bluuebunny/crossref_metadata_2025 huggingface dataset:
Release of endogenous opioids during a chronic IBD model suppresses the excitability of colonic DRG neurons
Authors: Valdez‐Morales E. , Guerrero‐Alba R. , Ochoa‐Cortes F. , Benson J. , Spreadbury I. , Hurlbut D. , Miranda‐Morales M. , Lomax A. E. , Vanner S.
Published: September 2012

Background  Endogenous opioids are implicated in pain‐regulation in chronic inflammatory bowel disease (IBD). We sought to examine whether endogenous opioids suppress the excitability of colonic nociceptive dorsal root ganglia (DRG) neurons during chronic IBD, and if so, whether modulation of underlying voltage‐gated K+ currents was involved.

Methods  The effects of chronic dextran sulfate sodium (DSS) colitis on afferent signaling in mice was studied using patch clamp recordings. Colonic DRG neurons were identified using Fast Blue retrograde labeling and recordings obtained from small DRG neurons (<40 pF).

Key Results  In current‐clamp recordings, the rheobase of neurons was increased 47% (P < 0.01) and action potential discharge at twice rheobase decreased 23% (P < 0.05) following incubation in colonic supernatants from chronic DSS mice. β‐endorphin increased 14‐fold, and tissue opioid immunoreactivity and expression in CD4+ cells observed by flow cytometry increased in chronic DSS colons. Incubation of naïve neurons in the μ‐opioid receptor agonist D‐Ala2, N‐ MePhe4, Gly‐ol (DAMGO) (10 nM) partially recapitulated the effects of supernatants from DSS mice on rheobase. Supernatant effects were blocked by the μ‐opioid receptor antagonist naloxone. In voltage clamp, chronic DSS supernatants and DAMGO increased IA K+ currents.

Conclusions & Inferences  The release of endogenous opioids during chronic inflammation in mice suppresses the excitability of nociceptive DRG neurons. Targeting immune cells may provide a novel means of modulating IBD pain.
Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients
Authors: Buhner S. , Li Q. , Berger T. , Vignali S. , Barbara G. , De Giorgio R. , Stanghellini V. , Schemann M.
Published: September 2012

Background  We previously showed that colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS) activate neurons of the human submucous plexus, an area with densely packed immune cells. Based on the concept that mucosa‐nerve signaling is altered in IBS, we tested in this study whether the nerve sensitizing effect of IBS mucosal biopsy supernatants is more prominent in the submucous than myenteric plexus.

Methods  Fast neuroimaging with the voltage‐sensitive dye Di‐8‐ANEPPS was used to record activity of guinea‐pig submucous and myenteric neurons after application of constipation (C)‐ and diarrhea (D)‐IBS supernatants (three each) and four supernatants from healthy control subjects. Results are based on recordings from 4731 neurons.

Key Results  Control supernatants did not evoke significant responses in submucous or myenteric neurons. In contrast, all IBS supernatants evoked a significant spike discharge (median 3.6 Hz) in 46% of submucous neurons. This activation was significantly stronger than in the myenteric plexus where even twice the amount of supernatants evoked a lower spike frequency (median 2.1 Hz) in only 8.5% of neurons. Pharmacological studies revealed serotonin, histamine, and proteases as components mediating neuronal activation. Individual application of these components revealed that only serotonin evoked a significantly stronger activation of submucous compared with myenteric neurons.

Conclusions & Inferences  Direct neuronal activation by IBS mucosal biopsy supernatants is primarily a feature of submucous rather than myenteric neurons. This is associated with a stronger excitation of submucous neurons by serotonin. The plexus‐specific effects support the concept that altered mucosa‐nerve signaling underlies disturbances in IBS.
Association between craniofacial asymmetry and unilateral temporomandibular joint sounds in adult patients using 3D‐computed tomography
Authors: Yáñez‐Vico R‐M , Iglesias‐Linares A , Torres‐Lagares D , Gutiérrez‐Pérez J‐L , Solano‐Reina E
Published: September 2012

Objectives

The purpose of this study was to investigate the possible relationship between unilateral temporomandibular joint (TMJ) sounds and craniofacial asymmetry, using 3D‐computed tomography (CT) measurements.

Subjects and Methods

Forty‐one reconstructed 3D‐CT models of adult subjects were measured to analyze craniofacial asymmetry. Subjects were divided into two groups depending on the presence (n = 20) or absence (n = 21) of unilateral joint sounds, and the results compared using the Mann–Whitney U‐test. To investigate the association between these parameters, the Pearson correlation coefficient was calculated.

Results

Asymmetries in the maxillary and mandibular structures were statistically significant (P < 0.05) for subjects with unilateral TMJ sounds and for controls, except in the case of maxillary rotation and mandibular ramus height (P > 0.05). The highest deviations found were frontal and lateral ramal inclination, goniac angle and canting of occlusal plane.

Conclusions

Adult patients with unilateral joint sounds may have skeletal jaw asymmetry and a canted occlusal plane.
SIZ1 deficiency causes reduced stomatal aperture and enhanced drought tolerance via controlling salicylic acid‐induced accumulation of reactive oxygen species in Arabidopsis
Authors: Miura Kenji , Okamoto Hiroyuki , Okuma Eiji , Shiba Hayato , Kamada Hiroshi , Hasegawa Paul M. , Murata Yoshiyuki
Published: September 2012

Transpiration and gas exchange occur through stomata. Thus, the control of stomatal aperture is important for the efficiency and regulation of water use, and for the response to drought. Here, we demonstrate that SIZ1‐mediated endogenous salicylic acid (SA) accumulation plays an important role in stomatal closure and drought tolerance. siz1 reduced stomatal apertures. The reduced stomatal apertures of siz1 were inhibited by the application of peroxidase inhibitors, salicylhydroxamic acid and azide, which inhibits SA‐dependent reactive oxygen species (ROS) production, but not by an NADPH oxidase inhibitor, diphenyl iodonium chloride, which inhibits ABA‐dependent ROS production. Furthermore, the introduction of nahG into siz1, which reduces SA accumulation, restored stomatal opening. Stomatal closure is generally induced by water deficit. The siz1 mutation caused drought tolerance, whereas nahG siz1 suppressed the tolerant phenotype. Drought stresses also induced expression of SA‐responsive genes, such as PR1 and PR2. Furthermore, other SA‐accumulating mutants, cpr5 and acd6, exhibited stomatal closure and drought tolerance, and nahG suppressed the phenotype of cpr5 and acd6, as did siz1 and nahG siz1. Together, these results suggest that SIZ1 negatively affects stomatal closure and drought tolerance through the accumulation of SA.
The Brauer characters of the sporadic simple Harada–Norton group and its automorphism group in characteristics 2 and 3
Authors: Hiss Gerhard , Müller Jürgen , Noeske Felix , Thackray Jon
Published: September 2012

We determine the 2-modular and 3-modular character tables of the sporadic simple Harada–Norton group and its automorphism group.
High blood pressure associates with the remodelling of inward rectifier K+ channels in mice mesenteric vascular smooth muscle cells
Authors: Tajada Sendoa , Cidad Pilar , Moreno‐Domínguez Alejandro , Pérez‐García M. Teresa , López‐López José R.
Published: September 2012

Key points

Essential hypertension involves an electrical remodelling of vascular smooth muscle cells (VSMCs), particularly relevant for K+ channels, as key determinants of resting membrane potential (VM) and excitability.

We explored mRNA expression levels of inward rectifier K+ channel genes in five different vascular beds from normotensive (BPN) and hypertensive (BPH) mice. In mesenteric VSMCs, their functional contribution to cell excitability and vascular reactivity was investigated.

BPH mesenteric VSMCs show a decreased functional expression of both classical inward rectifiers (KIR, Kir2 and Kir4 channels) and ATP‐sensitive K+ channels (KATP, Kir6 channels). However, only the changes in the functional expression of KATP channels seem to contribute to the increased vascular reactivity of BPH arteries.

BPN and BPH mice are a useful model to provide integrated information of the impact in the pathophysiology of essential hypertension of the changes in ion channel functional expression.

Abstract  The increased vascular tone that defines essential hypertension is associated with depolarization of vascular smooth muscle cells (VSMCs) and involves a change in the expression profile of ion channels promoting arterial contraction. As a major regulator of VSMC resting membrane potential (VM), K+ channel activity is an important determinant of vascular tone and vessel diameter. However, hypertension‐associated changes in the expression and/or modulation of K+ channels are poorly defined, due to their large molecular diversity and their bed‐specific pattern of expression. Moreover, the impact of these changes on the integrated vessel function and their contribution to the development of altered vascular tone under physiological conditions need to be confirmed. Hypertensive (BPH) and normotensive (BPN) mice strains obtained by phenotypic selection were used to explore whether changes in the functional expression of VSMC inward rectifier K+ channels contribute to the more depolarized resting VM and the increased vascular reactivity of hypertensive arteries. We determined the expression levels of inward rectifier K+ channel mRNA in several vascular beds from BPN and BPH animals, and their functional contribution to VSMC excitability and vascular tone in mesenteric arteries. We found a decrease in the expression of Kir2.1, Kir4.1, Kir6.x and SUR2 mRNA in BPH VSMCs, and a decreased functional contribution of both KIR and KATP channels in isolated BPH VSMCs. However, only the effect of KATP channel modulators was impaired when exploring vascular tone, suggesting that decreased functional expression of KATP channels may be an important element in the remodelling of VSMCs in essential hypertension.
Reduced corticomotor excitability and motor skills development in children born preterm
Authors: Pitcher Julia B. , Schneider Luke A. , Burns Nicholas R. , Drysdale John L. , Higgins Ryan D. , Ridding Michael C. , Nettelbeck Theodore J. , Haslam Ross R. , Robinson Jeffrey S.
Published: September 2012

Key points

Children born preterm commonly experience motor and cognitive difficulties, but the physiology underlying this dysfunction is unknown.

We used transcranial magnetic stimulation techniques and age‐appropriate assessments of motor skills development to investigate neurodevelopment in 151 children born between 25 and 41 weeks of gestation.

Reduced gestational age at birth was associated with a reduction in corticomotor excitability that persisted in late childhood, poorer development of manual dexterity skills and reduced hemispheric lateralization of hand preference.

We suggest this reduced corticomotor excitability at least partly reflects reduced white matter integrity and functional connectivity in the brain regions subserving movement control.

These findings show that preterm birth, which is increasingly common, impacts neuromotor development and related physiology into adolescence. Whether this altered neurophysiology and motor function persists in adulthood is unknown.

Abstract  The mechanisms underlying the altered neurodevelopment commonly experienced by children born preterm, but without brain lesions, remain unknown. While individuals born the earliest are at most risk, late preterm children also experience significant motor, cognitive and behavioural dysfunction from school age, and reduced income and educational attainment in adulthood. We used transcranial magnetic stimulation and functional assessments to examine corticomotor development in 151 children without cerebral palsy, aged 10–13 years and born after gestations of 25–41 completed weeks. We hypothesized that motor cortex and corticospinal development are altered in preterm children, which underpins at least some of their motor dysfunction. We report for the first time that every week of reduced gestation is associated with a reduction in corticomotor excitability that remains evident in late childhood. This reduced excitability was associated with poorer motor skill development, particularly manual dexterity. However, child adiposity, sex and socio‐economic factors regarding the child's home environment soon after birth were also powerful influences on development of motor skills. Preterm birth was also associated with reduced left hemisphere lateralization, but without increasing the likelihood of being left handed per se. These corticomotor findings have implications for normal motor development, but also raise questions regarding possible longer term consequences of preterm birth on motor function.
Partial opening and subconductance gating of mechanosensitive ion channels in dystrophic skeletal muscle
Authors: Vasquez Ivan , Tan Nhi , Boonyasampant Mark , Koppitch Kari A. , Lansman Jeffry B.
Published: September 2012

Key points

Mechanosensitive (MS) channels in skeletal muscle are heteromeric proteins composed of TRPV4 and other subunits. Experiments investigated subconductance fluctuations associated with gating of independent subunits.

MS channels open by passing through subconductance states and fluctuate between at least four subconductance levels.

MS channels in mdx muscle spend ∼60% of the time at smaller subconductance levels; applying pressure to the membrane increases occupancy of the fully open state. Channels in wild‐type muscle spend more time at the open state.

Recordings show partial opening of MS channels that fail to reach the open state. Partial openings occur ∼3–4 times more frequently in mdx than wild‐type muscle.

During single activations, burst durations and charge/burst are greater in mdx than in wild‐type muscle.

Partial opening and prolonged burst duration are distinct mechanisms contributing to excess Ca2+ entry through MS channels in dystrophic muscle

Abstract  We recorded the activity of single mechanosensitive (MS) ion channels in skeletal muscle from the mdx mouse, a deletion mutant that lacks the cytoskeletal protein, dystrophin. Experiments were designed to examine the influence of dystrophin, a major component of skeletal muscle costameres, on the behaviour of single MS channels. In the majority of recordings from cell‐attached patches, MS channels have a conductance of ∼23 pS. Recordings from some patches, however, showed a smaller conductance channel of ∼7–14 pS. Large and small conductance channels were detected in a single patch and showed serial, non‐random gating, suggesting different opening levels of a single channel. Analysis of the distribution of current amplitudes within the open channel showed MS channels fluctuate between subconductance levels. MS channels in dystrophic muscle spend ∼60% of the time at smaller subconductance levels, often failing to reach the fully open level. Applying pressure to the membrane of mdx fibres increases in a graded manner occupancy of the fully open state, while reducing occupancy of subconductance levels. Recordings also show partial openings of MS channels in both wild‐type and mdx muscle that fail to reach the fully open state. Partial openings occur at a higher frequency in mdx muscle and reflect occupancy of subconductance levels seen during complete activations. In muscle from mdx/utrn−/− double knockout mice, MS channels also spend more time at subconductance levels than the fully open state. Conductance variability of MS channels may represent gating of a heteromeric protein composed of different channel subunits. The results also show that partial opening and prolonged burst duration are distinct mechanisms that contribute to excess Ca2+ entry in dystrophic muscle.
A First-in-Human, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study To Assess the Safety and Tolerability of LFF571 in Healthy Volunteers
Authors: Ting Lillian S. L. , Praestgaard Jens , Grunenberg Nicole , Yang Jenny C. , Leeds Jennifer A. , Pertel Peter
Published: September 2012

Clostridium difficile
is the leading cause of hospital-acquired infectious diarrhea. LFF571 is a novel inhibitor of the prokaryotic translation elongation factor Tu and is active against a range of bacterial species, including
C. difficile
. This first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of LFF571 in healthy subjects. This was a randomized, double-blind, placebo-controlled study. Except for one cohort, LFF571 was given with a high-fat meal to all single-dose cohorts (25 mg, 100 mg, 400 mg, and 1,000 mg). In the multiple-dose cohorts (25 mg, 100 mg, or 200 mg every 6 h for 10 days), LFF571 was given without regard to food. A total of 56 subjects completed the study, with 32 and 25 receiving single and multiple doses, respectively. There were no deaths, no serious adverse events, and no subject withdrawals due to an adverse event. The most common adverse event was diarrhea; gastrointestinal pain or distension was also noted. Diarrhea did not develop more frequently among subjects who received LFF571 than among those who received a placebo. LFF571 had limited systemic exposure and high steady-state fecal concentrations. The highest concentration of LFF571 in serum (3.2 ng/ml) was observed after the last dose in a subject who received 200 mg every 6 h for 10 days. LFF571 was generally safe and well tolerated in single and multiple oral doses in healthy subjects. The minimal serum and high fecal concentrations support the further development of LFF571 for the treatment of
C. difficile
infections.
Comparison of the
In Vivo
Pharmacokinetics and
In Vitro
Dissolution of Raltegravir in HIV Patients Receiving the Drug by Swallowing or by Chewing
Authors: Cattaneo Dario , Baldelli Sara , Cerea Matteo , Landonio Simona , Meraviglia Paola , Simioni Emanuela , Cozzi Valeria , Fucile Serena , Gazzaniga Andrea , Clementi Emilio , Galli Massimo , Rizzardini Giuliano , Gervasoni Cristina
Published: September 2012

The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interpatient/intrapatient variability. We investigated the potential contribution of the drug pharmaceutical formulation to RAL pharmacokinetics. We first compared
in vivo
the pharmacokinetics of RAL for 67 patients to whom the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients who chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated
in vitro
the dissolution of RAL tablets under different conditions. In the
in vivo
study, we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterized by significantly higher RAL absorption than did patients receiving the drug by swallowing. The
in vitro
studies showed that when the whole tablets were exposed to an acidic medium, the release of RAL was very low, whereas when the tablets were crushed, the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL. HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics.
Safety and Pharmacokinetics of Intravaginal Rings Delivering Tenofovir in Pig-Tailed Macaques
Authors: Moss John A. , Malone Amanda M. , Smith Thomas J. , Butkyavichene Irina , Cortez Cassandra , Gilman Joshua , Kennedy Sean , Kopin Etana , Nguyen Cali , Sinha Preetha , Hendry R. Michael , Guenthner Patricia , Holder Angela , Martin Amy , McNicholl Janet , Mitchell James , Pau Chou-Pong , Srinivasan Priya , Smith James M. , Baum Marc M.
Published: September 2012

Antiretroviral-based microbicides applied topically to the vagina may play an important role in protecting women from HIV infection. Incorporation of the nucleoside reverse transcriptase inhibitor tenofovir (TFV) into intravaginal rings (IVRs) for sustained mucosal delivery may lead to increased microbicide product adherence and efficacy compared with those of conventional vaginal formulations. Formulations of a novel “pod IVR” platform spanning a range of IVR drug loadings and daily release rates of TFV were evaluated in a pig-tailed macaque model. The rings were safe and exhibited sustained release at controlled rates over 28 days. Vaginal secretion TFV levels were independent of IVR drug loading and were able to be varied over 1.5 log units by changing the ring configuration. Mean TFV levels in vaginal secretions were 72.4 ± 109 μg ml
−1
(slow releasing) and 1.84 ± 1.97 mg ml
−1
(fast releasing). The mean TFV vaginal tissue concentration from the slow-releasing IVRs was 76.4 ± 54.8 μg g
−1
and remained at steady state 7 days after IVR removal, consistent with the long intracellular half-life of TFV. Intracellular tenofovir diphosphate (TFV-DP), the active moiety in defining efficacy, was measured in vaginal lymphocytes collected in the study using the fast-releasing IVR formulation. Mean intracellular TFV-DP levels of 446 ± 150 fmol/10
6
cells fall within a range that may be protective of simian-human immunodeficiency virus strain SF162p3 (SHIV
SF162p3
) infection in nonhuman primates. These data suggest that TFV-releasing IVRs based on the pod design have potential for the prevention of transmission of human immunodeficiency virus type 1 (HIV-1) and merit further clinical investigation.
Pseudomonas aeruginosa Syntrophy in Chronically Colonized Airways of Cystic Fibrosis Patients
Authors: Qin Xuan , Zerr Danielle M. , McNutt Michael A. , Berry Jessica E. , Burns Jane L. , Kapur Raj P.
Published: September 2012

Pseudomonas aeruginosa
isolates from cystic fibrosis (CF) patients undergo remarkable phenotypic divergence over time, including loss of pigmentation, hemolysis, motility, and quorum sensing and emergence of antibiotic hypersusceptibility and/or auxotrophism. With prolonged antibiotic treatment and steady decline in lung function in chronically infected patients, the divergent characteristics associated with CF isolates have traditionally been regarded as “adapted/unusual virulence,” despite the degenerative nature of these adaptations. We examined the phenotypic and genotypic diversity in clonally related isogenic strains of
P. aeruginosa
from individual CF patients. Our observations support a novel model of intra-airway pseudomonal syntrophy and accompanying loss of virulence. A 2007 calendar year collection of CF
P. aeruginosa
isolates (
n
= 525) from 103 CF patients yielded
in vitro
MICs of sulfamethoxazole-trimethoprim (SMX-TMP, which typically has no activity against
P. aeruginosa
) ranging from 0.02 to >32 μg/ml (median, 1.5). Coisolation of clonally related SMX-TMP-susceptible and -resistant
P. aeruginosa
strains from the same host was common (57%), as were isogenic coisolates with mutations in efflux gene determinants (
mexR
,
mexAB-oprM
, and
mexZ
) and genes governing DNA mismatch repair (
mutL
and
mutS
). In this cohort, complete
in vitro
growth complementation between auxotrophic and prototrophic
P. aeruginosa
isogenic strains was evident and concurrent with the coding sequence mosaicism in resistance determinants. These observations suggest that syntrophic clonal strains evolve
in situ
in an organized colonial structure. We propose that
P. aeruginosa
adopts a multicellular lifestyle in CF patients due to host selection of an energetically favorable, less-virulent microbe restricted within and symbiotic with the airway over the host's lifetime.
In Vitro
and
In Vivo
Antimicrobial Activities of Gallium Nitrate against Multidrug-Resistant Acinetobacter baumannii
Authors: Antunes Luísa C. S. , Imperi Francesco , Minandri Fabrizia , Visca Paolo
Published: September 2012

Multidrug-resistant
Acinetobacter baumannii
poses a tremendous challenge to traditional antibiotic therapy. Due to the crucial role of iron in bacterial physiology and pathogenicity, we investigated iron metabolism as a possible target for anti-
A. baumannii
chemotherapy using gallium as an iron mimetic. Due to chemical similarity, gallium competes with iron for binding to several redox enzymes, thereby interfering with a number of essential biological reactions. We found that Ga(NO
3
)
3
, the active component of an FDA-approved drug (Ganite), inhibits the growth of a collection of 58
A. baumannii
strains in both chemically defined medium and human serum, at concentrations ranging from 2 to 80 μM and from 4 to 64 μM, respectively. Ga(NO
3
)
3
delayed the entry of
A. baumannii
into the exponential phase and drastically reduced bacterial growth rates. Ga(NO
3
)
3
activity was strongly dependent on iron availability in the culture medium, though the mechanism of growth inhibition was independent of dysregulation of gene expression controlled by the ferric uptake regulator Fur. Ga(NO
3
)
3
also protected
Galleria mellonella
larvae from lethal
A. baumannii
infection, with survival rates of ≥75%. At therapeutic concentrations for humans (28 μM plasma levels), Ga(NO
3
)
3
inhibited the growth in human serum of 76% of the multidrug-resistant
A. baumannii
isolates tested by ≥90%, raising expectations on the therapeutic potential of gallium for the treatment of
A. baumannii
bloodstream infections. Ga(NO
3
)
3
also showed strong synergism with colistin, suggesting that a colistin-gallium combination holds promise as a last-resort therapy for infections caused by pan-resistant
A. baumannii
.
Cysteine-Scanning Mutagenesis Supports the Importance of Clostridium perfringens Enterotoxin Amino Acids 80 to 106 for Membrane Insertion and Pore Formation
Authors: Chen Jianwu , Theoret James R. , Shrestha Archana , Smedley James G. , McClane Bruce A.
Published: September 2012

Clostridium perfringens
enterotoxin (CPE) causes the gastrointestinal symptoms of the second most common bacterial food-borne illness. Previous studies suggested that a region named TM1, which has amphipathic characteristics and spans from amino acids 81 to 106 of the native CPE protein, forms a β-hairpin involved in β-barrel pore formation. To further explore the potential role of TM1 in pore formation, the single Cys naturally present in CPE at residue 186 was first altered to alanine by mutagenesis; the resultant rCPE variant, named C186A, was shown to retain cytotoxic properties. Cys-scanning mutagenesis was then performed in which individual Cys mutations were introduced into each TM1 residue of the C186A variant. When those Cys variants were characterized, three variants were identified that exhibit reduced cytotoxicity despite possessing binding and oligomerization abilities similar to those of the C186A variant from which they were derived. Pronase challenge experiments suggested that the reduced cytotoxicity of those two Cys variants, i.e., the F91C and F95C variants, which model to the tip of the β-hairpin, was attributable to a lessened ability of these variants to insert into membranes after oligomerization. In contrast, another Cys variant, i.e., the G103C variant, with impaired cytotoxicity apparently inserted into membranes after oligomerization but could not form a pore with a fully functional channel. Collectively, these results support the TM1 region forming a β-hairpin as an important step in CPE insertion and pore formation. Furthermore, this work identifies the first amino acid residues specifically involved in those two steps in CPE action.
Inflammatory Monocyte Recruitment Is Regulated by Interleukin-23 during Systemic Bacterial Infection
Authors: Indramohan Mohanalaxmi , Sieve Amy N. , Break Timothy J. , Berg Rance E.
Published: September 2012

Listeria monocytogenesis a Gram-positive intracellular pathogen that causes meningitis and septicemia in immunocompromised individuals and spontaneous abortion in pregnant women. The innate immune response againstL. monocytogenesis primarily mediated by neutrophils and monocytes. Interleukin-23 (IL-23) is an important proinflammatory cytokine well known for its role in neutrophil recruitment in various infectious and autoimmune diseases. We have previously shown that IL-23 is required for host resistance againstL. monocytogenesand for neutrophil recruitment to the liver, but not the spleen, during infection. Despite efficient neutrophil recruitment to the spleen, IL-23p19 knockout (KO) mice have an increased bacterial burden in this organ, suggesting that IL-23 may regulate the recruitment/function of another cell type to the spleen. In this study, we show that specific depletion of neutrophils abrogated the differences in bacterial burdens in the livers but not the spleens of C57BL/6 (B6) and IL-23p19 KO mice. Interestingly,L. monocytogenes-infected IL-23p19 KO mice had fewer monocytes in the spleen than B6 mice, as well as a reduction in the monocyte-recruiting chemokines CCL2 and CCL7. Additionally, the overall concentrations of tumor necrosis factor alpha (TNF-α) and nitric oxide (NO•), as well as the percentages and total numbers of monocytes producing TNF-α and NO•, were reduced in IL-23p19 KO mice compared to levels in B6 mice, leading to increased bacterial burdens in the spleens ofL. monocytogenes-infected IL-23p19 KO mice. Collectively, our data establish that IL-23 is required for the optimal recruitment of TNF-α- and NO•-producing inflammatory monocytes, thus revealing a novel mechanism by which this proinflammatory cytokine provides protection against bacterial infection.
Kinetics of Innate Immune Response to Yersinia pestis after Intradermal Infection in a Mouse Model
Authors: Bosio Christopher F. , Jarrett Clayton O. , Gardner Donald , Hinnebusch B. Joseph
Published: September 2012

A hallmark ofYersinia pestisinfection is a delayed inflammatory response early in infection. In this study, we use an intradermal model of infection to study early innate immune cell recruitment. Mice were injected intradermally in the ear with wild-type (WT) or attenuatedY. pestislacking the pYV virulence plasmid (pYV−). The inflammatory responses in ear and draining lymph node samples were evaluated by flow cytometry and immunohistochemistry. As measured by flow cytometry, total neutrophil and macrophage recruitment to the ear in WT-infected mice did not differ from phosphate-buffered saline (PBS) controls or mice infected with pYV−, except for a transient increase in macrophages at 6 h compared to the PBS control. Limited inflammation was apparent even in animals with high bacterial loads (105to 106CFU). In addition, activation of inflammatory cells was significantly reduced in WT-infected mice as measured by CD11b and major histocompatibility complex class II (MHC-II) expression. When mice infected with WT were injected 12 h later at the same intradermal site with purified LPS,Y. pestisdid not prevent recruitment of neutrophils. However, significant reduction in neutrophil activation remained compared to that of PBS and pYV−controls. Immunohistochemistry revealed qualitative differences in neutrophil recruitment to the skin and draining lymph node, with WT-infected mice producing a diffuse inflammatory response. In contrast, focal sites of neutrophil recruitment were sustained through 48 h postinfection in pYV−-infected mice. Thus, an important feature ofY. pestisinfection is reduced activation and organization of inflammatory cells that is at least partially dependent on the pYV virulence plasmid.
Analysis of the Mechanisms That Underlie Absorption of Botulinum Toxin by the Inhalation Route
Authors: Al-Saleem Fetweh H. , Ancharski Denise M. , Joshi Suresh G. , Elias M. , Singh Ajay , Nasser Zidoon , Simpson Lance L.
Published: September 2012

Botulinum toxin is a highly potent oral and inhalation poison, which means that the toxin must have an efficient mechanism for penetration of epithelial barriers. To date, three models for toxin passage across epithelial barriers have been proposed: (i) the toxin itself undergoes binding and transcytosis; (ii) an auxiliary protein, HA35, transports toxin from the apical to the basal side of epithelial cells; and (iii) an auxiliary protein, HA35, acts on the basal side of epithelial cells to disrupt tight junctions, and this permits paracellular flux of toxin. These models were evaluated by studying toxin absorption following inhalation exposure in mice. Three types of experiments were conducted. In the first, the potency of pure neurotoxin was compared with that of progenitor toxin complex, which contains HA35. The results showed that the rate and extent of toxin absorption, as well as the potency of absorbed toxin, did not depend upon, nor were they enhanced by, the presence of HA35. In the second type of experiment, the potencies of pure neurotoxin and progenitor toxin complex were compared in the absence or presence of antibodies on the apical side of epithelial cells. Antibodies directed against the neurotoxin protected against challenge, but antibodies against HA35 did not. In the final type of experiment, the potency of pure neurotoxin and toxin complex was compared in animals pretreated to deliver antibodies to the basal side of epithelial cells. Once again, antibodies directed against the neurotoxin provided resistance to challenge, but antibodies directed against HA35 did not. Taken collectively, the data indicate that the toxin by itself is capable of crossing epithelial barriers. The data do not support any hypothesis in which HA35 is essential for toxin penetration of epithelial barriers.
YbcL of Uropathogenic Escherichia coli Suppresses Transepithelial Neutrophil Migration
Authors: Lau Megan E. , Loughman Jennifer A. , Hunstad David A.
Published: September 2012

Uropathogenic
Escherichia coli
(UPEC) strains suppress the acute inflammatory response in the urinary tract to ensure access to the intracellular uroepithelial niche that supports the propagation of infection. Our understanding of this initial cross talk between host and pathogen is incomplete. Here we report the identification of a previously uncharacterized periplasmic protein, YbcL, encoded by UPEC that contributes to immune modulation in the urinary tract by suppressing acute neutrophil migration. In contrast to wild-type UPEC, an isogenic strain lacking
ybcL
expression (UTI89 Δ
ybcL
) failed to suppress transepithelial polymorphonuclear leukocyte (PMN) migration
in vitro
, a defect complemented by expressing
ybcL
episomally. YbcL homologs are present in many
E. coli
genomes; expression of the YbcL variant encoded by nonpathogenic
E. coli
K-12 strain MG1655 (YbcL
MG
) failed to complement the UTI89 Δ
ybcL
defect, whereas expression of the UPEC YbcL variant (YbcL
UTI
) in MG1655 conferred the capacity for suppressing PMN migration. This phenotypic difference was due to a single amino acid difference (V78T) between the two YbcL homologs, and a majority of clinical UPEC strains examined were found to encode the suppressive YbcL variant. Purified YbcL
UTI
protein suppressed PMN migration in response to live or killed MG1655, and YbcL
UTI
was detected in the supernatant during UPEC infection of bladder epithelial cells or PMNs. Lastly, early PMN influx to murine bladder tissue was augmented upon
in vivo
infection with UTI89 Δ
ybcL
compared with wild-type UPEC. Our findings demonstrate a role for UPEC YbcL in suppression of the innate immune response during urinary tract infection.
The possible absence of a healthy-worker effect: a cross-sectional survey among educated Japanese women
Authors: Nishikitani Mariko , Nakao Mutsuhiro , Tsurugano Shinobu , Yano Eiji
Published: September 2012

Objectives

Despite being highly educated in comparison with women in other member countries of the Organisation for Economic Cooperation and Development, Japanese women are expected to assume traditional gender roles, and many dedicate themselves to full-time housewifery. Women working outside the home do so under poor conditions, and their health may not be better than that of housewives. This study compared the self-rated health status and health behaviours of housewives and working women in Japan.

Design

Cross-sectional survey.

Setting

A national university in Tokyo with 9864 alumnae.

Participants

A total 1344 women who graduated since 1985 and completed questionnaires in an anonymous mail-based survey.

Primary and secondary outcome measures

Health anxiety and satisfaction, receipt of health check-ups, eating breakfast, smoking, and sleep problems according to job status and family demands: housewives (n=247) and working women with (n=624) and without (n=436) family demands. ORs were used for risk assessment, with housewives as a reference.

Results

After adjustment for satisfaction with present employment status and other confounding factors, working women were more likely than housewives to feel health anxiety (with family demands, OR: 1.68, 95% CI1.10 to 2.57; without family demands, OR: 3.57, 95% CI 2.19 to 4.50) and health dissatisfaction (without family demands, OR: 3.50, 95% CI 2.35 to 5.21); they were also more likely than housewives to eat an insufficient breakfast (with family demands, OR: 1.91, 95% CI 1.22 to 3.00; without family demands, OR: 4.02, 95% CI 2.47 to 6.57) and to have sleep problems (ORs: 2.08 to 4.03).

Conclusions

No healthy-worker effect was found among Japanese women. Housewives, at least those who are well educated, appear to have better health status and health-related behaviours than do working women with the same level of education.
Impact of a reduced red and processed meat dietary pattern on disease risks and greenhouse gas emissions in the UK: a modelling study
Authors: Aston Louise M , Smith James N , Powles John W
Published: September 2012

Objectives

Consumption of red and processed meat (RPM) is a leading contributor to greenhouse gas (GHG) emissions, and high intakes of these foods increase the risks of several leading chronic diseases. The aim of this study was to use newly derived estimates of habitual meat intakes in UK adults to assess potential co-benefits to health and the environment from reduced RPM consumption.

Design

Modelling study using dietary intake data from the National Diet and Nutrition Survey of British Adults.

Setting

British general population.

Methods

Respondents were divided into fifths by energy-adjusted RPM intakes, with vegetarians constituting a sixth stratum. GHG emitted in supplying the diets of each stratum was estimated using data from life-cycle analyses. A feasible counterfactual UK population was specified, in which the proportion of vegetarians measured in the survey population doubled, and the remainder adopted the dietary pattern of the lowest fifth of RPM consumers.

Outcome measures

Reductions in risks of coronary heart disease, diabetes and colorectal cancer, and GHG emissions, under the counterfactual.

Results

Habitual RPM intakes were 2.5 times higher in the top compared with the bottom fifth of consumers. Under the counterfactual, statistically significant reductions in population aggregate risks ranged from 3.2% (95% CI 1.9 to 4.7) for diabetes in women to 12.2% (6.4 to 18.0) for colorectal cancer in men, with those moving from the highest to lowest consumption levels gaining about twice these averages. The expected reduction in GHG emissions was 0.45 tonnes CO2equivalent/person/year, about 3% of the current total, giving a reduction across the UK population of 27.8 million tonnes/year.

Conclusions

Reduced consumption of RPM would bring multiple benefits to health and environment.
Rates of obstetric intervention among low-risk women giving birth in private and public hospitals in NSW: a population-based descriptive study
Authors: Dahlen Hannah Grace , Tracy Sally , Tracy Mark , Bisits Andrew , Brown Chris , Thornton Charlene
Published: September 2012

Objectives

To compare the risk profile of women giving birth in private and public hospitals and the rate of obstetric intervention during birth compared with previous published rates from a decade ago.

Design

Population-based descriptive study.

Setting

New South Wales, Australia.

Participants

691 738 women giving birth to a singleton baby during the period 2000 to 2008.

Main outcome measures

Risk profile of women giving birth in public and private hospitals, intervention rates and changes in these rates over the past decade.

Results

Among low-risk women rates of obstetric intervention were highest in private hospitals and lowest in public hospitals. Low-risk primiparous women giving birth in a private hospital compared to a public hospital had higher rates of induction (31% vs 23%); instrumental birth (29% vs 18%); caesarean section (27% vs 18%), epidural (53% vs 32%) and episiotomy (28% vs 12%) and lower normal vaginal birth rates (44% vs 64%). Low-risk multiparous women had higher rates of instrumental birth (7% vs 3%), caesarean section (27% vs 16%), epidural (35% vs 12%) and episiotomy (8% vs 2%) and lower normal vaginal birth rates (66% vs 81%). As interventions were introduced during labour, the rate of interventions in birth increased. Over the past decade these interventions have increased by 5% for women in public hospitals and by over 10% for women in private hospitals. Among low-risk primiparous women giving birth in private hospitals 15 per 100 women had a vaginal birth with no obstetric intervention compared to 35 per 100 women giving birth in a public hospital.

Conclusions

Low-risk primiparous women giving birth in private hospitals have more chance of a surgical birth than a normal vaginal birth and this phenomenon has increased markedly in the past decade.
ANALYZING FLOW ANISOTROPIES WITH EXCURSION SETS IN RELATIVISTIC HEAVY-ION COLLISIONS
Authors: MOHAPATRA RANJITA K. , SAUMIA P. S. , SRIVASTAVA AJIT M.
Published: September 2012

We show that flow anisotropies in relativistic heavy-ion collisions can be analyzed using a certain technique of shape analysis of excursion sets recently proposed by us for CMBR fluctuations to investigate anisotropic expansion history of the universe. The technique analyzes shapes (sizes) of patches above (below) certain threshold value for transverse energy/particle number (the excursion sets) as a function of the azimuthal angle and rapidity. Modeling flow by imparting extra anisotropic momentum to the momentum distribution of particles from HIJING, we compare the resulting distributions for excursion sets at two different azimuthal angles. Angles with maximum difference in the two distributions identify the event plane, and the magnitude of difference in the two distributions relates to the magnitude of momentum anisotropy, i.e. elliptic flow.
DIMENSIONALITY REDUCTION FOR DAMAGE DETECTION IN ENGINEERING STRUCTURES
Authors: PRADA MIGUEL A. , DOMÍNGUEZ MANUEL , BARRIENTOS PABLO , GARCÍA SERGIO
Published: September 2012

The detection of damages in engineering structures by means of the changes in their vibration response is called structural health monitoring (SHM). It is a promising field but presents fundamental challenges. Accurate theoretical models of the structure are generally unfeasible, so data-based approaches are required. Indeed, only data from the undamaged condition are usually available, so the approach needs to be framed as novelty detection. Data are acquired from a network of sensors to measure local changes in the operating condition of the structures. In order to distinguish changes produced by damages from those caused by the environmental conditions, several physically meaningful features have been proposed, most of them in the frequency domain. Nevertheless, multiple measurement locations and the absence of a principled criterion to select among the potentially damage-sensitive features contribute to increase data dimensionality. Since high dimensionality affects the effectiveness of damage detection, we evaluate the effect of a dimensionality reduction approach in the diagnostic accuracy of damage detection.
A NETWORK OF OSCILLATORS EMULATING THE ITALIAN HIGH-VOLTAGE POWER GRID
Authors: FORTUNA LUIGI , FRASCA MATTIA , SARRA FIORE ANGELO
Published: September 2012

In this paper, a dynamical model based on Kuramoto-like oscillators is used to represent the Italian high-voltage power grid. Nodes of the network are generators/substations, while links are the physical connections between generators/substations. The normal operating regime of the power grid corresponds to the regime in which the oscillations of all the nodes are synchronized. We studied the conditions for synchronization and the effect of dynamical perturbations on the nodes. The analysis allows to define several dynamical parameters assessing the dynamical robustness of the network.
PSS CONTROLLER FOR WIND POWER GENERATION SYSTEMS
Authors: DOMÍNGUEZ-GARCÍA J. L. , GOMIS-BELLMUNT O. , BIANCHI F. , SUMPER A.
Published: September 2012

Small signal stability analysis for power systems with wind farm interaction is presented. Power systems oscillation modes can be excited by disturbance or fault in the grid. Variable speed wind turbines can be regulated to reduce these oscillations, stabilising the power system. A power system stabiliser (PSS) control loop for wind power is designed in order to increase the damping of the oscillation modes. The proposed power system stabiliser controller is evaluated by small signal analysis.
GENERALIZED SEMIFLOWS AND CHAOS IN MULTIVALUED DYNAMICAL SYSTEMS
Authors: BERAN ZDENĚK , ČELIKOVSÝ SERGEJ
Published: September 2012

This contribution addresses a possible description of the chaotic behavior in multivalued dynamical systems. For the multivalued system formulated via differential inclusion the practical conditions on the right-hand side are derived to guarantee existence of a solution, which leads to the chaotic behavior. Our approach uses the notion of the generalized semiflow but it does not require construction of a selector on the set of solutions. Several applications are provided by concrete examples of multivalued dynamical systems including the one having a clear physical motivation.
IMPROVED MAGNETIC PROPERTIES OF Sm COMBINING Co OR/AND Zn SUBSTITUTED BARIUM M-TYPE HEXAFERRITES
Authors: HAN Y. B. , SHA J. , SUN L. N. , TANG Q. , LU Q. , JIN H. X. , JIN D. F. , GE H. L. , WANG X. Q.
Published: September 2012

Sm (Co or/and Zn) substituted nanocrystalline barium hexaferrites were synthesized by the sol–gel auto-combustion process, then X-ray diffraction (XRD) and vibrating sample magnetometer (VSM) were used to characterize and discuss the phase composition and the magnetic properties of the as-prepared barium hexaferrites. All results showed that the phase composition and magnetic properties were closely related to the doping elements and x. Owing to hyperfine field, canting spin, magnetic dilution and impurity phases, the saturation magnetization (Ms) of all samples increased firstly, and then decreased. Considering the crystallization, the magnetocrystalline anisotropy and the ions occupancy, the doping elements and x critically affected the coercivity (Hc). Compared the magnetic properties of all the samples, it is concluded that Zn 2+ and Co 2+ influenced each other and Zn 2+ occupied 4f2 sites prior to Co 2+, which led to the increase of Ms and the decrease of Hc.
VARIATIONAL APPROACH TO THE BRIGHT-SOLITON OF THE FOURTH ORDER NONLINEAR SCHRÖDINGER EQUATION WITH CUBIC NONLINEARITY
Authors: ZHANG WEI-MIN
Published: September 2012

Via He's semi-inverse method, variational principles are established for the fourth order nonlinear Schrödinger equation with cubic nonlinearity. Based on the obtained variational formulations, a bright-soliton solution can be obtained using He's variational method.