bluuebunny/crossref_metadata_2025 huggingface dataset:
A Role of the Sulfonylurea Receptor 1 in Endocytic Trafficking of ATP‐Sensitive Potassium Channels
Authors: Bruederle Cathrin E. , Gay Joel , Shyng Show‐Ling
Published: June 2011

The ATP‐sensitive potassium (KATP) channel consisting of sulfonylurea receptor 1 (SUR1) and inward‐rectifier potassium channel 6.2 (Kir6.2) has a well‐established role in insulin secretion. Mutations in either subunit can lead to disease due to aberrant channel gating, altered channel density at the cell surface or a combination of both. Endocytic trafficking of channels at the plasma membrane is one way to influence surface channel numbers. It has been previously reported that channel endocytosis is dependent on a tyrosine‐based motif in Kir6.2, while SUR1 alone is unable to internalize. In this study, we followed endocytic trafficking of surface channels in real time by live‐cell imaging of channel subunits tagged with an extracellular minimal α‐bungarotoxin‐binding peptide labeled with a fluorescent dye. We show that SUR1 undergoes endocytosis independent of Kir6.2. Moreover, mutations in the putative endocytosis motif of Kir6.2, Y330C, Y330A and F333I are unable to prevent channel endocytosis. These findings challenge the notion that Kir6.2 bears the sole endocytic signal for KATP channels and support a role of SUR1 in this trafficking process.
Abnormal gait and bradykinesia in the preclinical phase of Huntington's disease – psychogenic movement disorder?
Authors: Soltan Witold , Sitek Emilia , Wichowicz Hubert , Wieczorek Dariusz , Slawek Jaroslaw
Published: June 2011

Soltan W, Sitek E, Wichowicz H, Wieczorek D, Slawek J. Abnormal gait and bradykinesia in the preclinical phase of Huntington's disease – psychogenic movement disorder?

Objective: Psychiatric symptoms may occur in individuals at risk of Huntington's disease (HD) regardless of their genetic status. Psychopathological symptomatology is attributed to both genetic and environmental factors. In case of asymptomatic gene carriers, psychiatric symptoms may precede involuntary movements.

Methods: We report the first case with abnormal gait and bradykinesia in preclinical adult HD. A 33-year-old woman blind to her mother's HD diagnosis and her own genetic status developed motor slowing and gait disturbance. The symptoms withdrew due to counselling and antidepressant medications. Subsequently, she was informed her own and her mother's genetic testing results, but 2-year follow-up did not reveal the onset of choreic movements, cognitive deterioration or depressive symptoms in the patient. Personality assessment (Minnesota Multiphasic Personality Inventory) and neurological examination results are presented, accompanied by 2-year follow-up data. Follow-up examination included Unified Huntington's Disease Rating Scale (motor, behaviour and function), Beck Depression Inventory, Hamilton Depression Rating Scale and neuropsychological assessment (trail-making test, Stroop test, verbal fluency trials, symbol digit modalities test, digit span, serial seven subtraction, Hopkins verbal learning test and nine-hole peg test).

Conclusion: Motor abnormalities in individuals at risk of HD may be of psychogenic origin. It is a matter of debate if this psychogenic reaction presented as hypokinetic syndrome may be a result of choreic movements of her mother (hyperkinetic syndrome) and depression or if this psychogenic reaction represents the preclinical psychiatric abnormalities in an asymptomatic gene carrier preceding the onset of the disease.
A Mixed‐Methods Evaluation of the Effectiveness of Tailored Smoking Cessation Training for Healthcare Practitioners Who Work with Older People
Authors: Kerr Susan , Whyte Rosemary , Watson Hazel , Tolson Debbie , McFadyen Angus K.
Published: June 2011

Background: Older people who smoke derive significant health benefits from stopping smoking in later life. Healthcare practitioners have an important role to play in raising the issue of smoking cessation with this client group; however, they often fail to do so.

Aim: To assess the effectiveness of smoking cessation training for healthcare practitioners who have regular contact with older adults.

Methods: Mixed‐methods were used to explore satisfaction with the training, the participants’ learning and any resultant changes in behaviour. The effectiveness of the training was assessed using a two‐group parallel design randomised controlled trial, followed by semistructured qualitative interviews. Participants (n = 57) were recruited from a cohort of community nurses and allied health professionals (e.g., occupational therapists) working in Scotland. The intervention was 1‐day brief intervention smoking cessation training. Validated measures of knowledge, attitudes and practice, were used to assess learning and behaviour at baseline, 1 week and 3 months post training. Data were analysed using two‐factor repeated measure analysis of variance, where the factors were “group” and “time.” Qualitative data were gathered from members of the intervention group during semistructured interviews (n = 8) and were analysed thematically.

Results/Findings: Levels of satisfaction with the training were high. There was a statistically significant improvement in the knowledge and attitudes of the intervention group following the training, with a noticeable, but nonsignificant, improvement in practice. The qualitative findings demonstrate how the training impacted positively on practice.

Conclusions: Smoking cessation interventions in later life are important, as older smokers generally have long‐term conditions caused or complicated by smoking. The delivery of brief smoking cessation interventions is known to be highly cost‐effective; however, research demonstrates that practitioners often fail to raise the issue of smoking cessation with older adults. This study has demonstrated the effectiveness of a 1‐day training course for practitioners. Further research is recommended.
The Defeat of Shaped Charge Jets by Explosively Driven Ceramic and Glass Plates
Authors: Hazell Paul J. , Lawrence Trevor , Stennett Chris
Published: June 2011

In this work, we investigate the penetration of shaped charge jets into explosively driven brittle materials. Using a simple tri‐plate explosive reactive armor (ERA) design, ∅89 mm shaped charge warheads have been used to assess the performance of armor configurations with flyer plates constructed from alumina, silicon carbide, borosilicate glass, and steel. In particular, it was noted that the performance of silicon carbide and alumina flyer plates were comparable to steel. Furthermore, there is evidence that increasing the mass of the explosive material behind a ceramic layer improves the performance of the armor thereby providing room for optimization of a brittle material ERA system. Finally, numerical simulations are also presented using the JH‐1 material model that elucidate the damage mechanisms that occur when a ceramic ERA flyer plate is explosively loaded.
Massive black hole binary eccentricity in rotating stellar systems
Authors: Sesana Alberto , Gualandris Alessia , Dotti Massimo
Published: June 2011

In this Letter we study the eccentricity evolution of a massive black hole (MBH) binary (MBHB) embedded in a rotating stellar cusp. Following the observation that stars on counter-rotating (with respect to the MBHB) orbits extract angular momentum from the binary more efficiently than their corotating counterparts, the eccentricity evolution of the MBHB must depend on the degree of corotation (counter-rotation) of the surrounding stellar distribution. Using an hybrid scheme that couples numerical three-body scatterings to an analytical formalism for the cusp—binary interaction, we verify this hypothesis by evolving the MBHB in spherically symmetric cusps with different fractions of corotating stars. Consistent with previous works, binaries in isotropic cusps () tend to increase their eccentricity, and when approaches zero (counter-rotating cusps) the eccentricity rapidly increases to almost unity. Conversely, binaries in cusps with a significant degree of corotation () tend to become less and less eccentric, circularizing quite quickly for approaching unity. Direct N-body integrations performed to test the theory corroborate the results of the hybrid scheme, at least at a qualitative level. We discuss quantitative differences, ascribing their origin to the oversimplified nature of the hybrid approach.
Effects on blood pressure and autonomic nervous system function of a 12‐week exercise or exercise plus DASH‐diet intervention in individuals with elevated blood pressure
Authors: Edwards K. M. , Wilson K. L. , Sadja J. , Ziegler M. G. , Mills P. J.
Published: June 2011

Aim:  Hypertension is related to abnormalities in autonomic nervous system (ANS) function, with increased sympathetic output and decreased parasympathetic tone. Lifestyle interventions are the first line of treatment in hypertension, and decreased blood pressure (BP) effects may be related to changes in ANS function. Using heart rate recovery (HRR) from exercise as an index of parasympathetic tone and plasma noradrenaline as an index of sympathetic tone, we investigated the effects of lifestyle interventions on ANS function in patients with elevated BP.

Methods:  Sedentary participants with elevated BP were randomly assigned to either an exercise only (N = 25), exercise plus dietary approaches to stop hypertension (DASH) diet (N = 12), or waitlist control (N = 15) 12‐week intervention. Plasma noradrenaline was measured at rest and participants performed a peak exercise test before and after the intervention. HRR was calculated as peak heart rate (HR) minus HR at 1 min post‐exercise.

Results:  Heart rate recovery showed a significant group by time interaction; both intervention groups showed increases in HRR from pre‐ to post‐intervention, while waitlist showed no change. Similarly, both exercise plus diet and exercise groups, but not waitlist, showed significant reductions in BP from pre‐ to post‐intervention. Linear regression revealed that BP post‐intervention was significantly predicted by change in HRR when controlling for pre‐BP, age, gender and BMI.

Conclusions:  Lifestyle interventions induced training‐reduced BP and altered autonomic tone, indexed by HRR. This study indicates the importance of behavioural modification in hypertension and that increased parasympathetic function is associated with success in reduction of BP.
Role of l‐arginine uptake mechanisms in renal blood flow responses to angiotensin II in rats
Authors: Rajapakse N. W. , Mattson D. L.
Published: June 2011

Aim:  To examine whether reduced renal arginine transport increases the responsiveness of the renal circulation to angiotensin II in salt sensitivity, renal perfusion responses to angiotensin II were examined in the presence of l‐arginine transport inhibitor, l‐lysine and subsequent l‐arginine in Sprague Dawley (SD) and Dahl salt‐sensitive (Dahl S) rats.

Methods:  Laser Doppler probes and a transonic flow probe were used to measure regional renal perfusion and total renal perfusion respectively. Renal perfusion responses to intravenous (i.v.) angiotensin II were sequentially examined under control conditions and during i.v. infusion of l‐lysine, l‐arginine or nitric oxide synthase inhibitor, NG‐nitro‐l‐arginine.

Results:  Angiotensin II (10 and 100 ng kg−1 min−1, i.v.) reduced total renal (−10 ± 3 and −36 ± 5%) and cortical (−10 ± 2 and −28 ± 4%) but not medullary perfusion in SD rats. In these rats l‐lysine enhanced the renal perfusion response (P = 0.003), whereas subsequent l‐arginine reversed this effect (P = 0.04). Angiotensin II reduced total renal, cortical and medullary perfusion in Dahl S rats. In Dahl S rats fed high salt, l‐lysine did not affect renal perfusion responses to angiotensin II, but subsequent l‐arginine blunted the renal blood flow response (P = 0.01) and increased the medullary perfusion during angiotensin II infusion (P = 0.006).

Conclusion:  Intact renal l‐arginine transport attenuates the vasoconstrictor effects of circulating angiotensin II in the renal cortex in SD rats. l‐arginine also plays an important role in protecting the renal medullary circulation from the ischemic effects of angiotensin II in Dahl S rats.
Acupuncture for Anxiety
Authors: Errington‐Evans Nick
Published: June 2011

This review aims to examine the volume and quality of the evidence base which supports the use of acupuncture in the treatment of anxiety disorders. A literature review was conducted using Pubmed, Google scholar, AMED, BMJ, Embase, Psychinfo, Cochrane library, Ingenta connect, and Cinahl databases. Keywords were “anxiety,”“anxious,”“panic,”“stress,”“phobia,” and “acupuncture” limited to year 2000 onwards and English language where available. The quality of research examining the use of acupuncture in the treatment of anxiety disorders is extremely variable. There is enormous variety regarding points used, number of points used in a session, duration of sessions, frequency of treatment and duration of treatment programme. While the generally poor methodological quality, combined with the wide range of outcome measures used, number and variety of points, frequency of sessions, and duration of treatment makes firm conclusions difficult. Against this, the volume of literature, consistency of statistically significant results, wide range of conditions treated and use of animal test subjects suggests very real, positive outcomes using a treatment method preferred by a population of individuals who tend to be resistant to conventional medicine.
Late‐onset Bipolar Illness: The Geriatric Bipolar Type VI
Authors: Azorin Jean‐Michel , Kaladjian Arthur , Adida Marc , Fakra Eric
Published: June 2011

In parallel to considerable progress in understanding and treatment of bipolarity and despite growing interest in old age psychiatry, late‐onset bipolar illness (LOBI) has remained relatively understudied so far, probably in reason of its complexity. To update available data, a systematic review was conducted, focusing on the main issues addressed in literature in regard to this topic. In addition to data on epidemiology, clinical features and treatment, five main issues could be identified: LOBI as secondary disorder, LOBI as expression of a lower vulnerability to the disease, LOBI as subform of pseudodementia, LOBI as risk factor for developing dementia, and LOBI as bipolar type VI (bipolarity in the context of dementia like processes). Levels of available evidence were found to vary according to the addressed issue. Although the concept of bipolar type VI could be criticized for subsuming under one single heading all the four other issues, this concept may be of pragmatic value in helping clinicians to orientate both diagnosis process and treatment decisions. Among others, the question as to whether some forms of bipolar type VI could constitute a special risk factor for developing dementia deserves further investigation. More studies are also needed to better disentangle the effects of age at onset from those of age itself.
EXOGENOUS SHOCKS AND MARINE RESERVES
Authors: KVAMSDAL STURLA F.
Published: June 2011

Abstract The impact on the value of a fishery from exogenous shocks is investigated. Part of the habitat is protected by a marine reserve, while the remaining fishery is managed by optimal, total allowable catch quotas. Shocks of different, spatial nature and with different probability distributions are investigated. The results suggest that reserves are of minor interest as a management tool when shocks affect the stock uniformly. Reserves may substantially enhance the value of the fishery when shocks are nonuniformly spatially distributed.
Automated measurement of zebrafish larval movement
Authors: Cario Clinton L. , Farrell Thomas C. , Milanese Chiara , Burton Edward A.
Published: June 2011

Abstract The zebrafish is a powerful vertebrate model that is readily amenable to genetic, pharmacological and environmental manipulations to elucidate the molecular and cellular basis of movement and behaviour. We report software enabling automated analysis of zebrafish movement from video recordings captured with cameras ranging from a basic camcorder to more specialized equipment. The software, which is provided as open‐source MATLAB functions, can be freely modified and distributed, and is compatible with multiwell plates under a wide range of experimental conditions. Automated measurement of zebrafish movement using this technique will be useful for multiple applications in neuroscience, pharmacology and neuropsychiatry.
Cannabinoid receptor agonists potentiate action potential‐independent release of GABA in the dentate gyrus through a CB1 receptor‐independent mechanism
Authors: Hofmann Mackenzie E. , Bhatia Chinki , Frazier Charles J.
Published: June 2011

Non‐technical summary Communication between many types of neurons in the brain can be strongly modulated by activation of cannabinoid receptors. Such receptors are likely to be responsible for mediating many of the effects of marijuana on the central nervous system, and yet they can also be activated by both endogenous and synthetic compounds. Here we describe a novel effect of two well‐known cannabinoid receptor ligands on spontaneous synaptic transmission in an area of the brain that is essential for the formation of new memories, and that is strongly implicated in the aetiology of temporal lobe epilepsy. Interestingly, this effect appears to be receptor dependent, and yet does not require any currently known cannabinoid receptor. Further exploration of this phenomenon may help us better understand how spontaneous release of neurotransmitters is regulated in the central nervous system, and could also ultimately help to inform new strategies for therapeutic regulation of cortical excitability.
Oxidized Graphite Nanoplatelets as an Improved Filler for Thermally Conducting Epoxy-Matrix Composites
Authors: Sun Xiaobo , Yu Aiping , Ramesh Palanisamy , Bekyarova Elena , Itkis Mikhail E. , Haddon Robert C.
Published: June 2011

We report a 40% improvement of the thermal conductivity of graphite nanoplatelets–epoxy composites by chemical functionalization of graphite nanoplatelets utilizing nitric acid treatment, which also serves to enhance the spreadability of the material. FTIR and Raman spectroscopy confirmed the presence of a variety of oxygen functional groups at the edges and basal plane of the functionalized graphite nanoplatelets, which contributed to improved interaction with the polymer matrix. A comparative statistical analysis of the particle size distributions in pristine and functionalized graphite nanoplatelets based on scanning electron microscopy showed an increasing degree of exfoliation of the functionalized material. We compare the performance of the functionalized graphite nanoplatelets and carbon nanotubes as fillers in the polymer matrix and discuss the prospects for utilization of graphite nanoplatelets-based thermal interface materials in electronic packaging.
Flow Bistability Downstream of Three-Dimensional Double Backward Facing Steps at Zero-Degree Sideslip
Authors: Herry Benjamin B. , Keirsbulck Laurent , Labraga Larbi , Paquet Jean-Bernard
Published: June 2011

The flow downstream of a three-dimensional double backward facing step (3D DBWFS) is investigated for Reynolds number Reh ranging from 5×103 to8×104 (based on the first step height h). The flow is studied both qualitatively by means of laser tomoscopy and oil-flow visualizations and quantitatively by means of particle image velocimetry (PIV) measurements. In particular, the results show a mean flow asymmetry. A sensitivity study around zero degree sideslip has shown that the flow is bistable for this geometry. This bistability has been observed in two different wind tunnels for very different upstream conditions. As a main consequence, the zero degree drift angle could be a relevant validation case of unstable flow computation. More tests are carried out to understand and control this particular flow feature.
Dissipation and Cavitation Characteristics of Single-Hole Orifices
Authors: Malavasi Stefano , Messa Gianandrea Vittorio
Published: June 2011

The purpose of this work is to study the dependence of the pressure losses through sharp-edged orifices with respect to the most significant parameters and to find an efficient way to check whether cavitation is likely to occur. Computational fluid dynamics was used to simulate the flow through orifices with different geometrical characteristics for various incoming flow velocities. In particular, the diameter ratio was varied between 0.39 and 0.70, the relative thickness between 0.30 and 1.40, and the pipe Reynolds number between 3.85 × 104 and 1.54 × 105. The computed pressure drop coefficient in the region of self-similarity with respect to the pipe Reynolds number was first compared to that obtained from some literature models. Afterwards, the comparison with experimental data revealed that an extended pressure criterion is suitable to predict the presence of cavitating conditions. A dimensionless minimum pressure coefficient was then defined, and its dependence upon the above mentioned geometrical and flow parameters was investigated. Finally, a practical formula for the prediction of cavitation was provided.
Influence of Geometry on Starting Vortex and Ejector Performance
Authors: Zheng Fei , Kuznetsov Andrey V. , Roberts William L. , Paxson Daniel E.
Published: June 2011

For many propulsion devices, the thrust may be augmented considerably by adding a passive ejector, and these devices are especially attractive for unsteady propulsion systems such as pulse detonation engines and pulsejets. Starting vortices from these unsteady devices dominate the flowfield and control to a great extent the level of the thrust augmentation. Therefore, it is of fundamental interest to understand the geometric influences on the starting vortex and how these manifest themselves in augmenter/ejector performance. An unsteady Reynolds averaged Navier–Stokes calculation was used to study the physics of a starting vortex generated at the exit of a pulsed jet and its interaction with an ejector. A 50 cm long pulsejet (typical hobby scale, allowing comparison with experimental data) with a circular exit was modeled as the resonant driving source and used to suggest an optimal ejector geometry and relative position. Computed limit-cycle thrust augmentation values compared favorably to experimentally obtained values for the same ejector geometries. Results suggest that the optimal diameter of the ejector is related to its relative position, dictated by the trajectory of the vortex toroid. The effect of the length of the ejector (which determines the natural frequency of the ejector, related to the acoustic processes occurring in the ejector) on overall performance was also investigated and shown to be less important than the ejector diameter.
Beyond the Balance of Activator and Repressor
Authors: Whitington Thomas , Jolma Arttu , Taipale Jussi
Published: June 2011

Transcription factor binding site affinity has a counterintuitive effect on the regulation of gene expression in response to Hedgehog.
Raptor Not Required
Authors: VanHook Annalisa M.
Published: June 2011

mTOR phosphorylates an RNA binding protein in a raptor-independent manner to stimulate translation of an insulin-like growth factor.
Structural Variations of Staphylococcal Cassette Chromosome
mec
Type IVa in
Staphylococcus aureus
Clonal Complex 8 and Unrelated Lineages
Authors: Damborg Peter , Bartels Mette Damkjær , Boye Kit , Guardabassi Luca , Westh Henrik
Published: June 2011

PCR mapping of staphylococcal cassette chromosome
mec
type IVa and adjacent mobile elements in 94 methicillin-resistant
Staphylococcus aureus
(MRSA) strains identified two primary structures (A and B) that could be further classified into two (A1 and A2) and five (B1 to B5) variants, primarily based on structural differences in the
orfX
-J3 region. While
spa
type t008 (USA300) invariably contained the A variants, other
spa
types belonging to clonal complex 8 and unrelated lineages generally contained B variants. These findings have important implications for the typing and identification of MRSA strains containing B variants.
Impact of the E540V Amino Acid Substitution in GyrB of
Mycobacterium tuberculosis
on Quinolone Resistance
Authors: Kim Hyun , Nakajima Chie , Yokoyama Kazumasa , Rahim Zeaur , Kim Youn Uck , Oguri Hiroki , Suzuki Yasuhiko
Published: June 2011

Amino acid substitutions conferring resistance to quinolones in
Mycobacterium tuberculosis
have generally been found within the quinolone resistance-determining regions (QRDRs) in the A subunit of DNA gyrase (GyrA) rather than the B subunit of DNA gyrase (GyrB). To clarify the contribution of an amino acid substitution, E540V, in GyrB to quinolone resistance in
M. tuberculosis
, we expressed recombinant DNA gyrases in
Escherichia coli
and characterized them
in vitro
. Wild-type and GyrB-E540V DNA gyrases were reconstituted
in vitro
by mixing recombinant GyrA and GyrB. Correlation between the amino acid substitution and quinolone resistance was assessed by the ATP-dependent DNA supercoiling assay, quinolone-inhibited supercoiling assay, and DNA cleavage assay. The 50% inhibitory concentrations of eight quinolones against DNA gyrases bearing the E540V amino acid substitution in GyrB were 2.5- to 36-fold higher than those against the wild-type enzyme. Similarly, the 25% maximum DNA cleavage concentrations were 1.5- to 14-fold higher for the E540V gyrase than for the wild-type enzyme. We further demonstrated that the E540V amino acid substitution influenced the interaction between DNA gyrase and the substituent(s) at R-7, R-8, or both in quinolone structures. This is the first detailed study of the contribution of the E540V amino acid substitution in GyrB to quinolone resistance in
M. tuberculosis
.
Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model
Authors: Moore Brioni R. , Page-Sharp Madhu , Stoney Jillian R. , Ilett Kenneth F. , Jago Jeffrey D. , Batty Kevin T.
Published: June 2011

Chloroquine (CQ) is an important antimalarial drug for the treatment of special patient groups and as a comparator for preclinical testing of new drugs. Pharmacokinetic data for CQ in animal models are limited; thus, we conducted a three-part investigation, comprising (i) pharmacodynamic studies of CQ and CQ plus dihydroartemisinin (DHA) in
Plasmodium berghei
-infected mice, (ii) pharmacokinetic studies of CQ in healthy and malaria-infected mice, and (iii) interspecies allometric scaling for CQ from 6 animal and 12 human studies. The single-dose pharmacodynamic study (10 to 50 mg CQ/kg of body weight) showed dose-related reduction in parasitemia (5- to >500-fold) and a nadir 2 days after the dose. Multiple-dose regimens (total dose, 50 mg/kg CQ) demonstrated a lower nadir and longer survival time than did the same single dose. The CQ-DHA combination provided an additive effect compared to each drug alone. The elimination half-life (
t
1/2
), clearance (CL), and volume of distribution (
V
) of CQ were 46.6 h, 9.9 liters/h/kg, and 667 liters/kg, respectively, in healthy mice and 99.3 h, 7.9 liters/h/kg, and 1,122 liters/kg, respectively, in malaria-infected mice. The allometric equations for CQ in healthy mammals (CL = 3.86 ×
W
0.56
,
V
= 230 ×
W
0.94
, and
t
1/2
= 123 ×
W
0.2
) were similar to those for malaria-infected groups. CQ showed a delayed dose-response relationship in the murine malaria model and additive efficacy when combined with DHA. The biphasic pharmacokinetic profiles of CQ are similar across mammalian species, and scaling of specific parameters is plausible for preclinical investigations.
Low Fitness Cost of the Multidrug Resistance Gene
cfr
Authors: LaMarre Jacqueline M. , Locke Jeffrey B. , Shaw Karen J. , Mankin Alexander S.
Published: June 2011

The recently described rRNA methyltransferase Cfr that methylates the conserved 23S rRNA residue A2503, located in a functionally critical region of the ribosome, confers resistance to an array of ribosomal antibiotics, including linezolid. A number of reports of linezolid-resistant
cfr
-positive clinical strains indicate the possible rapid spread of this resistance mechanism. Since the rate of dissemination and the efficiency of maintenance of a resistance gene depend on the fitness cost associated with its acquisition, we investigated the fitness cost of
cfr
expression in a laboratory
Staphylococcus aureus
strain. We found that acquisition of the
cfr
gene does not produce any appreciable reduction in the cell growth rate. Only in a cogrowth competition experiment was some loss of fitness observed because Cfr-expressing cells slowly lose to the
cfr
-negative control strain. Interestingly, cells expressing wild-type and catalytically inactive Cfr had very similar growth characteristics, indicating that the slight fitness cost associated with
cfr
acquisition stems from expression of the Cfr polypeptide rather than from the modification of the conserved rRNA residue. In some clinical isolates,
cfr
is coexpressed with the
erm
gene, which encodes a methyltransferase targeting another 23S rRNA residue, A2058. Dimethylation of A2058 by Erm notably increases the fitness cost associated with the Cfr-mediated methylation of A2503. The generally low fitness cost of
cfr
acquisition observed in our experiments with the laboratory
S. aureus
strain offers a microbiological explanation for the apparent spread of the
cfr
gene among pathogens.
The
pmrCAB
Operon Mediates Polymyxin Resistance in
Acinetobacter baumannii
ATCC 17978 and Clinical Isolates through Phosphoethanolamine Modification of Lipid A
Authors: Arroyo Luis A. , Herrera Carmen M. , Fernandez Lucia , Hankins Jessica V. , Trent M. Stephen , Hancock Robert E. W.
Published: June 2011

The emergence of multidrug resistance among
Acinetobacter baumannii
is leading to an increasing dependence on the use of polymyxins as last-hope antibiotics. Here, we utilized genetic and biochemical methods to define the involvement of the
pmrCAB
operon in polymyxin resistance in this organism. Sequence analysis of 16 polymyxin B-resistant strains, including 6 spontaneous mutants derived from strain ATCC 17978 and 10 clinical isolates from diverse sources, revealed that they had independent mutations in the
pmrB
gene, encoding a sensor kinase, or in the response regulator PmrA. Knockout of the
pmrB
gene in two mutants and two clinical isolates led to a decrease in the polymyxin B susceptibility of these strains, which could be restored with the cloned
pmrAB
genes from the mutants but not from the wild type. Reverse transcription-quantitative PCR (RT-qPCR) analysis also showed a correlation between the expression of
pmrC
and polymyxin B resistance. Characterization of lipid A species from the mutant strains, by thin-layer chromatography and mass spectrometry, indicated that the addition of phosphoethanolamine to lipid A correlated with resistance. This addition is performed in
Salmonella enterica
serovar Typhimurium by the product of the
pmrC
gene, which is a homolog of the
pmrC
gene from
Acinetobacter
. Knockout of this gene in the mutant R2 [
pmrB
(
T235I
)] reversed resistance as well as phosphoethanolamine modification of lipid A. These results demonstrate that specific alterations in the sequence of the
pmrCAB
operon are responsible for resistance to polymyxins in
A. baumannii
.
Commonality among Fluoroquinolone-Resistant Sequence Type ST131 Extraintestinal
Escherichia coli
Isolates from Humans and Companion Animals in Australia
Authors: Platell Joanne L. , Cobbold Rowland N. , Johnson James R. , Heisig Anke , Heisig Peter , Clabots Connie , Kuskowski Michael A. , Trott Darren J.
Published: June 2011

Escherichia coli
sequence type 131 (ST131), an emergent multidrug-resistant extraintestinal pathogen, has spread epidemically among humans and was recently isolated from companion animals. To assess for human-companion animal commonality among ST131 isolates, 214 fluoroquinolone-resistant extraintestinal
E. coli
isolates (205 from humans, 9 from companion animals) from diagnostic laboratories in Australia, provisionally identified as ST131 by PCR, selectively underwent PCR-based O typing and
bla
CTX-M-15
detection. A subset then underwent multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) analysis, extended virulence genotyping, antimicrobial susceptibility testing, and fluoroquinolone resistance genotyping. All isolates were O25b positive, except for two O16 isolates and one O157 isolate, which (along with six O25b-positive isolates) were confirmed by MLST to be ST131. Only 12% of isolates (25 human, 1 canine) exhibited
bla
CTX-M-15
. PFGE analysis of 20 randomly selected human and all 9 companion animal isolates showed multiple instances of ≥94% profile similarity across host species; 12 isolates (6 human, 6 companion animal) represented pulsotype 968, the most prevalent ST131 pulsotype in North America (representing 23% of a large ST131 reference collection). Virulence gene and antimicrobial resistance profiles differed minimally, without host species specificity. The analyzed ST131 isolates also exhibited a conserved, host species-independent pattern of chromosomal fluoroquinolone resistance mutations. However, eight (89%) companion animal isolates, versus two (10%) human isolates, possessed the plasmid-borne
qnrB
gene (
P
< 0.001). This extensive across-species strain commonality, plus the similarities between Australian and non-Australian ST131 isolates, suggest that ST131 isolates are exchanged between humans and companion animals both within Australia and intercontinentally.
Bacterial Virulence in the Moonlight: Multitasking Bacterial Moonlighting Proteins Are Virulence Determinants in Infectious Disease
Authors: Henderson Brian , Martin Andrew
Published: June 2011

Men may not be able to multitask, but it is emerging that proteins can. This capacity of proteins to exhibit more than one function is termed protein moonlighting, and, surprisingly, many highly conserved proteins involved in metabolic regulation or the cell stress response have a range of additional biological actions which are involved in bacterial virulence. This review highlights the multiple roles exhibited by a range of bacterial proteins, such as glycolytic and other metabolic enzymes and molecular chaperones, and the role that such moonlighting activity plays in the virulence characteristics of a number of important human pathogens, includingStaphylococcus aureus,Streptococcus pyogenes,Streptococcus pneumoniae,Helicobacter pylori, andMycobacterium tuberculosis.
Bacteriophage-Encoding Cytolethal Distending Toxin Type V Gene Induced from Nonclinical Escherichia coli Isolates
Authors: Allué-Guardia Anna , García-Aljaro Cristina , Muniesa Maite
Published: June 2011

Cytolethal distending toxin (Cdt) is produced by a variety of pathogenic bacteria, including pathogenic serotypes of Shiga toxin-producing
Escherichia coli
(STEC). The Cdt family comprises five variants (Cdt-I to Cdt-V) encoded by three genes located within the chromosome or plasmids or, in the case of Cdt-I, within bacteriophages. In this study, we evaluated the occurrence of the
cdt
gene in a collection of 140 environmental STEC isolates.
cdt
was detected in 12.1% of strains, of which five strains carried inducible bacteriophages containing the Cdt-V variant. Two Cdt-V phages of the
Siphoviridae
morphology lysogenized
Shigella sonnei
, generating two lysogens: a single Cdt phage lysogen and a double lysogen, containing a Cdt phage and an Stx phage, both from the wild-type strain. The rates of induction of Cdt phages were evaluated by quantitative PCR, and spontaneous induction of Cdt-V phage was observed, whereas induction of Stx phage in the double lysogen was mitomycin C dependent. The Cdt distending effect was observed in HeLa cells inoculated with the supernatant of the Cdt-V phage lysogen. A ClaI fragment containing the
cdt-V
gene of one phage was cloned, and sequencing confirmed the presence of Cdt-V, as well as a fragment downstream from the
cdt
homolog to
gpA
, encoding a replication protein of bacteriophage P2. Evaluation of Cdt-V phages in nonclinical water samples showed densities of 10
2
to 10
9
gene copies in 100 ml, suggesting the high prevalence of Cdt phages in nonclinical environments.
Structure/Function Analysis of Neisseria meningitidis PilW, a Conserved Protein That Plays Multiple Roles in Type IV Pilus Biology
Authors: Szeto Tim H. , Dessen Andréa , Pelicic Vladimir
Published: June 2011

Type IV pili (Tfp) are widespread filamentous bacterial organelles that mediate multiple functions and play a key role in pathogenesis in several important human pathogens, including
Neisseria meningitidis
. Tfp biology remains poorly understood at a molecular level because the roles of the numerous proteins that are involved remain mostly obscure. Guided by the high-resolution crystal structure we recently reported for
N. meningitidis
PilW, a widely conserved protein essential for Tfp biogenesis, we have performed a structure/function analysis by targeting a series of key residues through site-directed mutagenesis and analyzing the corresponding variants using an array of phenotypic assays. Here we show that PilW's involvement in the functionality of Tfp can be genetically uncoupled from its concurrent role in the assembly/stabilization of the secretin channels through which Tfp emerge on the bacterial surface. These findings suggest that PilW is a multifunctional protein.
AN INTELLIGENT AND EFFECTIVE MECHANISM FOR MENTAL DISORDER TREATMENT BY USING BIOFEEDBACK ANALYSIS AND WEB TECHNOLOGIES
Authors: SHIE BAI-EN , JANG FONG-LIN , TSENG VINCENT S.
Published: June 2011

In the medical science field, the treatment of mental disorders has been an important issue. Recently, the treatment of mental disorders through biofeedback therapy is emerging as an important topic. A number of studies on the integration of mental healthcare and the Internet have also been proposed, since the Internet plays a more and more crucial role in various healthcare applications. By performing biofeedback therapy via the Internet, the treatment time can be highly reduced and the medical costs can also be significantly cut down. In view of this, this research aims at developing an intelligent treatment system for the patients with mental disorders by integrating biofeedback therapy and web technology. The system provides not only a convenient mechanism for the patients to perform biofeedback therapy at home but also an effective communication channel for patients and medical professionals. Moreover, the functions which enable the therapists to manage their patients more conveniently are proposed. The results of this research are expected to bring a pivotal impact on the healthcare industry with increased and enhanced levels of technology and services.
METRIC SELECTION FOR SOFTWARE DEFECT PREDICTION
Authors: WANG HUANJING , KHOSHGOFTAAR TAGHI M. , VAN HULSE JASON , GAO KEHAN
Published: June 2011

Real-world software systems are becoming larger, more complex, and much more unpredictable. Software systems face many risks in their life cycles. Software practitioners strive to improve software quality by constructing defect prediction models using metric (feature) selection techniques. Finding faulty components in a software system can lead to a more reliable final system and reduce development and maintenance costs. This paper presents an empirical study of six commonly used filter-based software metric rankers and our proposed ensemble technique using rank ordering of the features (mean or median), applied to three large software projects using five commonly used learners. The classification accuracy was evaluated in terms of the AUC (Area Under the ROC (Receiver Operating Characteristic) Curve) performance metric. Results demonstrate that the ensemble technique performed better overall than any individual ranker and also possessed better robustness. The empirical study also shows that variations among rankers, learners and software projects significantly impacted the classification outcomes, and that the ensemble method can smooth out performance.
A FRAMEWORK FOR INTEGRATING FORMAL SPECIFICATION, REVIEW, AND TESTING TO ENHANCE SOFTWARE RELIABILITY
Authors: LIU SHAOYING , TAMAI TETSUO , NAKAJIMA SHIN
Published: June 2011

Software risk comes mainly from its poor reliability, but how to effectively achieve high reliability still remains a challenge. This paper puts forward a framework for systematically integrating formal specification, review, and testing, and shows how it can be applied to effectively eliminate errors in the major phases of software development process to enhance software reliability. In this framework, requirements errors can be removed and missing requirements can be identified by formalizing requirements into formal specifications whose validity can be ensured by rigorous review. The valid specification can then be used as a firm foundation for implementation and for rigorous inspection, testing, and walkthrough of the implemented program. We discuss how formalization, review, and testing work together at different levels of software development to improve software reliability through detecting and removing errors in documentation.
Reconstruction of Nasal Skin Cancer Defects with Local Flaps
Authors: Salgarelli A. C. , Bellini P. , Multinu A. , Magnoni C. , Francomano M. , Fantini F. , Consolo U. , Seidenari S.
Published: June 2011

Reconstruction of nasal defects must preserve the integrity of complex facial functions and expressions, as well as facial symmetry and a pleasing aesthetic outcome. The reconstructive modality of choice will depend largely on the location, size, and depth of the surgical defect. Individualized therapy is the best course, and numerous flaps have been designed to provide coverage of a variety of nasal-specific defects. We describe our experience in the aesthetic reconstruction of nasal skin defects following oncological surgery. The use of different local flaps for nasal skin cancer defects is reported in 286 patients. Complications in this series were one partial flap dehiscence that healed by secondary intention, two forehead flaps, and one bilobed flap with minimal rim necrosis that resulted in an irregular scar requiring revision. Aesthetic results were deemed satisfactory by all patients and the operating surgeons. The color and texture matches were aesthetically good, and the nasal contour was distinct in all patients. All scars were inconspicuous and symmetrical. No patient had tenting or a flat nose.
Isobaric Study of the Elastic Properties for Alkaline Earth Oxides under High Temperature
Authors: Gupta Seema , Singh S. P. , Goyal S. C.
Published: June 2011

A simple and straightforward theoretical model is developed to investigate the elastic properties of alkaline earth oxides under the effect of temperature as well as pressure. The calculation is performed with the help of high pressure-high temperature equation of state based on thermodynamic analysis. The anharmonic term arising due to thermal expansion has been taken into account in the expansion of logarithmic series of the thermodynamic data. The results obtained for alkaline earth oxides are discussed and compared with experimental data under the combined effect of high temperature and high pressure. The results are found to be in good agreement with available experimental results.
Role of Phosphorylation in the Control of Clathrin-Mediated Internalization of GPCR
Authors: Delom Frederic , Fessart Delphine
Published: June 2011

The process by which G protein-coupled receptors (GPCRs) are internalized through the clathrin-coated vesicles involves interactions of multifunctional adaptor proteins. These interactions are tightly controlled by phosphorylation and dephosphorylation mechanisms resulting in the regulation of receptor endocytosis. However, the identities of the kinases involved in this process remained largely unknown until recently. This paper discusses advances in our knowledge of the important role played by protein phosphorylation in the regulation of the endocytic machinery and how phosphorylation controls the coated vesicle cycle.
Breast Fistula Repair after Autologous Fat Graft: A Case Report
Authors: Klinger Francesco Maria , Caviggioli Fabio , Forcellini Davide , Vinci Valeriano , Maione Luca , Pajardi Giorgio , Klinger Marco
Published: June 2011

We report the case of a 55-year-old female patient who attended our clinic for the presence of a scar retraction in the upper pole of the left breast as a complication of breast augmentation. In the scar area, we observed an orifice that probing revealed to be a fistula. The patient was referred to surgical intervention under general anesthesia to obtain scar contracture release using autologous fat graft; one month after autologous fat injection, following healing of the fistula, the patient underwent a second surgical procedure to replace the left breast implant. Unexpectedly, two weeks after the surgical procedure, complete healing of the breast fistula within the scar area was observed; this observation was confirmed during the second surgical step for left breast implant repositioning, when we observed the absence of the fistula orifice in the breast implant cavity. Upon clinical examination at 1-year followup, tissue integrity was preserved. The patient's satisfaction was excellent. We have observed a possible additional effect of fat graft.
High Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Promote Vγ9Vδ2 T-Cell Chemotaxis and Cytotoxicity In Vivo
Authors: Benzaïd Ismahène , Mönkkönen Hannu , Stresing Verena , Bonnelye Edith , Green Jonathan , Mönkkönen Jukka , Touraine Jean-Louis , Clézardin Philippe
Published: June 2011

The nitrogen-containing bisphosphonate zoledronic acid (ZOL), a potent inhibitor of farnesyl pyrophosphate synthase, blocks the mevalonate pathway, leading to intracellular accumulation of isopentenyl pyrophosphate/triphosphoric acid I-adenosin-5′-yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI) mevalonate metabolites. IPP/ApppI accumulation in ZOL-treated cancer cells may be recognized by Vγ9Vδ2 T cells as tumor phosphoantigens in vitro. However, the significance of these findings in vivo remains largely unknown. In this study, we investigated the correlation between the anticancer activities of Vγ9Vδ2 T cells and the intracellular IPP/ApppI levels in ZOL-treated breast cancer cells in vitro and in vivo. We found marked differences in IPP/ApppI production among different human breast cancer cell lines post-ZOL treatment. Coculture with purified human Vγ9Vδ2 T cells led to IPP/ApppI-dependent near-complete killing of ZOL-treated breast cancer cells. In ZOL-treated mice bearing subcutaneous breast cancer xenografts, Vγ9Vδ2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels, but not those expressing low IPP/ApppI levels. Moreover, IPP/ApppI not only accumulated in cancer cells but it was also secreted, promoting Vγ9Vδ2 T-cell chemotaxis to the tumor. Without Vγ9Vδ2 T-cell expansion, ZOL did not inhibit tumor growth. These findings suggest that cancers-producing high IPP/ApppI levels after ZOL treatment are most likely to benefit from Vγ9Vδ2 T-cell–mediated immunotherapy. Cancer Res; 71(13); 4562–72. ©2011 AACR.