regner Kevin R. , Channon Keith M. , Alp Nicholas J. , Pieper Galen M.
Published: April 2010

GTP cyclohydrolase I (GTPCH) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis. Decreases in GTPCH activity and expression have been shown in late stages of acute cardiac rejection, suggesting a deficit in BH4. We hypothesized that increasing intracellular levels of BH4by cardiac myocyte-targeted overexpression of GTPCH would diminish acute cardiac allograft rejection. Transgenic mice overexpressing GTPCH in the heart were generated and crossed on C57BL6 background. Wild-type and transgenic mouse donor hearts were transplanted into BALB/c recipient mice. Left ventricular (LV) function, histological rejection, BH4levels, and inflammatory cytokine gene expression (mRNA) were examined. Expression of human GTPCH was documented by PCR, Western analysis, and function by a significant ( P < 0.001) increase in cardiac BH4levels. GTPCH transgene decreased histological rejection (46%; P < 0.003) and cardiac myocyte injury (eosin autofluorescence; 56%; P < 0.0001) independent of changes in inflammatory cytokine expression or nitric oxide content. GTPCH transgene decreased IL-2 (88%; P < 0.002), IL-1R2 (42%; P < 0.0001), and programmed cell death-1 (67%; P < 0.0001) expression, whereas it increased fms-like tyrosine kinase 3 (156%; P < 0.0001) and stromal-derived factor-1 (2; 190%; P < 0.0001) expression. There was no difference in ejection fraction or fractional shortening; however, LV mass was significantly increased ( P < 0.05) only in wild-type grafts. The decreases in LV mass, cardiac injury, and histological rejection support a protective role of cardiac GTPCH overexpression and increased BH4synthesis in cardiac allografts. The mechanism of the decreased rejection appears related to decreased T cell proliferation and modulation of immune function by higher expression of genes involved in hematopoietic/stromal cell development and recruitment.
Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2
Authors: Ungvari Zoltan , Bagi Zsolt , Feher Attila , Recchia Fabio A. , Sonntag William E. , Pearson Kevin , de Cabo Rafael , Csiszar Anna
Published: April 2010

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. Resveratrol was also shown to confer vasoprotection in animal models of type 2 diabetes and aging. However, the mechanisms by which resveratrol exerts its antioxidative vasculoprotective effects are not completely understood. Using a nuclear factor-E2-related factor-2 (Nrf2)/antioxidant response element-driven luciferase reporter gene assay, we found that in cultured coronary arterial endothelial cells, resveratrol, in a dose-dependent manner, significantly increases transcriptional activity of Nrf2. Accordingly, resveratrol significantly upregulates the expression of the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1, γ-glutamylcysteine synthetase, and heme oxygenase-1. Resveratrol treatment also significantly attenuated high glucose (30 mM)-induced mitochondrial and cellular oxidative stress (assessed by flow cytometry using MitoSox and dihydroethidine staining). The aforementioned effects of resveratrol were significantly attenuated by the small interfering RNA downregulation of Nrf2 or the overexpression of Kelch-like erythroid cell-derived protein 1, which inactivates Nrf2. To test the effects of resveratrol in vivo, we used mice fed a high-fat diet (HFD), which exhibit increased vascular oxidative stress associated with an impaired endothelial function. In HFD-fed Nrf2+/+ mice, resveratrol treatment attenuates oxidative stress (assessed by the Amplex red assay), improves acetylcholine-induced vasodilation, and inhibits apoptosis (assessed by measuring caspase-3 activity and DNA fragmentation) in branches of the femoral artery. In contrast, the aforementioned endothelial protective effects of resveratrol were diminished in HFD-fed Nrf2−/− mice. Taken together, our results indicate that resveratrol both in vitro and in vivo confers endothelial protective effects which are mediated by the activation of Nrf2.
Dose-related effects of red wine and alcohol on heart rate variability
Authors: Spaak Jonas , Tomlinson George , McGowan Cheri L. , Soleas George J. , Morris Beverley L. , Picton Peter , Notarius Catherine F. , Floras John S.
Published: April 2010

In healthy subjects a standard drink of either red wine (RW) or ethanol (EtOH) has no effect on muscle sympathetic nerve activity or on heart rate (HR), whereas two drinks increase both. Using time- and frequency-domain indexes of HR variability (HRV), we now tested in 12 subjects (24–47 yr, 6 men) the hypotheses that 1) this HR increase reflects concurrent dose-related augmented sympathetic HR modulation and 2) RW with high-polyphenol content differs from EtOH in its acute HRV effects. RW, EtOH, and water were provided on 3 days, 2 wk apart according to a randomized, single-blind design. Eight-minute segments were analyzed. One alcoholic drink increased blood concentrations to 36 ± 2 mg/dl (mean ± SE), and 2 drinks to 72 ± 4 (RW) and 80 ± 2 mg/dl (EtOH). RW quadrupled plasma resveratrol ( P < 0.001). HR fell after both water drinks. When compared with respective baselines, one alcoholic drink had no effect on HR or HRV, whereas two glasses of both increased HR (RW, +5.4 ± 1.2; and EtOH, +5.7 ± 1.2 min−1; P < 0.001), decreased total HRV by 28–33% ( P < 0.05) and high-frequency spectral power by 32–42% (vagal HR modulation), and increased low-frequency power by 28–34% and the ratio of low frequency to high frequency by 98–119% (sympathetic HR modulation) (all, P ≤ 0.01). In summary, when compared with water, one standard drink lowered time- and frequency-domain markers of vagal HR modulation. When compared with respective baselines, two alcoholic drinks increased HR by diminished vagal and augmented sympathetic HR modulation. Thus alcohol exerts dose-dependent HRV responses, with RW and EtOH having a similar effect.
Coexistence of cardiac troponin T variants reduces heart efficiency
Authors: Feng Han-Zhong , Jin J.-P.
Published: April 2010

Corresponding to the synchronized contraction of the myocardium and rhythmic pumping function of the heart, a single form of cardiac troponin T (cTnT) is present in the adult cardiac muscle of humans and most other vertebrate species. Alternative splicing variants of cTnT are found in failing human hearts and animal dilated cardiomyopathies. Biochemical analyses have shown that these cTnT variants are functional and produce shifted myofilament Ca2+sensitivity. We proposed a hypothesis that the coexistence of two or more functionally distinct TnT variants in the adult ventricular muscle that is normally activated as a syncytium may decrease heart function and cause cardiomyopathy (Huang et al., Am J Physiol Cell Physiol 294: C213–C222, 2008). In the present study, we studied transgenic mouse hearts expressing one or two cTnT variants in addition to normal adult cTnT to investigate whether desynchronized myofilament activation decreases ventricular efficiency. The function of ex vivo working hearts was examined in the absence of systemic neurohumoral influence. The results showed that the transgenic mouse hearts produced lower maximum left ventricular pressure, slower contractile and relaxation velocities, and decreased stroke volume compared with wild-type controls. Ventricular pumping efficiency, calculated by the ejection integral versus total systolic integral and cardiac work versus oxygen consumption, was significantly lower in transgenic mouse hearts and corresponded to the number of cTnT variants present. The results indicated a pathogenic mechanism in which the coexistence of functionally different cTnT variants in cardiac muscle reduces myocardial efficiency due to desynchronized thin filament activation.
Long-term tracking of bone marrow progenitor cells following intracoronary injection post-myocardial infarction in swine using MRI
Authors: Graham John J. , Foltz Warren D. , Vaags Andrea K. , Ward Michael R. , Yang Yuesong , Connelly Kim A. , Vijayaraghavan Ram , Detsky Jay S. , Hough Margaret R. , Stewart Duncan J. , Wright Graham A. , Dick Alexander J.
Published: April 2010

Magnetic resonance imaging (MRI) can track progenitor cells following direct intramyocardial injection. However, in the vast majority of post-myocardial infarction (MI) clinical trials, cells are delivered by the intracoronary (IC) route, which results in far greater dispersion within the myocardium. Therefore, we assessed whether the more diffuse distribution of cells following IC delivery could be imaged longitudinally with MRI. In 11 pigs (7 active, 4 controls), MI was induced by 90-min balloon occlusion of the left anterior descending coronary artery. Seven (0) days [median (interquartile range)] following MI, bone marrow progenitor cells (BMCs) were colabeled with an iron-fluorophore and a cell viability marker and delivered to the left anterior descending coronary artery distal to an inflated over-the-wire percutaneous transluminal coronary angioplasty balloon. T2*-weighted images were used to assess the location of the magnetically labeled cells over a 6-wk period post-MI. Immediately following cell delivery, hypointensity characteristic of the magnetic label was observed in the infarct border rather than within the infarct itself. At 6 wk, the cell signal hypointensity persisted, albeit with significantly decreased intensity. BMC delivery resulted in significant improvement in infarct volume and ejection fraction (EF): infarct volume in cell-treated animals decreased from 7.1 ± 1.5 to 4.9 ± 1.0 ml ( P < 0.01); infarct volume in controls was virtually unchanged at 4.64 ± 2.1 to 4.39 ± 2.1 ml ( P = 0.7). EF in cell-treated animals went from 30.4 ± 5.2% preinjection to 34.5 ± 2.5% 6 wk postinjection ( P = 0.013); EF in control animals went from 34.3 ± 4.7 to 31.9 ± 6.8% ( P = 0.5). Immunohistochemical analysis revealed intracellular colocalization of the iron fluorophore and cell viability dye with the labeled cells continuing to express the same surface markers as at baseline. MRI can track the persistence and distribution of magnetically labeled BMCs over a 6-wk period following IC delivery. Signal hypointensity declines with time, particularly in the first week following delivery. These cells maintain their original phenotype during this time course. Delivery of these cells appears safe and results in improvement in infarct size and left ventricular ejection fraction.
Oxidative lipidomics of hyperoxic acute lung injury: mass spectrometric characterization of cardiolipin and phosphatidylserine peroxidation
Authors: Tyurina Yulia Y. , Tyurin Vladimir A. , Kaynar A. Murat , Kapralova Valentyna I. , Wasserloos Karla , Li Jin , Mosher Mackenzie , Wright Lindsay , Wipf Peter , Watkins Simon , Pitt Bruce R. , Kagan Valerian E.
Published: April 2010

Reactive oxygen species have been shown to play a significant role in hyperoxia-induced acute lung injury, in part, by inducing apoptosis of pulmonary endothelium. However, the signaling roles of phospholipid oxidation products in pulmonary endothelial apoptosis have not been studied. Using an oxidative lipidomics approach, we identified individual molecular species of phospholipids involved in the apoptosis-associated peroxidation process in a hyperoxic lung. C57BL/6 mice were killed 72 h after exposure to hyperoxia (100% oxygen). We found that hyperoxia-induced apoptosis (documented by activation of caspase-3 and -7 and histochemical terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining of pulmonary endothelium) was accompanied by nonrandom oxidation of pulmonary lipids. Two anionic phospholipids, mitochondria-specific cardiolipin (CL) and extramitochondrial phosphatidylserine (PS), were the two major oxidized phospholipids in hyperoxic lung. Using electrospray ionization mass spectrometry, we identified several oxygenation products in CL and PS. Quantitative assessments revealed a significant decrease of CL and PS molecular species containing C18:2, C20:4, C22:5, and C22:6fatty acids. Similarly, exposure of mouse pulmonary endothelial cells (MLEC) to hyperoxia (95% oxygen; 72 h) resulted in activation of caspase-3 and -7 and significantly decreased the content of CL molecular species containing C18:2and C20:4as well as PS molecular species containing C22:5and C22:6. Oxygenated molecular species were found in the same two anionic phospholipids, CL and PS, in MLEC exposed to hyperoxia. Treatment of MLEC with a mitochondria-targeted radical scavenger, a conjugate of hemi-gramicidin S with nitroxide, XJB-5-131, resulted in significantly lower oxidation of both CL and PS and a decrease in hyperoxia-induced changes in caspase-3 and -7 activation. We speculate that cytochrome c driven oxidation of CL and PS is associated with the signaling role of these oxygenated species participating in the execution of apoptosis and clearance of pulmonary endothelial cells, thus contributing to hyperoxic lung injury.