bluuebunny/crossref_metadata_2025 huggingface dataset:
dpr
and
sod
in Streptococcus mutans Are Involved in Coexistence with S. sanguinis, and PerR Is Associated with Resistance to H
2
O
2
Authors: Fujishima Kei , Kawada-Matsuo Miki , Oogai Yuichi , Tokuda Masayuki , Torii Mitsuo , Komatsuzawa Hitoshi
Published: December 2012

Large numbers of bacteria coexist in the oral cavity.
Streptococcus sanguinis
, one of the major bacteria in dental plaque, produces hydrogen peroxide (H
2
O
2
), which interferes with the growth of other bacteria.
Streptococcus mutans
, a cariogenic bacterium, can coexist with
S. sanguinis
in dental plaque, but to do so, it needs a means of detoxifying the H
2
O
2
produced by
S. sanguinis
. In this study, we investigated the association of three oxidative stress factors, Dpr, superoxide dismutase (SOD), and AhpCF, with the resistance of
S. sanguinis
to H
2
O
2
. The knockout of
dpr
and
sod
significantly increased susceptibility to H
2
O
2
, while the knockout of
ahpCF
had no apparent effect on susceptibility. In particular,
dpr
inactivation resulted in hypersensitivity to H
2
O
2
. Next, we sought to identify the factor(s) involved in the regulation of these oxidative stress genes and found that PerR negatively regulated
dpr
expression. The knockout of
perR
caused increased
dpr
expression levels, resulting in low-level susceptibility to H
2
O
2
compared with the wild type. Furthermore, we evaluated the roles of
perR
,
dpr
, and
sod
when
S. mutans
was cocultured with
S. sanguinis
. Culturing of the
dpr
or
sod
mutant with
S. sanguinis
showed a significant decrease in the
S. mutans
population ratio compared with the wild type, while the
perR
mutant increased the ratio. Our results suggest that
dpr
and
sod
in
S. mutans
are involved in coexistence with
S. sanguinis
, and PerR is associated with resistance to H
2
O
2
in regulating the expression of Dpr.
Survival of Mycobacterium avium subsp. paratuberculosis in Synthetic Human Gastric Juice and Acidified Porcine Bile
Authors: Dalton J. P. , Hill C.
Published: December 2012

The bactericidal activities of synthetic gastric juice and acidified porcine bile on
Mycobacterium avium
subsp.
paratuberculosis
were assessed using propidium monoazide (PMA)-mediated quantitative reverse transcription-PCR, which allowed rapid relative quantitative analysis of viable
M. avium
subsp.
paratuberculosis
cells.
Transcriptional Changes in the Transition from Vegetative Cells to Asexual Development in the Model Fungus Aspergillus nidulans
Authors: Garzia Aitor , Etxebeste Oier , Rodríguez-Romero Julio , Fischer Reinhard , Espeso Eduardo A. , Ugalde Unai
Published: December 2012

Morphogenesis encompasses programmed changes in gene expression that lead to the development of specialized cell types. In the model fungus
Aspergillus nidulans
, asexual development involves the formation of characteristic cell types, collectively known as the conidiophore. With the aim of determining the transcriptional changes that occur upon induction of asexual development, we have applied massive mRNA sequencing to compare the expression pattern of 19-h-old submerged vegetative cells (hyphae) with that of similar hyphae after exposure to the air for 5 h. We found that the expression of 2,222 (20.3%) of the predicted 10,943
A. nidulans
transcripts was significantly modified after air exposure, 2,035 being downregulated and 187 upregulated. The activation during this transition of genes that belong specifically to the asexual developmental pathway was confirmed. Another remarkable quantitative change occurred in the expression of genes involved in carbon or nitrogen primary metabolism. Genes participating in polar growth or sexual development were transcriptionally repressed, as were those belonging to the HogA/SakA stress response mitogen-activated protein (MAP) kinase pathway. We also identified significant expression changes in several genes purportedly involved in redox balance, transmembrane transport, secondary metabolite production, or transcriptional regulation, mainly binuclear-zinc cluster transcription factors. Genes coding for these four activities were usually grouped in metabolic clusters, which may bring regulatory implications for the induction of asexual development. These results provide a blueprint for further stage-specific gene expression studies during conidiophore development.
Control of Polarized Growth by the Rho Family GTPase Rho4 in Budding Yeast: Requirement of the N-Terminal Extension of Rho4 and Regulation by the Rho GTPase-Activating Protein Bem2
Authors: Gong Ting , Liao Yuan , He Fei , Yang Yang , Yang Dan-Dan , Chen Xiang-Dong , Gao Xiang-Dong
Published: December 2012

In the budding yeast
Saccharomyces cerevisiae
, Rho4 GTPase partially plays a redundant role with Rho3 in the control of polarized growth, as deletion of
RHO4
and
RHO3
together, but not
RHO4
alone, caused lethality and a loss of cell polarity at 30°C. Here, we show that overexpression of the constitutively active
rho4

Q131L

mutant in an
rdi1
Δ strain caused a severe growth defect and generated large, round, unbudded cells, suggesting that an excess of Rho4 activity could block bud emergence. We also generated four temperature-sensitive
rho4-Ts
alleles in a
rho3
Δ
rho4
Δ strain. These mutants showed growth and morphological defects at 37°C. Interestingly, two
rho4-Ts
alleles contain mutations that cause amino acid substitutions in the N-terminal region of Rho4. Rho4 possesses a long N-terminal extension that is unique among the six Rho GTPases in the budding yeast but is common in Rho4 homologs in other yeasts and filamentous fungi. We show that the N-terminal extension plays an important role in Rho4 function since
rho3
Δ
rho4
Δ

61

cells expressing truncated Rho4 lacking amino acids (aa) 1 to 61 exhibited morphological defects at 24°C and a growth defect at 37°C. Furthermore, we show that Rho4 interacts with Bem2, a Rho GTPase-activating protein (RhoGAP) for Cdc42 and Rho1, by yeast two-hybrid, bimolecular fluorescence complementation (BiFC), and glutathione
S
-transferase (GST) pulldown assays. Bem2 specifically interacts with the GTP-bound form of Rho4, and the interaction is mediated by its RhoGAP domain. Overexpression of
BEM2
aggravates the defects of
rho3
Δ
rho4
mutants. These results suggest that Bem2 might be a novel GAP for Rho4.
Association of a Novel Preribosomal Complex in Trypanosoma brucei Determined by Fluorescence Resonance Energy Transfer
Authors: Wang Lei , Ciganda Martin , Williams Noreen
Published: December 2012

We have previously reported that the trypanosome-specific proteins P34 and P37 form a unique preribosomal complex with ribosomal protein L5 and 5S rRNA in the nucleoplasm. We hypothesize that this novel trimolecular complex is necessary for stabilizing 5S rRNA in
Trypanosoma brucei
and is essential for the survival of the parasite.
In vitro
quantitative analysis of the association between the proteins L5 and P34 is fundamental to our understanding of this novel complex and thus our ability to exploit its unique characteristics. Here we used
in vitro
fluorescence resonance energy transfer (FRET) to analyze the association between L5 and P34. First, we demonstrated that FRET can be used to confirm the association between L5 and P34. We then determined that the binding constant for L5 and P34 is 0.60 ± 0.03 μM, which is in the range of protein-protein binding constants for RNA binding proteins. In addition, we used FRET to identify the critical regions of L5 and P34 involved in the protein-protein association. We found that the N-terminal APK-rich domain and RNA recognition motif (RRM) of P34 and the L18 domain of L5 are important for the association of the two proteins with each other. These results provide us with the framework for the discovery of ways to disrupt this essential complex.
Novel Bilobe Components in Trypanosoma brucei Identified Using Proximity-Dependent Biotinylation
Authors: Morriswood Brooke , Havlicek Katharina , Demmel Lars , Yavuz Sevil , Sealey-Cardona Marco , Vidilaseris Keni , Anrather Dorothea , Kostan Julius , Djinović-Carugo Kristina , Roux Kyle J. , Warren Graham
Published: December 2012

The trypanosomes are a family of parasitic protists of which the African trypanosome,
Trypanosoma brucei
, is the best characterized. The complex and highly ordered cytoskeleton of
T. brucei
has been shown to play vital roles in its biology but remains difficult to study, in large part owing to the intractability of its constituent proteins. Existing methods of protein identification, such as bioinformatic analysis, generation of monoclonal antibody panels, proteomics, affinity purification, and yeast two-hybrid screens, all have drawbacks. Such deficiencies—troublesome proteins and technical limitations—are common not only to
T. brucei
but also to many other protists, many of which are even less well studied. Proximity-dependent biotin identification (BioID) is a recently developed technique that allows forward screens for interaction partners and near neighbors in a native environment with no requirement for solubility in nonionic detergent. As such, it is extremely well suited to the exploration of the cytoskeleton. In this project, BioID was adapted for use in
T. brucei
. The trypanosome bilobe, a discrete cytoskeletal structure with few known protein components, represented an excellent test subject. Use of the bilobe protein TbMORN1 as a probe resulted in the identification of seven new bilobe constituents and two new flagellum attachment zone proteins. This constitutes the first usage of BioID on a largely uncharacterized structure, and demonstrates its utility in identifying new components of such a structure. This remarkable success validates BioID as a new tool for the study of unicellular eukaryotes in particular and the eukaryotic cytoskeleton in general.
Cryptococcus neoformans Growth and Protection from Innate Immunity Are Dependent on Expression of a Virulence-Associated DEAD-Box Protein, Vad1
Authors: Qiu Jin , Olszewski Michal A. , Williamson Peter R.
Published: December 2012

The fungus
Cryptococcus neoformans
has emerged as a major cause of meningoencephalitis worldwide. Host response to the fungus involves both innate and adaptive immunity, but fungal genes that modulate these processes are poorly understood. Previous studies demonstrated attenuated virulence of a mutant of a
v
irulence-
a
ssociated
D
EAD-box protein (
VAD1
) in mice, despite normal growth at host temperatures, suggesting modulation of the immune response. In the present study, the
Δvad1
mutant demonstrated progressive clearance from lung and was unable to induce pathological lesions or to cause extrapulmonary disease, despite retaining its ability to grow in mouse serum and a J774.16 macrophage cell line. Pulmonary clearance occurred with a minimal cellular infiltrate, marked by reduced CD4 cells, CD11b
+
Ly6C
high
monocytes, and F4/80
+
macrophages, but the mutant strain retained recruitment of CD8 cells, compared to infections with wild-type fungi. Adaptive cytokine responses were reduced, including Th1, Th2, and Th17 cytokines; however, early gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) responses were retained while nonprotective interleukin 4 (IL-4) and IL-5 were diminished. Furthermore, the
Δvad1
mutant was controlled in lungs despite CD4/CD8 cell depletion. These data, along with improved phagocytosis by macrophages and increases in early/innate IL-1α, IFN-γ, and chemokines elicited in the lungs within 3 days of infection with the
Δvad1
mutant, indicate that
VAD1
expression reduces innate recognition of
C. neoformans
, rendering the yeast resistant to elimination by the innate mechanisms of host defense. Thus, our studies define a novel role of the cryptococcal Vad1 protein as a central regulator of cryptococcal virulence and illustrate that Vad1 promotes microbe resistance to innate host defenses.
Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens: Role in Virulence Mechanisms
Authors: Cerveny Lukas , Straskova Adela , Dankova Vera , Hartlova Anetta , Ceckova Martina , Staud Frantisek , Stulik Jiri
Published: December 2012

The tetratricopeptide repeat (TPR) structural motif is known to occur in a wide variety of proteins present in prokaryotic and eukaryotic organisms. The TPR motif represents an elegant module for the assembly of various multiprotein complexes, and thus, TPR-containing proteins often play roles in vital cell processes. As the TPR profile is well defined, the complete TPR protein repertoire of a bacterium with a known genomic sequence can be predicted. This provides a tremendous opportunity for investigators to identify new TPR-containing proteins and study them in detail. In the past decade, TPR-containing proteins of bacterial pathogens have been reported to be directly related to virulence-associated functions. In this minireview, we summarize the current knowledge of the TPR-containing proteins involved in virulence mechanisms of bacterial pathogens while highlighting the importance of TPR motifs for the proper functioning of class II chaperones of a type III secretion system in the pathogenesis of
Yersinia
,
Pseudomonas
, and
Shigella
.
Estrogenic Modulation of Uropathogenic Escherichia coli Infection Pathogenesis in a Murine Menopause Model
Authors: Wang Caihong , Symington Jane W. , Ma Emily , Cao Bin , Mysorekar Indira U.
Published: December 2012

Recurrent urinary tract infections (UTIs), primarily caused by uropathogenic
Escherichia coli
(UPEC), annually affect over 13 million patients in the United States. Menopausal women are disproportionally susceptible, suggesting estrogen deficiency is a significant risk factor for chronic and recurrent UTI. How estrogen status governs susceptibility to UTIs remains unknown, and whether hormone therapy protects against UTIs remains controversial. Here, we used a mouse model of surgical menopause by ovariectomy and demonstrate a protective role for estrogen in UTI pathogenesis. We found that ovariectomized mice had significantly higher bacteriuria, a more robust inflammatory response, and increased production of the proinflammatory cytokine interleukin-6 (IL-6) upon UPEC infection compared to sham-operated controls. We further show that response of the urothelial stem cell niche to infection, normally activated to restore homeostasis after infection, was aberrant in ovariectomized mice with defective superficial urothelial cell differentiation. Finally, UPEC-infected ovariectomized mice showed a significant increase in quiescent intracellular bacterial reservoirs, which reside in the urothelium and can seed recurrent infections. Importantly, this and other ovariectomy-induced outcomes of UTI were reversible upon estrogen supplementation. Together, our findings establish ovariectomized mice as a model for UTIs in menopausal women and pinpoint specific events during course of infection that are most susceptible to estrogen deficiency. These findings have profound implications for the understanding of the role of estrogen and estrogen therapy in bladder health and pathogen defense mechanisms and open the door for prophylaxis for menopausal women with recurrent UTIs.
Complex T Cell Interactions Contribute to Helicobacter pylori Gastritis in Mice
Authors: Gray Brian M. , Fontaine Clinton A. , Poe Sara A. , Eaton Kathryn A.
Published: December 2012

Disease due to the gastric pathogenHelicobacter pylorivaries in severity from asymptomatic to peptic ulcer disease and cancer. Accumulating evidence suggests that one source of this variation is an abnormal host response. The goal of this study was to use a mouse model ofH. pylorigastritis to investigate the roles of regulatory T cells (Treg) as well as proinflammatory T cells (Th1 and Th17) in gastritis, gastric T cell engraftment, and gastric cytokine production. Our results support published data indicating that severe gastritis in T cell recipient mice is due to failure of Treg engraftment, that Treg ameliorate gastritis, and that the proinflammatory response is attributable to interactions between several cell subsets and cytokines. We confirmed that gamma interferon (IFN-γ) is essential for induction of gastritis but showed that IFN-γ-producing CD4 T cells are not necessary. Interleukin 17A (IL-17A) also contributed to gastritis, but to a lesser extent than IFN-γ. Tumor necrosis factor alpha (TNF-α) and IL-17F were also elevated in association with disease. These results indicate that whileH. pylori-specific CD4+T cells and IFN-γ are both essential for induction of gastritis due toH. pylori, IFN-γ production by T cells is not essential. It is likely that other proinflammatory cytokines, such as IL-17F and TNF-α, shown to be elevated in this model, also contribute to the induction of disease. We suggest that gastritis due toH. pyloriis associated with loss of immunoregulation and alteration of several cytokines and cell subsets and cannot be attributed to a single immune pathway.
Glomus tumour of the stomach: an unusual cause of gastrointestinal bleeding
Authors: Diaz-Zorrilla Carmina , Grube-Pagola Peter , Remes-Troche Jose María , Ramos-De la Medina Antonio
Published: December 2012

Glomus tumours are a rare type of subepithelial mesenchymal tumours that present in deep visceral organs such as the stomach, which are difficult to diagnose. We report a case of a 44-year-old woman with diabetes who presented with anaemia, abdominal pain and melena diagnosed preoperatively with a gastric glomus tumour initially misdiagnosed as a gastric ulcer located at the lesser curvature. Upon referral to our centre a repeat endoscopy and biopsy were performed. A partial gastrectomy was performed with no complications. Histopathological analysis of the tumour reported clear margins and immunostaining was positive for smooth muscle actin and collagen IV. The patient remains asymptomatic at 3-month follow-up.
Abdominal hypertension characterised by severe haemodynamic changes as a complication of percutanous nephrolithotomy
Authors: Ozer Ayse Belin , Firdolas Fatih , Aydin Ahmet , Erhan Omer L
Published: December 2012

Percutanous nephrolithotomy (PCNL) was performed on a patient in a prone position. During the first hour of intervention, some unwanted haemodynamic complications arose, which included a decrease in systemic blood pressure, an increase in heart rate and an increase in peak inspiratory pressures. Owing to worsening of those unexplained haemodynamic abnormalities, surgery was terminated. As the patient turned from prone to supine position, abdominal distention was noticed. Later, 3 litres of fluid were removed from the abdomen via peritoneal lavage. Upon fluid removal, a dramatic haemodynamic improvement was observed. The problem was thought to have been caused by a technical error in placing the dilator inside the abdomen, which allowed the irrigation fluid to accumulate inside the abdominal cavity. The aim of this presentation is to raise awareness of intra-abdominal hypertension when the aforementioned haemodynamic abnormalities are detected during PCNL. Early detection and treatment may prevent morbidity and mortality in similar cases.
A tectonic model for hyperextension at magma-poor rifted margins: an example from the West Iberia–Newfoundland conjugate margins
Authors: Pérez-Gussinyé Marta
Published: December 2012

Hyperextended, magma-poor margins are characterized by a wide continent–ocean transition and anomalously small fractions of magmatism during mantle exhumation prior to oceanic spreading. Here, I bring together several aspects of their rift to drift transition and give a coherent picture of their evolution from platform to deep-sea environments. I focus mainly on the West Iberia Margin (WIM)–Newfoundland (NF) conjugates in the North Atlantic Ocean. The architectural evolution of these margins is characterized by upper-crustal faulting and lower-crustal deformation that are tightly coupled, resulting in fault displacement that is accompanied by underlying, equal and coeval crustal thinning. Lower crust deforms first ductilely, but then progressively switches to brittle due to enhanced conductive cooling at very slow extension velocities (<
c.
6 mm a
−1
half-rate). The switch from ductile to progressively brittle lower crust is accompanied by the emergence of a dominant basinwards fault dip and oceanwards younging of fault activity. It is shown that these processes, acting in concert: (1) reconcile the horizontal extension on faults with crustal thinning without the need of lower-crustal flow; (2) explain, within one common Andersonian framework (faults active at 65°–30°), the change in fault geometry from planar to listric to detachment-like with increasing extension; and (3) generate the tectonic asymmetry observed between conjugate pairs. This work also discusses a high-resolution seismic section of the WIM showing that the ‘detachment-like’ fault S is truncated prior to the peridotite ridge where mantle exhumation first takes place. This suggests that serpentinized mantle rises due to its own buoyancy, separating and pulling the thinned crustal blocks apart. Once the crust has been separated, further mantle exhumation takes place by magma-poor extension of the underlying mantle. I show with numerical models that either a small reduction of mantle potential temperature (
c.
25–50 °C), a mantle depletion of more than 10% or very slow half-extension velocities (
c.
6 mm a
−1
) are required to reproduce the small amount of magmatism inferred. Available observations support either a very slow extension velocity or a smaller than normal mantle temperature; however, estimation errors may be large. Ultimately, unravelling which of these factors most contribute to magma-poor mantle exhumation will provide an improved understanding of the mantle lateral homogeneity and the three-dimensional nature of the rifting to drifting process.
Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice
Authors: Potthoff Matthew J. , Potts Austin , He Tianteng , Duarte João A. G. , Taussig Ronald , Mangelsdorf David J. , Kliewer Steven A. , Burgess Shawn C.
Published: December 2012

Bile acid sequestrants are nonabsorbable resins designed to treat hypercholesterolemia by preventing ileal uptake of bile acids, thus increasing catabolism of cholesterol into bile acids. However, sequestrants also improve hyperglycemia and hyperinsulinemia through less characterized metabolic and molecular mechanisms. Here, we demonstrate that the bile acid sequestrant, colesevelam, significantly reduced hepatic glucose production by suppressing hepatic glycogenolysis in diet-induced obese mice and that this was partially mediated by activation of the G protein-coupled bile acid receptor TGR5 and glucagon-like peptide-1 (GLP-1) release. A GLP-1 receptor antagonist blocked suppression of hepatic glycogenolysis and blunted but did not eliminate the effect of colesevelam on glycemia. The ability of colesevelam to induce GLP-1, lower glycemia, and spare hepatic glycogen content was compromised in mice lacking TGR5. In vitro assays revealed that bile acid activation of TGR5 initiates a prolonged cAMP signaling cascade and that this signaling was maintained even when the bile acid was complexed to colesevelam. Intestinal TGR5 was most abundantly expressed in the colon, and rectal administration of a colesevelam/bile acid complex was sufficient to induce portal GLP-1 concentration but did not activate the nuclear bile acid receptor farnesoid X receptor (FXR). The beneficial effects of colesevelam on cholesterol metabolism were mediated by FXR and were independent of TGR5/GLP-1. We conclude that colesevelam administration functions through a dual mechanism, which includes TGR5/GLP-1-dependent suppression of hepatic glycogenolysis and FXR-dependent cholesterol reduction.
Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium
Authors: Mazagova Magdalena , Buikema Hendrik , Landheer Sjoerd W. , Vavrinec Peter , Buiten Azuwerus van , Henning Robert H. , Deelman Leo E.
Published: December 2012

Growth differentiation factor 15 (GDF15) is an independent predictor of cardiovascular disease, and increased GDF15 levels have been associated with endothelial dysfunction in selected patients. We therefore investigated whether GDF15 modulates endothelial function in aortas of wild-type (WT) and GDF15 knockout (KO) mice. Vascular contractions to phenylephrine and relaxation to ACh were assessed in aortas obtained from healthy WT and GDF15 KO mice. The effects of GDF15 pretreatment and the involvement of ROS or caveolae were determined. Phenylephrine-induced contractions and ACh-mediated relaxations were similar in WT and GDF15 KO mice. Pretreatment with GDF15 inhibited contraction and relaxation in both groups. Inhibition of contraction by GDF15 was absent in denuded vessels or after blockade of nitric oxide (NO) synthase. Relaxation in WT mice was mediated mainly through NO and an unidentified endothelium-derived hyperpolarizin factor (EDHF), whereas GDF15 KO mice mainly used prostaglandins and EDHF. Pretreatment with GDF15 impaired relaxation in WT mice by decreasing NO; in GDF15 KO mice, this was mediated by decreased action of prostaglandins. Disruption of caveolae resulted in a similar inhibition of vascular responses as GDF15. ROS inhibition did not affect vascular function. In cultured endothelial cells, GDF15 pretreatment caused a dissociation between caveolin-1 and endothelial NO synthase. In conclusion, GDF15 impairs aortic contractile and relaxing function through an endothelium-dependent mechanism involving altered caveolar endothelial NO synthase signaling.
Periodontal bacteria aggravate experimental autoimmune myocarditis in mice
Authors: Ashigaki Norihiko , Suzuki Jun-ichi , Ogawa Masahito , Watanabe Ryo , Aoyama Norio , Kobayashi Naho , Hanatani Tomoya , Sekinishi Asuka , Zempo Hirofumi , Tada Yuko , Takamura Chisato , Wakayama Kouji , Hirata Yasunobu , Nagai Ryozo , Izumi Yuichi , Isobe Mitsuaki
Published: December 2012

Periodontitis is one of the most common infections in humans. Recently, published reports assert that periodontitis is associated with cardiovascular disease. Although it is said that viral, bacterial infections and autoimmune diseases may be the cause of myocarditis, the pathogenesis of it remains unclear. The aim of this study was to investigate the influence of a periodontal pathogen on experimental autoimmune myocarditis (EAM). Porphyromonas gingivalis (P.g.), PBS as a control, were injected into the mice. Histopathological and immunohistochemical analyses were performed. We examined heart mRNA levels using quantitative RT-PCR. The anti-P.g. IgG antibody level in plasma samples of the P.g.-injected group significantly increased compared with the PBS-injected group. Histopathological analysis detected that the myocarditis-affected areas and the fibrotic area in the P.g.-injected EAM group significantly increased compared with the PBS-injected EAM group ( P < 0.05). Immunohistochemical analysis detected that more CD11b-positive cells were shown in the heart of the P.g.-injected EAM group compared with the PBS EAM-injected group ( P < 0.05). Hearts from the P.g.-injected EAM group showed significantly increased expression of monocyte chemoattractant protein-1, IFN-γ, and matrix metalloproteinase-9 (MMP-9) mRNA compared with the hearts from the PBS-injected EAM group ( P < 0.05). On day 7, serum levels of IL-6 were significantly enhanced in the P.g.-injected EAM group compared with the PBS-injected EAM group ( P < 0.05). These results showed that P.g. injection could deteriorate EAM in mice through CD11b-positive cells, cytokines, and MMP-9 expression.
Perfusion pressure and movement-induced hyperemia: evidence of limited vascular function and vasodilatory reserve with age
Authors: Groot H. Jonathan , Trinity Joel D. , Layec Gwenael , Rossman Matthew J. , Ives Stephen J. , Richardson Russell S.
Published: December 2012

To better understand the mechanisms contributing to reduced blood flow with age, this study sought to elucidate the impact of altered femoral perfusion pressure (FPP) on movement-induced hyperemia. Passive leg movement was performed in 10 young (22 ± 1 yr) and 12 old (72 ± 2 yr) healthy men for 2 min, with and without a posture-induced change in FPP (∼7 ± 1 ΔmmHg). Second-by-second measurements of central and peripheral hemodynamic responses were acquired noninvasively (finger photoplethysmography and Doppler ultrasound, respectively), with FPP confirmed in a subset of four young and four old subjects with arterial and venous catheters. Central hemodynamic responses (heart rate, stroke volume, cardiac output, mean arterial pressure) were not affected by age or position. The young exhibited a ∼70% greater movement-induced peak change in leg blood flow (ΔLBFpeak) in the upright-seated posture (supine: 596±68 ml/min; upright: 1,026 ± 85 ml/min). However, in the old the posture change did not alter ΔLBFpeak(supine: 417±42 ml/min; upright: 412±56 ml/min), despite the similar increases in FPP. Similarly, movement-induced peak change in leg vascular conductance was ∼80% greater for the young in the upright-seated posture (supine: 7.1 ± 0.8 ml·min−1·mmHg−1; upright: 12.8 ± 1.3 ml·min−1·mmHg−1), while the old again exhibited no difference between postures (supine: 4.7 ± 0.4 ml·min−1·mmHg−1; upright: 4.8 ± 0.5 ml·min−1·mmHg−1). Thus this study reveals that, unlike the young, increased FPP does not elicit an increase in movement-induced hyperemia or vasodilation in the old. In light of recent evidence that the majority of the first minute of passive movement-induced hyperemia is predominantly nitric oxide (NO) dependent in the young, these findings in the elderly may be largely due to decreased NO bioavailability, but this remains to be definitively determined.
Blunted temporal activity of microvascular perfusion heterogeneity in metabolic syndrome: a new attractor for peripheral vascular disease?
Authors: Butcher Joshua T. , Goodwill Adam G. , Stanley Shyla C. , Frisbee Jefferson C.
Published: December 2012

A key clinical outcome for peripheral vascular disease (PVD) in patients is a progressive decay in skeletal muscle performance and its ability to resist fatigue with elevated metabolic demand. We have demonstrated that PVD in obese Zucker rats (OZR) is partially due to increased perfusion distribution heterogeneity at successive microvascular bifurcations within skeletal muscle. As this increased heterogeneity (γ) is longitudinally present in the network, its cumulative impact is a more heterogeneous distribution of perfusion between terminal arterioles than normal, causing greater regional tissue ischemia. To minimize this negative outcome, a likely compensatory mechanism against an increased γ should be an increased temporal switching at arteriolar bifurcations to minimize downstream perfusion deficits. Using in situ cremaster muscle, we determined that temporal activity (the cumulative sum of absolute differences between successive values of γ, taken every 20 s) was lower in OZR than in control animals, and this difference was present in both proximal (1A-2A) and distal (3A-4A) arteriolar bifurcations. Although adrenoreceptor blockade (phentolamine) improved temporal activity in 1A-2A arteriolar bifurcations in OZR, this was without impact in the distal microcirculation, where only interventions against oxidant stress (Tempol) and thromboxane A2 activity (SQ-29548) were effective. Analysis of the attractor for γ indicated that it was not only elevated in OZR but also exhibited severe reductions in range, suggesting that the ability of the microcirculation to respond to any challenge is highly restricted and may represent the major contributor to the manifestation of poor muscle performance at this age in OZR.
Modeling Transitions in Complex Systems by Multiplicative Effect of Temporal Patterns Extracted from Signal Flows
Authors: Bakhoum Ezzat G. , Toma Cristian
Published: December 2012

This study presents a mathematical model based on Fourier decomposition of a sequence of internal signals generated in a complex system by a sequence of external pulses (time series)
for characterizing suddenly emerging phenomena as nonlinear transitions. Newly created temporal patterns extracted from internal signal flow (mathematically represented as oscillations with long period) interact as new entities in a multiplicative manner with subsequent pulses from the external time series (already existing entities) in order to generate nonlinear transitions within the system. Such effects are enhanced when the period of external pulses creating new patterns is similar to the settling time of the complex system (this being the condition for an efficient external action). For complex systems where both classical and quantum phenomena generated by external time series are involved, this mathematical model can correctly explain the transition from classical to quantum behaviour (corresponding to a more ordered structure) avoiding typical contradictions generated by analysis performed on transient time intervals or by wave superposition.
Haemorrhagic Colitis Caused by Dasatinib
Authors: Patodi Nishant , Sagar Nidhi , Rudzki Zbigniew , Langman Gerald , Sharma Naveen
Published: December 2012

Gastrointestinal bleeding appears to be a common adverse event associated with dasatinib therapy. Here we present a case of a 59-year-old man with chronic myeloid leukaemia (CML) developing the rarest complication of haemorrhagic colitis with dasatinib therapy which resolved rapidly after treatment withdrawal.
Prosthodontic Rehabilitation of Hereditary Ectodermal Dysplasia in an 11-Year-Old Patient with Flexible Denture: A Case Report
Authors: Jain Neha , Naitam Dinesh , Wadkar Arti , Nemane Anuradha , Katoch Shiva , Dewangan Ashish
Published: December 2012

Hereditary ectodermal dysplasia is a rare group of inherited disorders characterized by aplasia or dysplasia of two or more tissues of ectodermal origin such as hair, nails, teeth, and skin. The dental characteristics of this syndrome include anodontia or hypodontia of the primary and/or permanent teeth, hypoplastic conical teeth, and underdevelopment of the alveolar ridges. The options for a definitive treatment plan include fixed, removable or implant-supported prostheses, singly or in combination. This clinical report describes the prosthetic rehabilitation of an 11-year-old boy with hereditary ectodermal dysplasia. Maxillary flexible removable partial denture and mandibular conventional complete denture were fabricated to establish an acceptable masticatory function, speech, and esthetics for the patient.
Risk-Taking Behavior for HIV Acquisition during Pregnancy in Porto Alegre, Brazil
Authors: Yeganeh Nava , Varella Ivana , Santos Breno Riegel , Gonçalves de Melo Marineide , Simon Mariana , Melo Taui , Nielsen-Saines Karin
Published: December 2012

Recent studies suggest that acquisition of HIV-1 infection during pregnancy and breastfeeding is associated with a high risk of HIV mother-to-child transmission. This study evaluates risk factors associated with HIV acquisition during pregnancy in women delivering at a large metropolitan medical facility located in the south of Brazil. From February to August 2009, our group conducted a cross-sectional study assessing women’s risk for HIV acquisition by administering an oral survey to peripartum women. Of 2465 participants, 42% (n=1046) knew that partner had been tested for HIV. During pregnancy, 82% (n=2022) of participants never used condoms; yet 97% (n=2399) practiced vaginal sex. Multivariate logistic regression analysis showed that patients with more years of education, in a relationship for more than 1 year, and who knew their own HIV status were more likely to know their partners' HIV status (P<0.05). Those who were in relationship for more than 1 year and were married/living together were more likely to be comfortable discussing HIV testing with partners (P<0.05). In conclusion, women in Brazil are at risk of HIV-infection during pregnancy as they remain sexually active, often do not know their sexual partner’s HIV status, and have minimal condom use.
Molecular Pathways: Involvement of Immune Pathways in the Therapeutic Response and Outcome in Breast Cancer
Authors: Andre Fabrice , Dieci Maria V. , Dubsky Peter , Sotiriou Christos , Curigliano Giuseppe , Denkert Carsten , Loi Sherene
Published: December 2012

The immune system could mediate the antitumor activity of several anticancer treatments. Several chemotherapy compounds, including anthracyclines and oxaliplatin, induce immunogenic cell death that in turn activates antitumor immune response. Trastuzumab induces antibody-dependant cell-mediated cytotoxicity. On the basis of this background, immune markers have recently been the focus of intense translational research to predict and monitor the efficacy of treatments. Gene expression arrays and immunohistochemistry have assessed immune activation and infiltration by macrophages, natural killer, and T and B lymphocytes. Using these approaches, several retrospective analyses of large trials have shown that activation of immune pathway may predict treatment efficacy and outcome in patients with breast cancers. As examples, intratumoral infiltration by lymphocytes and interferon-response in primary tumor predicted the efficacy of neoadjuvant chemotherapy. Intratumoral infiltration by lymphocytes was associated with good prognosis in patients with triple-negative breast cancer treated with adjuvant chemotherapy. More recently, it has been suggested that lymphocyte infiltration could also predict efficacy of trastuzumab. Finally, small retrospective studies have suggested that postchemotherapy lymphocyte infiltrates could be associated with better outcome in patients who did not reach pathologic complete response. This body of evidence suggests that assessing immune infiltration and activation could be useful in the future to stratify breast cancer patients. In addition, they provide evidence for the development of immunotherapies in breast cancer patients. Clin Cancer Res; 19(1); 28–. ©2012 AACR.
No Contribution of IP
3
-R(2) to Disease Phenotype in Models of Dilated Cardiomyopathy or Pressure Overload Hypertrophy
Authors: Cooley Nicola , Ouyang Kunfu , McMullen Julie R. , Kiriazis Helen , Sheikh Farah , Wu Wei , Mu Yongxin , Du Xiao-Jun , Chen Ju , Woodcock Elizabeth A.
Published: December 2012

Background—

We investigated the contribution of inositol(1,4,5)-
tris
phosphate (Ins(1,4,5)P
3
[IP
3
]) receptors (IP
3
-R) to disease progression in mouse models of dilated cardiomyopathy (DCM) and pressure overload hypertrophy. Mice expressing mammalian sterile 20–like kinase and dominant-negative phosphatidylinositol-3-kinase in heart (Mst1×dn-PI3K-2Tg; DCM-2Tg) develop severe DCM and conduction block, associated with increased expression of type 2 IP
3
-R (IP
3
-R(2)) and heightened generation of Ins(1,4,5)P
3
. Similar increases in Ins(1,4,5)P
3
and IP
3
-R(2) are caused by transverse aortic constriction.

Methods and Results—

To evaluate the contribution of IP
3
-R(2) to disease progression, the DCM-2Tg mice were further crossed with mice in which the type 2 IP
3
-R (IP
3
-R(2)−/−) had been deleted (DCM-2Tg×IP
3
-R(2)−/−) and transverse aortic constriction was performed on IP
3
-R(2)−/− mice. Hearts from DCM-2Tg mice and DCM-2Tg×IP
3
-R(2)−/− were similar in terms of chamber dilatation, atrial enlargement, and ventricular wall thinning. Electrophysiological changes were also similar in the DCM-2Tg mice, with and without IP
3
-R(2). Deletion of IP
3
-R(2) did not alter the progression of heart failure, because DCM-2Tg mice with and without IP
3
-R(2) had similarly reduced contractility, increased lung congestion, and atrial thrombus, and both strains died between 10 and 12 weeks of age. Loss of IP
3
-R(2) did not alter the progression of hypertrophy after transverse aortic constriction.

Conclusions—

We conclude that IP
3
-R(2) do not contribute to the progression of DCM or pressure overload hypertrophy, despite increased expression and heightened generation of the ligand, Ins(1,4,5)P
3
.
Baseline Characteristics of Patients in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial
Authors: Shah Sanjiv J. , Heitner John F. , Sweitzer Nancy K. , Anand Inder S. , Kim Hae-Young , Harty Brian , Boineau Robin , Clausell Nadine , Desai Akshay S. , Diaz Rafael , Fleg Jerome L. , Gordeev Ivan , Lewis Eldrin F. , Markov Valetin , O’Meara Eileen , Kobulia Bondo , Shaburishvili Tamaz , Solomon Scott D. , Pitt Bertram , Pfeffer Marc A. , Li Rebecca
Published: December 2012

Background—

Treatment of Preserved Cardiac Function with an Aldosterone Antagonist (TOPCAT) is an ongoing randomized controlled trial of spironolactone versus placebo for heart failure with preserved ejection fraction (HFpEF). We sought to describe the baseline clinical characteristics of subjects enrolled in TOPCAT relative to other contemporary observational studies and randomized clinical trials of HFpEF.

Methods and Results—

Between August 2006 and January 2012, 3445 patients with symptomatic HFpEF from 270 sites in 6 countries were enrolled in TOPCAT. At the baseline study visit, all subjects provided a detailed medical history and underwent physical examination, electrocardiography, quality of life, and laboratory assessment. Key parameters were compared with other large, contemporary HFpEF studies. The mean age was 68.6±9.6 years with a slight female predominance (52%); mean body mass index was 32 kg/m
2
; and comorbidities were common. History of hypertension (91% prevalence in TOPCAT) exceeded all other major HFpEF clinical trials. However, baseline blood pressure was well controlled (129/76 mm Hg; systolic blood pressure 7–16 mm Hg lower than other similar trials). Other common comorbidities included coronary artery disease (57%), atrial fibrillation (35%), chronic kidney disease (38%) and diabetes mellitus (32%). Self-reported activity levels were low, quality of life scores were comparable with those reported for patients with end-stage renal disease, and the prevalence of moderate or greater depression was 27%.

Conclusions—

TOPCAT subjects share many common characteristics with contemporary HFpEF cohorts. Low activity level, significantly decreased quality of life, and depression were common at baseline in TOPCAT, underscoring the continued unmet need for evidence-based treatment strategies in HFpEF.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00094302.
Zebrafish can hear sound pressure and particle motion in a synthesized sound field
Authors: Bretschneider Franklin , van Veen Herman , Teunis Peter F.M. , Peters Robert C. , van den Berg Albert V.
Published: December 2012

In order to investigate the hearing capacities of adult zebrafish (Danio rerio), wild type zebrafish were conditioned to both sound pressure and particle motion in a respondent conditioning paradigm. Sound fields were generated by five underwater loudspeakers in a cylindrical tank, which allows separate control of sound pressure and particle motion. Sound stimuli were soft-switched sound pulses having a strength (RMS) of 0.4 to 5 Pa sound pressure (112 to 134 dB re 1 μPa), 6.7 × 10−7 to 6.7 × 10−6 m/s particle velocity or a combination thereof. Frequencies used were 800 Hz or 250 Hz. During the test a fish was placed in the acoustic centre of the tank, confined in a soft nylon mesh fitted with two silver chloride recording electrodes to measure both changes in position and the ventilatory response. Each sound presentation was followed by a brief mechanical jerk of the fish cage (unconditioned stimulus). The startling response to the unconditioned stimulus was thus coupled to the sound signal (conditioned stimulus). Responses were scored as changes in fish position and/or ventilatory rhythm, occurring during or after the sound pulses, but before the unconditioned stimulus. In this way, we found that wildtype zebrafish respond to artificial sounds having either predominantly sound pressure or particle motion. Discrimination of directionally different sounds could not be established. The method is suited well to probe other auditory capabilities, and to test zebrafish mutants lacking one or more otoliths.
Does innate immune function decline with age in captive ruffs Philomachus pugnax?
Authors: Nebel Silke , Buehler Deborah M. , Kubli Shawn , Lank David B. , Guglielmo Christopher G.
Published: December 2012

Immunosenescence, the decline of immune function with age, results in increased risk of infection as an individual ages. The underlying reasons are still poorly understood. Here, we ask whether the rate of decline of an immune indicator is positively correlated with the cost of maintaining it, as predicted by optimal resource allocation theory. Using 30 female ruffs Philomachus pugnax ranging in age from 0.5-12 years we found no effect of age on five indicators of constitutive innate immunity, which is cheap to use and maintain. Body temperature increase following injection with lipopolysaccharide is an indicator of induced innate immunity, which is energetically expensive, and showed a curvilinear relationship with age, with a maximum in middle-aged birds. Our results suggest that changes in immune function with age may depend on the energetic cost of using an immune trait.
Assimilation of Infrared Radiances in the Context of Observing System Simulation Experiments
Authors: Heilliette Sylvain , Rochon Yves J. , Garand Louis , Kaminski Jacek W.
Published: December 2012

The Observing System Simulation Experiment (OSSE) capability developed at Environment Canada allows simulation of all observation types currently used operationally as well as future data types. Its infrastructure, based on the operational global data assimilation system used at the Canadian Meteorological Centre, was recently enhanced to conduct data assimilation experiments for two future satellite missions. This study presents a subcomponent of that system, focusing on the assimilation of infrared radiances from the Atmospheric Infrared Sounder (AIRS) and Infrared Atmospheric Sounding Interferometer (IASI) instruments. The goal is to realistically simulate the radiance observations and to reproduce statistical characteristics of these data seen in the real system, notably background and analysis departures. Care is taken to emulate the operational quality control procedures leading to the assimilation of clear radiances, which implies radiance simulation for all-sky conditions. It is found that the standard deviation of the Gaussian random perturbation applied to the simulated observations should be close to that of the radiometric noise level for sounding channels in the 13.0–14.5-μm region but that it should be significantly higher for water vapor channels in the 5.5–6.7-μm region. The study also allows evaluation of residual biases linked to cloud contamination. For atmospheric window channels, that bias can reach −0.4 K. It reduces rapidly with peak height of the channel response function. This suggests that improvements are needed in low-cloud detection. The realism of the OSSE is further demonstrated through the shown impact consistency of AIRS and IASI radiance assimilation in forecasts up to 5 days from the separate use of simulated and real observations.