bluuebunny/crossref_metadata_2025 huggingface dataset:
β1 integrin cytoplasmic tyrosines promote skin tumorigenesis independent of their phosphorylation
Authors: Meves Alexander , Geiger Tamar , Zanivan Sara , DiGiovanni John , Mann Matthias , Fässler Reinhard
Published: August 2011

β1 integrin tyrosine phosphorylation by oncogenic kinases, such as Src, has been predicted to induce tumorigenesis by disrupting adhesion and modifying integrin signaling. We directly tested this hypothesis by subjecting mice with “nonphosphorylatable” tyrosine-to-phenylalanine substitutions in the conserved β1 cytoplasmic tail NPxY motifs to a model of cutaneous carcinogenesis in the presence or absence of elevated Src activity. We found that hydrophobic phenylalanine substitutions of both tyrosines diminished the binding of tail-interacting proteins, including talins and kindlins, resulting in reduced β1-mediated adhesion, focal adhesion kinase (FAK) signaling, and epidermal progenitor cell–derived skin tumors. However, increased Src activity drove tumor formation independent of the phenylalanine substitutions by enhancing FAK activity, which in turn maintained the epidermal progenitor state and blocked keratinocyte differentiation. We conclude that a Src/FAK signaling unit inhibits differentiation to promote tumorigenesis downstream of β1 integrin and independent of β1 integrin tyrosine phosphorylation.
Control of the function of the transcription and repair factor TFIIH by the action of the cochaperone Ydj1
Authors: Moriel-Carretero María , Tous Cristina , Aguilera Andrés
Published: August 2011

Yeast
rad3-102
, a mutant of the TFIIH complex involved in nucleotide excision repair (NER) and transcription, can perform NER initial steps but not late steps of postincision gap filing. Because removal of early-acting NER proteins prevents
rad3-102
deleterious action, we used this feature to explore if chaperones act in early NER. We found that the cochaperone Ydj1 is required for NER and that Ydj1 guarantees TFIIH stoichiometry. Importantly, in the absence of Ydj1, the roles of TFIIH in transcription and transactivation, the ability to activate transcription by nuclear receptors in response to hormones, are strongly impaired. We propose that TFIIH constitutes a multitarget complex for Ydj1, as six of the seven TFIIH core components contain biologically relevant Ydj1- binding motives. Our results provide evidence for a role of chaperones in NER and transcription, with implications in cancer and TFIIH-associated syndromes.
PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis
Authors: Ilic Nina , Utermark Tamara , Widlund Hans R. , Roberts Thomas M.
Published: August 2011

The PI3K pathway is frequently activated in cancer; therefore, considerable effort is focused on identifying compounds that can inhibit specific pathway components, particularly the hallmark oncogene PIK3CA. Although targeted inhibition of a cancer survival gene holds significant promise, there are concerns that drug resistance may emerge within the cancerous cells, thus limiting clinical efficacy. Using genetically defined human mammary epithelial cells, we evolved resistance to the PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235, and by genome-wide copy number analyses, we identified
MYC
and
eIF4E
amplification within the resistant cells. Importantly, either MYC or eukaryotic translation initiation factor 4E (eIF4E) was required to bypass pharmacological PI3K/mTOR inhibition in resistant cells. Furthermore, these cells displayed elevated 5′ cap-dependent protein translation. Collectively, these findings suggest that analysis of drivers of protein translation could facilitate the identification of cancer lesions that confer resistance to PI3K pathway-targeted drugs.
Formation of plant metabolic gene clusters within dynamic chromosomal regions
Authors: Field Ben , Fiston-Lavier Anna-Sophie , Kemen Ariane , Geisler Katrin , Quesneville Hadi , Osbourn Anne E.
Published: August 2011

In bacteria, genes with related functions often are grouped together in operons and are cotranscribed as a single polycistronic mRNA. In eukaryotes, functionally related genes generally are scattered across the genome. Notable exceptions include gene clusters for catabolic pathways in yeast, synthesis of secondary metabolites in filamentous fungi, and the major histocompatibility complex in animals. Until quite recently it was thought that gene clusters in plants were restricted to tandem duplicates (for example, arrays of leucine-rich repeat disease-resistance genes). However, operon-like clusters of coregulated nonhomologous genes are an emerging theme in plant biology, where they may be involved in the synthesis of certain defense compounds. These clusters are unlikely to have arisen by horizontal gene transfer, and the mechanisms behind their formation are poorly understood. Previously in thale cress (
Arabidopsis thaliana
) we identified an operon-like gene cluster that is required for the synthesis and modification of the triterpene thalianol. Here we characterize a second operon-like triterpene cluster (the marneral cluster) from
A. thaliana
, compare the features of these two clusters, and investigate the evolutionary events that have led to cluster formation. We conclude that common mechanisms are likely to underlie the assembly and control of operon-like gene clusters in plants.
Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance
Authors: Kendal Adrian R. , Chen Ye , Regateiro Frederico S. , Ma Jianbo , Adams Elizabeth , Cobbold Stephen P. , Hori Shohei , Waldmann Herman
Published: August 2011

A paradigm shift in immunology has been the recent discovery of regulatory T cells (T reg cells), of which CD4+Foxp3+ cells are proven as essential to self-tolerance. Using transgenic B6.Foxp3hCD2 mice to isolate and ablate Foxp3+ T reg cells with an anti-hCD2 antibody, we show for the first time that CD4+Foxp3+ cells are crucial for infectious tolerance induced by nonablative anti–T cell antibodies. In tolerant animals, Foxp3+ T reg cells are constantly required to suppress effector T cells still capable of causing tissue damage. Tolerated tissue contains T cells that are capable of rejecting it, but are prevented from doing so by therapeutically induced Foxp3+ T reg cells. Finally, Foxp3+ cells have been confirmed as the critical missing link through which infectious tolerance operates in vivo. Peripherally induced Foxp3+ cells sustain tolerance by converting naive T cells into the next generation of Foxp3+ cells. Empowering Foxp3+ regulatory T cells in vivo offers a tractable route to avoid and correct tissue immunopathology.
Blow-up criteria for a parabolic problem due to a concentrated nonlinear source on a semi-infinite interval
Authors: Chan C. , Treeyaprasert T.
Published: August 2011

Let

α
\alpha

,

b
b

and

T
T

be positive numbers,

D
=

(
0
,
∞
)

D=\left ( 0,\infty \right )

,

D
¯

=

[
0
,
∞
)

\bar {D}=\left [0,\infty \right )

, and

Ω
=
D
×

(
0
,
T
]

\Omega =D\times \left (0,T\right ]

. This article studies the first initial-boundary value problem,
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartLayout 1st Row u Subscript t Baseline minus u Subscript x x Baseline equals alpha delta left-parenthesis x minus b right-parenthesis f left-parenthesis u left-parenthesis x comma t right-parenthesis right-parenthesis in normal upper Omega comma 2nd Row u left-parenthesis x comma 0 right-parenthesis equals psi left-parenthesis x right-parenthesis on upper D overbar comma 3rd Row u left-parenthesis 0 comma t right-parenthesis equals 0 equals limit Underscript x right-arrow normal infinity Endscripts u left-parenthesis x comma t right-parenthesis for 0 greater-than t less-than-or-equal-to upper T comma EndLayout">

u

t

−

u

x
x

=
α
δ
(
x
−
b
)
f

(
u
(
x
,
t
)
)

 in 
Ω
,

u
(
x
,
0
)
=
ψ
(
x
)
 on 

D
¯

,

u
(
0
,
t
)
=
0
=

lim

x
→
∞

u
(
x
,
t
)
 for 
0
>
t
≤
T
,

\begin {array} [c]{c} u_{t}-u_{xx}=\alpha \delta (x-b)f\left ( u(x,t)\right ) \text { in }\Omega ,\\ u(x,0)=\psi (x)\text { on }\bar {D},\\ u(0,t)=0=\lim _{x\rightarrow \infty }u(x,t)\text { for }0>t\leq T, \end {array}

\]
where

δ

(
x
)

\delta \left ( x\right )

is the Dirac delta function, and

f
f

and

ψ
\psi

are given functions. We assume that

f

(
0
)

≥
0

f\left ( 0\right ) \geq 0

,

f
(
u
)

f(u)

and its derivatives

f

′

(
u
)

f^{\prime }(u)

and

f

′
′

(
u
)

f^{\prime \prime }\left ( u\right )

are positive for

u
>
0

u>0

, and

ψ
(
x
)

\psi (x)

is nontrivial, nonnegative and continuous such that

ψ

(
0
)

=
0
=

lim

x
→
∞

ψ

(
x
)

\psi \left ( 0\right ) =0=\lim _{x\rightarrow \infty }\psi \left ( x\right )

, and
\[

ψ

′
′

+
α
δ
(
x
−
b
)
f

(
ψ
)

≥
0
 in 
D
.

\psi ^{\prime \prime }+\alpha \delta (x-b)f\left ( \psi \right ) \geq 0\text { in } D\text {.}

\]
It is shown that if

u
u

blows up, then it blows up in a finite time at the single point

b
b

only. A criterion for

u
u

to blow up in a finite time and a criterion for

u
u

to exist globally are given. It is also shown that there exists a critical position

b

∗

b^{\ast }

for the nonlinear source to be placed such that no blowup occurs for

b
≤

b

∗

b\leq b^{\ast }

, and

u
u

blows up in a finite time for

b
>

b

∗

b>b^{\ast }

. This also implies that

u
u

does not blow up in infinite time. The formula for computing

b

∗

b^{\ast }

is also derived. For illustrations, two examples are given.
Fast and accurate prediction of protein side-chain conformations
Authors: Liang Shide , Zheng Dandan , Zhang Chi , Standley Daron M.
Published: August 2011

Summary: We developed a fast and accurate side-chain modeling program [Optimized Side Chain Atomic eneRgy (OSCAR)-star] based on orientation-dependent energy functions and a rigid rotamer model. The average computing time was 18 s per protein for 218 test proteins with higher prediction accuracy (1.1% increase for χ1 and 0.8% increase for χ1+2) than the best performing program developed by other groups. We show that the energy functions, which were calibrated to tolerate the discrete errors of rigid rotamers, are appropriate for protein loop selection, especially for decoys without extensive structural refinement.

Availability: OSCAR-star and the 218 test proteins are available for download at http://sysimm.ifrec.osaka-u.ac.jp/OSCAR

Contact:  standley@ifrec.osaka-u.ac.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
COCOMAPS: a web application to analyze and visualize contacts at the interface of biomolecular complexes
Authors: Vangone Anna , Spinelli Raffaele , Scarano Vittorio , Cavallo Luigi , Oliva Romina
Published: August 2011

Summary: Herein we present COCOMAPS, a novel tool for analyzing, visualizing and comparing the interface in protein–protein and protein–nucleic acids complexes. COCOMAPS combines traditional analyses and 3D visualization of the interface with the effectiveness of intermolecular contact maps.

Availability: COCOMAPS is accessible as a public web tool at http://www.molnac.unisa.it/BioTools/cocomaps

Contact:  romina.oliva@uniparthenope.it; lcavallo@unisa.it
SCLpred: protein subcellular localization prediction by N-to-1 neural networks
Authors: Mooney Catherine , Wang Yong−Hong , Pollastri Gianluca
Published: August 2011

Summary: Knowledge of the subcellular location of a protein provides valuable information about its function and possible interaction with other proteins. In the post-genomic era, fast and accurate predictors of subcellular location are required if this abundance of sequence data is to be fully exploited. We have developed a subcellular localization predictor (SCLpred), which predicts the location of a protein into four classes for animals and fungi and five classes for plants (secreted, cytoplasm, nucleus, mitochondrion and chloroplast) using machine learning models trained on large non-redundant sets of protein sequences. The algorithm powering SCLpred is a novel Neural Network (N-to-1 Neural Network, or N1-NN) we have developed, which is capable of mapping whole sequences into single properties (a functional class, in this work) without resorting to predefined transformations, but rather by adaptively compressing the sequence into a hidden feature vector. We benchmark SCLpred against other publicly available predictors using two benchmarks including a new subset of Swiss-Prot Release 2010_06. We show that SCLpred surpasses the state of the art. The N1-NN algorithm is fully general and may be applied to a host of problems of similar shape, that is, in which a whole sequence needs to be mapped into a fixed-size array of properties, and the adaptive compression it operates may shed light on the space of protein sequences.

Availability: The predictive systems described in this article are publicly available as a web server at http://distill.ucd.ie/distill/.

Contact:  gianluca.pollastri@ucd.ie
Feature-based 3D motif filtering for ribosomal RNA
Authors: Shen Ying , Wong Hau−San , Zhang Shaohong , Yu Zhiwen
Published: August 2011

Motivation: RNA 3D motifs are recurrent substructures in an RNA subunit and are building blocks of the RNA architecture. They play an important role in binding proteins and consolidating RNA tertiary structures. RNA 3D motif searching consists of two steps: candidate generation and candidate filtering. We proposed a novel method, known as Feature-based RNA Motif Filtering (FRMF), for identifying motifs based on a set of moment invariants and the Earth Mover's Distance in the second step.

Results: A positive set of RNA motifs belonging to six characteristic types, with eight subtypes occurring in HM 50S, is compiled by us. The proposed method is validated on this representative set. FRMF successfully finds most of the positive fragments. Besides the proposed new method and the compiled positive set, we also recognize some new motifs, in particular a π-turn and some non-standard A-minor motifs are found. These newly discovered motifs provide more information about RNA structure conformation.

Availability: Matlab code can be downloaded from www.cs.cityu.edu.hk/~yingshen/FRMF.html

Contact:  cshswong@cityu.edu.hk

Supplementary information:  Supplementary data are available at Bioinformatics online.
Managing Childhood Obesity: Is it the Icing on the Cake?
Authors: Duncan Polly
Published: August 2011

One in four children starting primary school and one in three children leaving primary school in England are overweight or obese. This article will explore the problem of childhood obesity and in particular the role of the GP and other members of the primary care team in preventing and managing this complex problem.
Root-Localized Phytochrome Chromophore Synthesis Is Required for Photoregulation of Root Elongation and Impacts Root Sensitivity to Jasmonic Acid in Arabidopsis
Authors: Costigan Stephanie E. , Warnasooriya Sankalpi N. , Humphries Brock A. , Montgomery Beronda L.
Published: August 2011

Plants exhibit organ- and tissue-specific light responses. To explore the molecular basis of spatial-specific phytochrome-regulated responses, a transgenic approach for regulating the synthesis and accumulation of the phytochrome chromophore phytochromobilin (PΦB) was employed. In prior experiments, transgenic expression of the BILIVERDIN REDUCTASE (BVR) gene was used to metabolically inactivate biliverdin IXα, a key precursor in the biosynthesis of PΦB, and thereby render cells accumulating BVR phytochrome deficient. Here, we report analyses of transgenic Arabidopsis (Arabidopsis thaliana) lines with distinct patterns of BVR accumulation dependent upon constitutive or tissue-specific, promoter-driven BVR expression that have resulted in insights on a correlation between root-localized BVR accumulation and photoregulation of root elongation. Plants with BVR accumulation in roots and a PΦB-deficient elongated hypocotyl2 (hy2-1) mutant exhibit roots that are longer than those of wild-type plants under white illumination. Additional analyses of a line with root-specific BVR accumulation generated using a GAL4-dependent bipartite enhancer-trap system confirmed that PΦB or phytochromes localized in roots directly impact light-dependent root elongation under white, blue, and red illumination. Additionally, roots of plants with constitutive plastid-localized or root-specific cytosolic BVR accumulation, as well as phytochrome chromophore-deficient hy1-1 and hy2-1 mutants, exhibit reduced sensitivity to the plant hormone jasmonic acid (JA) in JA-dependent root inhibition assays, similar to the response observed for the JA-insensitive mutants jar1 and myc2. Our analyses of lines with root-localized phytochrome deficiency or root-specific phytochrome depletion have provided novel insights into the roles of root-specific PΦB, or phytochromes themselves, in the photoregulation of root development and root sensitivity to JA.
Charge-density distribution in hydrogen methylphosphonates of calcium and lithium
Authors: Mermer Adrian , Starynowicz Przemysław
Published: August 2011

Two new crystal structures, calcium bis(hydrogen methylphosphonate), Ca(CH3PO3H)2, and lithium hydrogen methylphosphonate, Li(CH3PO3H), have been obtained, and the experimental and theoretical charge densities, as well as their topological properties, are reported. Both compounds display layered structures. Each hydrogen methylphosphonate anion coordinates three metal cations in the calcium compound and four in the lithium one. Weak polarization of oxygen lone pairs is observed, with lithium showing somewhat stronger polarization strength than calcium. The reported topological properties from the density functional theory (DFT) and X-ray approach are consistent with each other. In both structures the P—O bonds have a significant share of ionic character. The hyperconjugation effects within the phosphonate group are quenched upon coordination of the metal cations.
A New PMHS Model for Lumbar Spine Injuries During Vertical Acceleration
Authors: Stemper Brian D. , Storvik Steven G. , Yoganandan Narayan , Baisden Jamie L. , Fijalkowski Ronald J. , Pintar Frank A. , Shender Barry S. , Paskoff Glenn R.
Published: August 2011

Ejection from military aircraft exerts substantial loads on the lumbar spine. Fractures remain common, although the overall survivability of the event has considerably increased over recent decades. The present study was performed to develop and validate a biomechanically accurate experimental model for the high vertical acceleration loading to the lumbar spine that occurs during the catapult phase of aircraft ejection. The model consisted of a vertical drop tower with two horizontal platforms attached to a monorail using low friction linear bearings. A total of four human cadaveric spine specimens (T12-L5) were tested. Each lumbar column was attached to the lower platform through a load cell. Weights were added to the upper platform to match the thorax, head-neck, and upper extremity mass of a 50th percentile male. Both platforms were raised to the drop height and released in unison. Deceleration characteristics of the lower platform were modulated by foam at the bottom of the drop tower. The upper platform applied compressive inertial loads to the top of the specimen during deceleration. All specimens demonstrated complex bending during ejection simulations, with the pattern dependent upon the anterior-posterior location of load application. The model demonstrated adequate inter-specimen kinematic repeatability on a spinal level-by-level basis under different subfailure loading scenarios. One specimen was then exposed to additional tests of increasing acceleration to induce identifiable injury and validate the model as an injury-producing system. Multiple noncontiguous vertebral fractures were obtained at an acceleration of 21 g with 488 g/s rate of onset. This clinically relevant trauma consisted of burst fracture at L1 and wedge fracture at L4. Compression of the vertebral body approached 60% during the failure test, with -6,106 N axial force and 168 Nm flexion moment. Future applications of this model include developing a better understanding of the vertebral injury mechanism during pilot ejection and developing tolerance limits for injuries sustained under a variety of different vertical acceleration scenarios.
Removing a Metabolic Roadblock
Authors: VanHook Annalisa M.
Published: August 2011

ERK signaling alters flux through the tricarboxylic acid cycle to influence cell proliferation.
Bovine Intestinal Bacteria Inactivate and Degrade Ceftiofur and Ceftriaxone with Multiple β-Lactamases
Authors: Wagner R. Doug , Johnson Shemedia J. , Cerniglia Carl E. , Erickson Bruce D.
Published: August 2011

The veterinary cephalosporin drug ceftiofur is rapidly degraded in the bovine intestinal tract. A cylinder-plate assay was used to detect microbiologically active ceftiofur, and high-performance liquid chromatography-mass spectrometry analysis was used to quantify the amount of ceftiofur remaining after incubation with bovine intestinal anaerobic bacteria, which were isolated from colon contents or feces from 8 cattle. Ninety-six percent of the isolates were able to inactivate ceftiofur to some degree, and 54% actually degraded the drug. None of 9 fungal isolates inactivated or degraded ceftiofur. Facultative and obligate anaerobic bacterial species that inactivated or degraded ceftiofur were identified with Vitek and Biolog systems, respectively. A subset of ceftiofur degraders also degraded the chemically similar drug ceftriaxone. Most of the species of bacteria that degraded ceftiofur belonged to the genera
Bacillus
and
Bacteroides
. PCR analysis of bacterial DNA detected specific β-lactamase genes.
Bacillus cereus
and
B. mycoides
isolates produced extended-spectrum β-lactamases and metallo-β-lactamases. Seven isolates of
Bacteroides
spp. produced multiple β-lactamases, including possibly CepA, and metallo-β-lactamases. Isolates of
Eubacterium biforme
,
Bifidobacterium breve
, and several
Clostridium
spp. also produced ceftiofur-degrading β-lactamases. An agar gel overlay technique on isoelectric focusing separations of bacterial lysates showed that β-lactamase enzymes were sufficient to degrade ceftiofur. These results suggest that ceftiofur is inactivated nonenzymatically and degraded enzymatically by multiple β-lactamases from bacteria in the large intestines of cattle.
Spider Venom Peptides for Gene Therapy of Chlamydia Infection
Authors: Lazarev Vassili N. , Polina Nadezhda F. , Shkarupeta Marina M. , Kostrjukova Elena S. , Vassilevski Alexander A. , Kozlov Sergey A. , Grishin Eugene V. , Govorun Vadim M.
Published: August 2011

Spider venoms are vast natural pharmacopoeias selected by evolution. The venom of the ant spider
Lachesana tarabaevi
contains a wide variety of antimicrobial peptides. We tested six of them (latarcins 1, 2a, 3a, 4b, 5, and cytoinsectotoxin 1a) for their ability to suppress
Chlamydia trachomatis
infection. HEK293 cells were transfected with plasmid vectors harboring the genes of the selected peptides. Controlled expression of the transgenes led to a significant decrease of
C. trachomatis
viability inside the infected cells.
SMB-1, a Novel Subclass B3 Metallo-β-Lactamase, Associated with IS
CR1
and a Class 1 Integron, from a Carbapenem-Resistant Serratia marcescens Clinical Isolate
Authors: Wachino Jun-ichi , Yoshida Hiroyuki , Yamane Kunikazu , Suzuki Satowa , Matsui Mari , Yamagishi Takuya , Tsutsui Atsuko , Konda Toshifumi , Shibayama Keigo , Arakawa Yoshichika
Published: August 2011

A carbapenem-resistant
Serratia marcescens
strain, 10mdr148, was identified in a Japanese hospital in 2010. The carbapenem resistance of this strain was attributed to the production of a novel metallo-β-lactamase (MBL), named SMB-1 (

S
erratia

m
etallo-
β
-lactamase). SMB-1 possessed a zinc binding motif, H(Q)XHXDH (residues 116 to 121), H196, and H263 and was categorized as a member of subclass B3 MBL. SMB-1 has 75% amino acid identity with the most closely related MBL, AMO1, of uncultured bacterium, recently identified through the metagenomic analysis of apple orchard soil. The introduction of
bla
SMB-1
into
Escherichia coli
conferred resistance to a variety of β-lactam antibiotics, penicillins, cephalosporins, and carbapenems, but not aztreonam, a resistance pattern consistent with those of other MBLs. SMB-1 demonstrated high
k
cat
values of >500 s
−1
for carbapenems, resulting in the highest hydrolyzing efficiency (
k
cat
/

K
m

) among the agents tested. The hydrolyzing activity of SMB-1 was well inhibited by chelating agents. The
bla
SMB-1
gene was located on the chromosome of
S. marcescens
strain 10mdr148 and at the 3′ end of the IS
CR1
element in complex with a typical class 1 integron carrying
aac
(
6′
)
-Ib
and
catB3
gene cassettes. Downstream of
bla
SMB-1
, the second copy of the 3′conserved segment and IS
CR1
were found. To our knowledge, this is the first subclass B3 MBL gene associated with an IS
CR1
element identified in an
Enterobacteriaceae
clinical isolate. A variety of antibiotic resistance genes embedded with IS
CR1
have been widely spread among
Enterobacteriaceae
clinical isolates, thus the further dissemination of
bla
SMB-1
mediated by IS
CR1
transposition activity may become a future concern.
Survival of Adhering Staphylococci during Exposure to a Quaternary Ammonium Compound Evaluated by Using Atomic Force Microscopy Imaging
Authors: Crismaru Mihaela , Asri Lia A. T. W. , Loontjens Ton J. A. , Krom Bastiaan P. , de Vries Joop , van der Mei Henny C. , Busscher Henk J.
Published: August 2011

Effects of a quaternary ammonium compound (QAC) on the survival of adhering staphylococci on a surface were investigated using atomic force microscopy (AFM). Four strains with different minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) for the QAC were exposed to three different concentrations of the QAC in potassium phosphate buffer (0.5×, 1×, and 2× MBC) while adhering to glass. Adhering staphylococci were repeatedly imaged with AFM in the contact mode, and the cell surface was found to wrinkle upon progressive exposure to the QAC until bacteria disappeared from the substratum. Higher concentrations of QAC yielded faster wrinkling and the disappearance of bacteria during imaging. Two slime-producing staphylococcal strains survived longer on the surface than two non-slime-producing strains despite similar MICs and MBCs. All staphylococci adhering in unscanned areas remained adhering during exposure to QAC. Since MICs and MBCs did not relate to bacterial cell surface hydrophobicities and zeta potentials, survival on the surface is probably not determined by the direct interaction of QAC molecules with the cell surface. Instead, it is suggested that the pressure of the AFM tip assists the incorporation of QAC molecules in the membrane and enhances their bactericidal efficacy. In addition, the prolonged survival under pressure from slime-producing strains on a surface may point to a new protective role of slime as a stress absorber, impeding the incorporation of QAC molecules. The addition of Ca
2+
ions to a QAC solution yielded longer survival of intact, adhering staphylococci, suggesting that Ca
2+
ions can impede the exchange of membrane Ca
2+
ions required for QAC incorporation.
Population Pharmacokinetics of Artemether, Lumefantrine, and Their Respective Metabolites in Papua New Guinean Children with Uncomplicated Malaria
Authors: Salman Sam , Page-Sharp Madhu , Griffin Susan , Kose Kaye , Siba Peter M. , Ilett Kenneth F. , Mueller Ivo , Davis Timothy M. E.
Published: August 2011

There are sparse published data relating to the pharmacokinetic properties of artemether, lumefantrine, and their active metabolites in children, especially desbutyl-lumefantrine. We studied 13 Papua New Guinean children aged 5 to 10 years with uncomplicated malaria who received the six recommended doses of artemether (1.7 mg/kg of body weight) plus lumefantrine (10 mg/kg), given with fat over 3 days. Intensive blood sampling was carried out over 42 days. Plasma artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine were assayed using liquid chromatography-mass spectrometry or high-performance liquid chromatography. Multicompartmental pharmacokinetic models for a drug plus its metabolite were developed using a population approach that included plasma artemether and dihydroartemisinin concentrations below the limit of quantitation. Although artemether bioavailability was variable and its clearance increased by 67.8% with each dose, the median areas under the plasma concentration-time curve from 0 h to infinity (AUC
0-∞
s) for artemether and dihydroartemisinin (3,063 and 2,839 μg·h/liter, respectively) were similar to those reported previously in adults with malaria. For lumefantrine, the median AUC
0–∞
(459,980 μg·h/liter) was also similar to that in adults with malaria. These data support the higher dose recommended for children weighing 15 to 35 kg (35% higher than that for a 50-kg adult) but question the recommendation for a lower dose in children weighing 12.5 to 15 kg. The median desbutyl-lumefantrine/lumefantrine ratio in the children in our study was 1.13%, within the range reported for adults and higher at later time points because of the longer desbutyl-lumefantrine terminal elimination half-life. A combined desbutyl-lumefantrine and lumefantrine AUC
0–∞
weighted on
in vitro
antimalarial activity was inversely associated with recurrent parasitemia, suggesting that both the parent drug and the metabolite contribute to the treatment outcome of artemether-lumefantrine.
Survey of Antimicrobial Resistance in Clinical Burkholderia pseudomallei Isolates over Two Decades in Northeast Thailand
Authors: Wuthiekanun Vanaporn , Amornchai Premjit , Saiprom Natnaree , Chantratita Narisara , Chierakul Wirongrong , Koh Gavin C. K. W. , Chaowagul Wipada , Day Nicholas P. J. , Limmathurotsakul Direk , Peacock Sharon J.
Published: August 2011

A 21-year survey conducted in northeast Thailand of antimicrobial resistance to parenteral antimicrobial drugs used to treat melioidosis identified 24/4,021 (0.6%) patients with one or more isolates resistant to ceftazidime (
n
= 8), amoxicillin-clavulanic acid (
n
= 4), or both drugs (
n
= 12). Two cases were identified at admission, and the remainder were detected a median of 15 days after starting antimicrobial therapy. Resistance to carbapenem drugs was not detected. These findings support the current prescribing recommendations for melioidosis.
Comparative Analysis of EspF Variants in Inhibition of Escherichia coli Phagocytosis by Macrophages and Inhibition of E. coli Translocation through Human- and Bovine-Derived M Cells
Authors: Tahoun Amin , Siszler Gabriella , Spears Kevin , McAteer Sean , Tree Jai , Paxton Edith , Gillespie Trudi L. , Martinez-Argudo Isabel , Jepson Mark A. , Shaw Darren J. , Koegl Manfred , Haas Juergen , Gally David L. , Mahajan Arvind
Published: August 2011

The EspF protein is secreted by the type III secretion system of enteropathogenic and enterohemorrhagic
Escherichia coli
(EPEC and EHEC, respectively). EspF sequences differ between EHEC O157:H7, EHEC O26:H11, and EPEC O127:H6 in terms of the number of SH3-binding polyproline-rich repeats and specific residues in these regions, as well as residues in the amino domain involved in cellular localization. EspF
O127
is important for the inhibition of phagocytosis by EPEC and also limits EPEC translocation through antigen-sampling cells (M cells). EspF
O127
has been shown to have effects on cellular organelle function and interacts with several host proteins, including N-WASP and sorting nexin 9 (SNX9). In this study, we compared the capacities of different
espF
alleles to inhibit (i) bacterial phagocytosis by macrophages, (ii) translocation through an M-cell coculture system, and (iii) uptake by and translocation through cultured bovine epithelial cells. The
espF
gene from
E. coli
serotype O157 (
espF
O157
) allele was significantly less effective at inhibiting phagocytosis and also had reduced capacity to inhibit
E. coli
translocation through a human-derived
in vitro
M-cell coculture system in comparison to
espF
O127
and
espF
O26
. In contrast,
espF
O157
was the most effective allele at restricting bacterial uptake into and translocation through primary epithelial cells cultured from the bovine terminal rectum, the predominant colonization site of EHEC O157 in cattle and a site containing M-like cells. Although LUMIER binding assays demonstrated differences in the interactions of the EspF variants with SNX9 and N-WASP, we propose that other, as-yet-uncharacterized interactions contribute to the host-based variation in EspF activity demonstrated here.
Necessary and Sufficient Role for T Helper Cells To Prevent Fungal Dissemination in Allergic Lung Disease
Authors: Porter Paul C. , Roberts Luz , Fields Anna , Knight Morgan , Qian Yuping , Delclos George L. , Han Shuhua , Kheradmand Farrah , Corry David B.
Published: August 2011

Mucosal immune responses to fungal infection range from T helper type 2 (Th2) cell-directed allergic inflammation to Th1-predominant neutrophilic inflammation, but the mechanisms directing these divergent mucosal immune outcomes and the role of T cells in host defense against mucosal fungal infections are not known. Here we examined the mouse mucosal immune responses to 12 filamentous environmental fungal species over a broad range of exposure doses and determined the requirement of T cells for host defense. For all tested fungi, low-grade conidium exposures induced Th2- and eosinophil-predominant allergic lung disease, whereas higher exposures led to rapid conversion to neutrophil- and Th1 cell-predominant inflammation, a phenomenon we term immune phenotype switching. All fungal exposure doses were further linked to the secretion of interleukin-17A (IL-17A). Fungal infections withCurvularia lunataandAspergillus fumigatuswere typically confined to the airway during allergic inflammation but became locally invasive and disseminated to the brain at higher conidium challenge doses, in association with predominant Th1 responses. Fungal dissemination occurred at relatively low challenge doses with the conidia ofAspergillus fumigatusadministered to recombinase activating gene 1 (Rag-1)-deficient mice, which lack B and T cells, but B cell-deficient μMT mice and T helper cell-reconstituted Rag-1-deficient mice were comparable to wild-type mice in preventing fungal dissemination. Our findings demonstrate that Th2 cell-predominant allergic responses followed by immune phenotype switching and fungal dissemination are highly predictable outcomes with progressive fungal infectious burdens and that T helper cell responses are protective against lethal fungal dissemination.
The Photobacterium damselae subsp. damselae Hemolysins Damselysin and HlyA Are Encoded within a New Virulence Plasmid
Authors: Rivas Amable J. , Balado Miguel , Lemos Manuel L. , Osorio Carlos R.
Published: August 2011

Photobacterium damselae
subsp.
damselae
(formerly
Vibrio damsela
) is a marine bacterium that causes infections and fatal disease in a wide range of marine animals and in humans. Highly hemolytic strains produce damselysin (Dly), a cytolysin encoded by the
dly
gene that is lethal for mice and has hemolytic activity. We found that Dly is encoded in the highly hemolytic strain RM-71 within a 153,429-bp conjugative plasmid that we dubbed pPHDD1. In addition to Dly, pPHDD1 also encodes a homologue of the pore-forming toxin HlyA. We found a direct correlation between presence of pPHDD1 and a strong hemolytic phenotype in a collection of
P. damselae
subsp.
damselae
isolates. Hemolysis was strongly reduced in a double
dly hlyA
mutant, demonstrating the role of the two pPHDD1-encoded genes in hemolysis. Interestingly, although single
hlyA
and
dly
mutants showed different levels of hemolysis reduction depending on the erythrocyte source, hemolysis was not abolished in any of the single mutants, suggesting that the hemolytic phenotype is the result of the additive effect of Dly and HlyA. We found that pPHDD1-encoded
dly
and
hlyA
genes are necessary for full virulence for mice and fish. Our results suggest that pPHDD1 can be considered as a driving force for the emergence of a highly hemolytic lineage of
P. damselae
subsp.
damselae
.
Protective Role of Naturally Occurring Interleukin-17A-Producing γδ T Cells in the Lung at the Early Stage of Systemic Candidiasis in Mice
Authors: Dejima Takashi , Shibata Kensuke , Yamada Hisakata , Hara Hiromitsu , Iwakura Yoichiro , Naito Seiji , Yoshikai Yasunobu
Published: August 2011

Interleukin-17A (IL-17A)-producing γδ T cells differentiate in the fetal thymus and reside in the peripheral tissues, such as the lungs of naïve adult mice. We show here that naturally occurring γδ T cells play a protective role in the lung at a very early stage after systemic infection withCandida albicans.Selective depletion of neutrophils byin vivoadministration of anti-Ly6G monoclonal antibody (MAb) impaired fungal clearance more prominently in the lung than in the kidney 24 h after intravenous infection withC. albicans.Rapid and transient production of IL-23 was detected in the lung at 12 h, preceding IL-17A production and the influx of neutrophils, which reached a peak at 24 h after infection. IL-17A knockout (KO) mice showed reduced infiltration of neutrophils concurrently with impaired fungal clearance in the lung after infection. The major source of IL-17A was the γδ T cell population in the lung, and Cδ KO mice showed little IL-17A production and reduced neutrophil infiltration after infection. Early IL-23 production in a TLR2/MyD88-dependent manner and IL-23-triggered tyrosine kinase 2 (Tyk2) signaling were essential for IL-17A production by γδ T cells. Thus, our study demonstrated a novel role of naturally occurring IL-17A-producing γδ T cells in the first line of host defense againstC. albicansinfection.
Decline of meticillin-resistantStaphylococcus aureusin Oxfordshire hospitals is strain-specific and preceded infection-control intensification
Authors: Wyllie David H , Walker A Sarah , Miller Ruth , Moore Catrin , Williamson Susan R , Schlackow Iryna , Finney John M , O'Connor Lily , Peto Tim E A , Crook Derrick W
Published: August 2011

Background

In the past, strains ofStaphylococcus aureushave evolved, expanded, made a marked clinical impact and then disappeared over several years. Faced with rising meticillin-resistantS aureus(MRSA) rates, UK government-supported infection control interventions were rolled out in Oxford Radcliffe Hospitals NHS Trust from 2006 onwards.

Methods

Using an electronic Database, the authors identified isolation of MRS among 611 434 hospital inpatients admitted to acute hospitals in Oxford, UK, 1 April 1998 to 30 June 2010. Isolation rates were modelled using segmented negative binomial regression for three groups of isolates: from blood cultures, from samples suggesting invasion (eg, cerebrospinal fluid, joint fluid, pus samples) and from surface swabs (eg, from wounds).

Findings

MRSA isolation rates rose rapidly from 1998 to the end of 2003 (annual increase from blood cultures 23%, 95% CI 16% to 30%), and then declined. The decline accelerated from mid-2006 onwards (annual decrease post-2006 38% from blood cultures, 95% CI 29% to 45%, p=0.003 vs previous decline). Rates of meticillin-sensitiveS aureuschanged little by comparison, with no evidence for declines 2006 onward (p=0.40); by 2010, sensitiveS aureuswas far more common than MRSA (blood cultures: 2.9 vs 0.25; invasive samples 14.7 vs 2.0 per 10 000 bedstays). Interestingly, trends in isolation of erythromycin-sensitive and resistant MRSA differed. Erythromycin-sensitive strains rose significantly faster (eg, from blood cultures p=0.002), and declined significantly more slowly (p=0.002), than erythromycin-resistant strains (global p<0.0001). Bacterial typing suggests this reflects differential spread of two major UK MRSA strains (ST22/36), ST36 having declined markedly 2006–2010, with ST22 becoming the dominant MRSA strain.

Conclusions

MRSA isolation rates were falling before recent intensification of infection-control measures. This, together with strain-specific changes in MRSA isolation, strongly suggests that incompletely understood biological factors are responsible for the much recent variation in MRSA isolation. A major, mainly meticillin-sensitive,S aureusburden remains.
Joint analysis of multiple biomarkers for identifying type 2 diabetes in middle-aged and older Chinese: a cross-sectional study
Authors: Wu Hongyu , Yu Zhijie , Qi Qibin , Li Huaixing , Sun Qi , Lin Xu
Published: August 2011

Objective

Identifying individuals with high risk of type 2 diabetes is important. To evaluate discriminatory ability of multiple biomarkers for type 2 diabetes in a Chinese population.

Methods

Plasma adiponectin, plasminogen activator inhibitor-1, retinol-binding protein 4, resistin, C-reactive protein, interleukin 6 (IL-6), tumour necrosis factor α receptor 2 and ferritin were measured in a population-based sample of 3189 Chinese (1419 men and 1770 women) aged 50–70 years. A weighted biomarkers risk score (BRS) was developed based on the strength of associations of these biomarkers with type 2 diabetes. The discriminatory ability was tested by the area under receiver operating characteristics curve (AUC).

Results

Adiponectin, plasminogen activator inhibitor-1, IL-6 and ferritin were independently associated with the prevalence of type 2 diabetes, and they were used to calculate the biomarkers risk score (BRS). After adjustment for the confounding factors, the ORs for type 2 diabetes and impaired fasting glucose with each point increment of BRS were 1.28 (95% CI 1.22 to 1.34) and 1.16 (1.12 to 1.20), respectively. Compared with those in the lowest quintile of the BRS, the participants in the highest quintile have an OR (95% CI) of 6.67 (4.21 to 10.55) for type 2 diabetes. The area under the curve for the BRS and conventional risk factors alone was 0.73 and 0.76, respectively, and substantially increased to 0.81 after combining both BRS and conventional risk factors (p<0.001).

Conclusions

These data suggest that combining multiple biomarkers and conventional risk factors might substantially enhance the ability to identify individuals with type 2 diabetes. More prospective data are warranted to confirm this observation.
The clinician’s response to a report of an incidental pulmonary embolism detected on multidetector CT
Authors: Franklin James M , Rahman Najib , Gleeson Fergus V
Published: August 2011

Background

The prevalence of incidental pulmonary emboli (PE) detected on contrast enhanced CT performed for other reasons is approximately 2.5%. The treatment decisions based upon the discovery of incidental PE have been less well reported. The purpose of this study was to report the clinician’s response to, and consequences of, the finding of incidental PE on contrast enhanced CT.

Methods

Retrospective cohort study. Patients with incidental PE detected on a contrast enhanced CT were retrospectively identified at a single institution between 1 January 2009 and 31 December 2009. Case note review was performed to assess clinicians' responses to this finding. Patients with synchronous venous thromboembolism, unrecognised symptoms or factors preventing response assessment were excluded from this analysis. Patient and PE characteristics, treatment, and outcomes related to treatment and non-treatment were recorded.

Results

There were 73 patients with incidental PE: 52 were in the proximal pulmonary arteries and 21 were distal. 16 patients were excluded from the treatment analysis. 52 of 57 (91.2%) patients were treated with therapeutic anticoagulation. There were 2 (3.8%) serious adverse events related to treatment. 5 (8.8%) patients were not treated; 2 (40%) developed recurrent venous thromboembolism. Treatment of incidental PE was not significantly associated with patient age, PE risk factors or PE location. A smaller proportion of single incidental PE were treated than multiple incidental PE (p=0.047).

Conclusion

There is morbidity associated with both treatment and non-treatment of incidental PE. However, despite the uncertainty about the natural history and clinical significance of incidental PE, the majority of patients at the authors' institution received prompt anticoagulation.
Improving STI counselling services of non-formal providers in Bangladesh: testing an alternative strategy: Table 1
Authors: Sarma Haribondhu , Oliveras Elizabeth
Published: August 2011

Objective

The authors conducted this study to assess the effectiveness of using a public health detailing approach by medical representatives of a private pharmaceutical company to disseminate sexually transmitted infection (STI) counselling information to non-formal providers (NFPs) to improve their STI counselling services.

Methods

An intervention was developed that included developing STI counselling guidelines and training medical representatives to disseminate the counselling guidelines to NFPs. To assess the effectiveness of this intervention, the authors conducted 67 mystery client visits to compare the counselling provided by NFPs in intervention areas with counselling provided in areas where the intervention was not implemented.

Results

A significantly higher proportion (p<0.05) of mystery clients in the intervention area received advice that was consistent with the national STI counselling guidelines compared with the mystery clients in the control area. No mystery clients in the control area were told to use condoms while the STI lasts compared with 44% (95% CI 28% to 62%) in the intervention area. Likewise, more than twice as many clients in the intervention area were advised not to visit sex workers (53% vs 23%; p=0.014).

Conclusion

Public health detailing of medical representatives is a feasible mechanism to improve STI counselling services of NFPs in Bangladesh. Private sector companies provide a potential avenue for reaching the vast number of NFPs with basic information that they can share with their clients. The immediate improvements seen in this study suggest the strong potential of public health detailing as a training tool for NFPs.
Realizing the future of wireless data communications
Authors: Partridge Craig
Published: August 2011

Technologies are available to unlock radio spectrum as consumers need it.
Q&A: Scaling up
Authors: Hoffmann Leah
Published: August 2011

Eric Brewer talks about infrastructure, connectivity, and computing for developing nations.
PrIMe
Authors: Miles Simon , Groth Paul , Munroe Steve , Moreau Luc
Published: August 2011

Provenance refers to the past processes that brought about a given (version of an) object, item or entity. By knowing the provenance of data, users can often better understand, trust, reproduce, and validate it. A provenance-aware application has the functionality to answer questions regarding the provenance of the data it produces, by using documentation of past processes. PrIMe is a software engineering technique for adapting application designs to enable them to interact with a provenance middleware layer, thereby making them provenance-aware. In this article, we specify the steps involved in applying PrIMe, analyze its effectiveness, and illustrate its use with two case studies, in bioinformatics and medicine.