bluuebunny/crossref_metadata_2025 huggingface dataset:
Room-temperature ultrahigh vacuum bonding of Ge∕GaAs p-n heterojunction wafer using 300eV hydrogen ion beam surface cleaning
Authors: Razek N. , Schindler A.
Published: September 2007

Low-energy (300eV) hydrogen-ion bombardment is used to clean the surfaces of GaAs at 150°C and of Ge at 300°C. The H-ion beam produces contamination-free surfaces without changes in surface composition (stoichiometry) and surface roughness. The wafers were brought into contact at room temperature after cleaning under ultrahigh vacuum and bonded over the whole area without application of external mechanical pressure. High-resolution transmission-electron microscopy images reveal that the wafers were directly bonded without damage of the crystal lattice or intermediate layer and the interface is smooth. Current-voltage characterization shows near-ideal forward characteristics and the recombination in p-n heterojunction of the Ge∕GaAs space charge region.
Capacitive discharges driven by combined dc/rf sources
Authors: Kawamura E. , Lieberman M. A. , Lichtenberg A. J. , Hudson E. A.
Published: September 2007

We have obtained analytic expressions for the sheath voltages and sheath widths for both collisional and collisionless sheaths driven by a combination of dc and rf voltage sources. A “dc/rf sheath” develops on the negatively biased electrode while a typical rf sheath develops on the other electrode. The dc/rf sheath has a dc region with negligible electron density near the negatively biased electrode. Furthermore, if the rf power is held constant (typical for industrial plasmas driven by rf power sources), the sheath voltage drop of the rf sheath is nearly independent of the dc voltage provided the discharge configuration does not lead to a significant increase in the ionization efficiency of the secondary electrons. The analysis is done for both symmetric (equal area) and asymmetric diode discharges, as well as a triode configuration. The analytical results for the symmetric and asymmetric diode discharges are compared to the results of numerical simulations using plane-parallel and cylindrical particle-in-cell (PIC) codes over a wide range of pressures and rf frequencies, finding good agreement. The effect of secondary electrons is also examined with the PIC codes, finding increased discharge efficiency.
The
Fusarium graminearum
Genome Reveals a Link Between Localized Polymorphism and Pathogen Specialization
Authors: Cuomo Christina A. , Güldener Ulrich , Xu Jin-Rong , Trail Frances , Turgeon B. Gillian , Di Pietro Antonio , Walton Jonathan D. , Ma Li-Jun , Baker Scott E. , Rep Martijn , Adam Gerhard , Antoniw John , Baldwin Thomas , Calvo Sarah , Chang Yueh-Long , DeCaprio David , Gale Liane R. , Gnerre Sante , Goswami Rubella S. , Hammond-Kosack Kim , Harris Linda J. , Hilburn Karen , Kennell John C. , Kroken Scott , Magnuson Jon K. , Mannhaupt Gertrud , Mauceli Evan , Mewes Hans-Werner , Mitterbauer Rudolf , Muehlbauer Gary , Münsterkötter Martin , Nelson David , O'Donnell Kerry , Ouellet Thérèse , Qi Weihong , Quesneville Hadi , Roncero M. Isabel G. , Seong Kye-Yong , Tetko Igor V. , Urban Martin , Waalwijk Cees , Ward Todd J. , Yao Jiqiang , Birren Bruce W. , Kistler H. Corby
Published: September 2007

We sequenced and annotated the genome of the filamentous fungus
Fusarium graminearum
, a major pathogen of cultivated cereals. Very few repetitive sequences were detected, and the process of repeat-induced point mutation, in which duplicated sequences are subject to extensive mutation, may partially account for the reduced repeat content and apparent low number of paralogous (ancestrally duplicated) genes. A second strain of
F. graminearum
contained more than 10,000 single-nucleotide polymorphisms, which were frequently located near telomeres and within other discrete chromosomal segments. Many highly polymorphic regions contained sets of genes implicated in plant-fungus interactions and were unusually divergent, with higher rates of recombination. These regions of genome innovation may result from selection due to interactions of
F. graminearum
with its plant hosts.
The Social Origin of Mind
Authors: Jolly Alison
Published: September 2007

Baboon Metaphysics
. The Evolution of a Social Mind .
By Dorothy L. Cheney and Robert M. Seyfarth
. University of Chicago Press, Chicago, 2007. 358 pp. $27.50, £16. ISBN 9780226102436.

Drawing on 15 years of fieldwork with baboons in the wild, the authors discuss how baboons understand themselves and their world.
Saturn's Gravitational Field, Internal Rotation, and Interior Structure
Authors: Anderson John D. , Schubert Gerald
Published: September 2007

Saturn's internal rotation period is unknown, though it must be less than 10 hours, 39 minutes, and 22 seconds, as derived from magnetic field plus kilometric radiation data. By using the Cassini spacecraft's gravitational data, along with Pioneer and Voyager radio occultation and wind data, we obtain a rotation period of 10 hours, 32 minutes, and 35 ± 13 seconds. This more rapid spin implies slower equatorial wind speeds on Saturn than previously assumed, and the winds at higher latitudes flow both east and west, as on Jupiter. Our related Saturn interior model has a molecular-to-metallic hydrogen transition about halfway to the planet's center.
A Vasculature-Associated Niche for Undifferentiated Spermatogonia in the Mouse Testis
Authors: Yoshida Shosei , Sukeno Mamiko , Nabeshima Yo-ichi
Published: September 2007

Mammalian spermatogenesis produces numerous sperm for a long period based on a highly potent stem cell system, which relies on a special microenvironment, or niche, that has not yet been identified. In this study, using time-lapse imaging of green fluorescent protein–labeled undifferentiated spermatogonia (A
undiff
) and three-dimensional reconstitution, we revealed a biased localization of A
undiff
to the vascular network and accompanying Leydig and other interstitial cells, in intact testes. Differentiating spermatogonia left these niche regions and dispersed throughout the basal compartment of the seminiferous epithelium. Moreover, rearrangement of A
undiff
accompanied the vasculature alteration. We propose that the mammalian germline niche is established as a consequence of vasculature pattern formation. This is different from what is observed in
Drosophila
or
Caenorhabditis elegans
, which display developmentally specified niche structures within polarized gonads.
Soft X-ray-Driven Femtosecond Molecular Dynamics
Authors: Gagnon Etienne , Ranitovic Predrag , Tong Xiao-Min , Cocke C. L. , Murnane Margaret M. , Kapteyn Henry C. , Sandhu Arvinder S.
Published: September 2007

The direct observation of molecular dynamics initiated by x-rays has been hindered to date by the lack of bright femtosecond sources of short-wavelength light. We used soft x-ray beams generated by high-harmonic upconversion of a femtosecond laser to photoionize a nitrogen molecule, creating highly excited molecular cations. A strong infrared pulse was then used to probe the ultrafast electronic and nuclear dynamics as the molecule exploded. We found that substantial fragmentation occurs through an electron-shakeup process, in which a second electron is simultaneously excited during the soft x-ray photoionization process. During fragmentation, the molecular potential seen by the electron changes rapidly from nearly spherically symmetric to a two-center molecular potential. Our approach can capture in real time and with angstrom resolution the influence of ionizing radiation on a range of molecular systems, probing dynamics that are inaccessible with the use of other techniques.
Intestinal preconditioning prevents inflammatory response by modulating heme oxygenase-1 expression in endotoxic shock model
Authors: Tamion Fabienne , Richard Vincent , Renet Sylvanie , Thuillez Christian
Published: September 2007

Gut mucosal injury observed during ischemia-reperfusion is believed to trigger a systemic inflammatory response leading to multiple organ failure. It should be interesting to demonstrate this relationship between gut and multiple organ failure in a sepsis model. Intestinal preconditioning (PC) can be used as a tool to assess the effect of intestinal ischemia in inflammatory response after LPS challenge. The aim of this study was to investigate the protective effect of PC against LPS-induced systemic inflammatory and intestinal heme oxygenase-1 (HO-1) expression. ES was performed with LPS (10 mg/kg iv) with or without PC, which was done before LPS. Rats were first subjected to sham surgery or PC with four cycles of 1 min ischemia and 4 min of reperfusion 24 h before LPS challenge or saline administration. PC significantly reduced fluid requirements, lung edema, intestinal lactate production, and intestinal injury. Inflammatory mRNA expressions for intestine and lung ICAM and TNF were significantly reduced after PC, and these effects were significantly abolished by zinc-protoporphyrin (a specific HO-1 activity inhibitor) and mimicked by bilirubin administration. Intestinal PC selectively increased HO-1 mRNA expression in intestine, but we have observed no expression in lungs. These findings demonstrate that intestinal injury is a important event for inflammatory response and multiple organ injury after LPS challenge. Intestinal HO-1 expression attenuates LPS-induced multiple organ failure by modulating intestine injury and its consequences on inflammatory response. Identification of the exact mechanisms responsible for intestine HO-1 induction may lead to the development of new pharmacological interventions.
Calcineurin inhibition normalizes β-adrenergic responsiveness in the spontaneously hypertensive rat
Authors: MacDonnell Scott M. , Kubo Hajime , Harris David M. , Chen Xiongwen , Berretta Remus , Barbe Mary F. , Kolwicz Stephen , Reger Patricia O. , Eckhart Andrea , Renna Brian F. , Koch Walter J. , Houser Steven R. , Libonati Joseph R.
Published: September 2007

Calcineurin, a Ca2+-regulated protein phosphatase, links myocardial Ca2+ signaling with hypertrophic gene transcription. Calcineurin abundance increases in pressure-overload hypertrophy and may reduce agonist-mediated phospholamban (PLB) phosphorylation to underlie blunted β-adrenergic receptor (β-AR) responsiveness in hypertension. This hypothesis was tested by measuring the effects of calcineurin inhibition on changes in cardiac contractility caused by β-adrenergic stimulation in spontaneously hypertensive rats (SHR). Female SHR (age: 7 mo) and age-matched female Wistar-Kyoto rats (WKY) were studied. Heart weight-to-body weight ratio ( P < 0.01) and systolic blood pressure ( P < 0.01) were greater in SHR compared with WKY and were associated with increased myocardial calcineurin mRNA (CnAβ) and activity ( P < 0.05). β-AR stimulation with isoproterenol (Iso) increased calcineurin activity ( P < 0.05) in both WKY and SHR hearts, and this activity was suppressed with cyclosporin A (CsA) treatment. In SHR, CsA improved left ventricular whole heart and isolated myocyte β-AR responsiveness by normalizing PLB phosphorylation at Ser16 and Thr17 ( P < 0.05). These CsA-induced, PLB-mediated effects were associated with an augmentation in cardiomyocyte peak Ca2+ and a reduced rate (time constant of isovolumic pressure relaxation, tau) and magnitude of diastolic Ca2+ during β-AR stimulation. In conclusion, CsA normalized the blunted β-AR responsiveness associated with hypertension, in part, by mitigating calcineurin activity while improving PLB phosphorylation and subsequent sarcoplasmic reticulum Ca2+ regulation.
Recruitment of single muscle fibers during submaximal cycling exercise
Authors: Altenburg T. M. , Degens H. , van Mechelen W. , Sargeant A. J. , de Haan A.
Published: September 2007

In literature, an inconsistency exists in the submaximal exercise intensity at which type II fibers are activated. In the present study, the recruitment of type I and II fibers was investigated from the very beginning and throughout a 45-min cycle exercise at 75% of the maximal oxygen uptake, which corresponded to 38% of the maximal dynamic muscle force. Biopsies of the vastus lateralis muscle were taken from six subjects at rest and during the exercise, two at each time point. From the first biopsy single fibers were isolated and characterized as type I and II, and phosphocreatine-to-creatine (PCr/Cr) ratios and periodic acid-Schiff (PAS) stain intensities were measured. Cross sections were cut from the second biopsy, individual fibers were characterized as type I and II, and PAS stain intensities were measured. A decline in PCr/Cr ratio and in PAS stain intensity was used as indication of fiber recruitment. Within 1 min of exercise both type I and, although to a lesser extent, type II fibers were recruited. Furthermore, the PCr/Cr ratio revealed that the same proportion of fibers was recruited during the whole 45 min of exercise, indicating a rather constant recruitment. The PAS staining, however, proved inadequate to fully demonstrate fiber recruitment even after 45 min of exercise. We conclude that during cycling exercise a greater proportion of type II fibers is recruited than previously reported for isometric contractions, probably because of the dynamic character of the exercise. Furthermore, the PCr/Cr ratio method is more sensitive in determining fiber activation than the PAS stain intensity method.
Unilateral microdialysis of gabazine in the dorsal medulla reverses thermal prolongation of the laryngeal chemoreflex in decerebrate piglets
Authors: Xia Luxi , Damon Tracey , Niblock Mary M. , Bartlett Donald , Leiter J. C.
Published: September 2007

The laryngeal chemoreflex (LCR) is elicited by water in the larynx and leads to apnea and respiratory disruption in immature animals. The LCR is exaggerated by the elevation of brain temperature within or near the nucleus of the solitary tract (NTS) in decerebrate piglets. Thermal prolongation of reflex apnea elicited by superior laryngeal nerve stimulation is reduced by systemic administration of GABAAreceptor antagonists. Therefore, we tested the hypothesis that microdialysis within or near the NTS of gabazine, a GABAAreceptor antagonist, would reverse thermal prolongation of the LCR. We examined this hypothesis in 21 decerebrate piglets (age 3–13 days). We elicited the LCR by injecting 0.1 ml of water into the larynx before and after each piglet's body temperature was elevated by ∼2.5°C and before and after 2–5 mM gabazine was dialyzed unilaterally and focally in the medulla. Elevated body temperature failed to prolong the LCR in one piglet, which was excluded from analysis. Elevated body temperature prolonged the LCR in all the remaining animals, and dialysis of gabazine into the region near the NTS ( n = 10) reversed the thermal prolongation of the LCR even though body temperature remained elevated. Dialysis of gabazine in other medullary sites ( n = 10) did not reverse thermal prolongation of the LCR. Gabazine had no consistent effect on baseline respiratory activity during hyperthermia. These findings are consistent with the hypothesis that hyperthermia activates GABAergic mechanisms in or near the NTS that are necessary for the thermal prolongation of the LCR.
Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle
Authors: Louis Emily , Raue Ulrika , Yang Yifan , Jemiolo Bozena , Trappe Scott
Published: September 2007

The aim of this study was to examine the time course induction of select proteolytic [muscle ring finger-1 (MuRF-1), atrogin-1, forkhead box 3A (FOXO3A), calpain-1, calpain-2], myostatin, and cytokine (IL -6, -8, -15, and TNF-α) mRNA after an acute bout of resistance (RE) or run (RUN) exercise. Six experienced RE (25 ± 4 yr, 74 ± 14 kg, 1.71 ± 0.11 m) and RUN (25 ± 4 yr, 72 ± 5 kg, 1.81 ± 0.07 m) subjects had muscle biopsies from the vastus lateralis (RE) or gastrocnemius (RUN) before, immediately after, and 1, 2, 4, 8, 12, and 24 h postexercise. RE increased ( P < 0.05) mRNA expression of MuRF-1 early (3.5-fold, 1–4 h), followed by a decrease in atrogin-1 (3.3-fold) and FOXO3A (1.7-fold) 8–12 h postexercise. Myostatin mRNA decreased (6.3-fold; P < 0.05) from 1 to 24 h postexercise, whereas IL-6, IL-8, and TNF-α mRNA were elevated 2–12 h. RUN increased ( P < 0.05) MuRF-1 (3.6-fold), atrogin-1 (1.6-fold), and FOXO3A (1.9-fold) 1–4 h postexercise. Myostatin was suppressed (3.6-fold; P < 0.05) 8–12 h post-RUN. The cytokines exhibited a biphasic response, with immediate elevation ( P < 0.05) of IL-6, IL-8, and TNF-α, followed by a second elevation ( P < 0.05) 2–24 h postexercise. In general, the timing of the gene induction indicated early elevation of proteolytic genes, followed by prolonged elevation of cytokines and suppression of myostatin. These data provide basic information for the timing of human muscle biopsy samples for gene expression studies involving exercise. Furthermore, this information suggests a greater induction of proteolytic genes following RUN compared with RE.
Inflamed Adipose Tissue
Authors: Gustafson Birgit , Hammarstedt Ann , Andersson Christian X. , Smith Ulf
Published: September 2007

The metabolic syndrome is associated with a dysregulated adipose tissue; in part a consequence of adipose cell enlargement and the associated infiltration of macrophages. Adipose cell enlargement leads to a proinflammatory state in the cells with reduced secretion of adiponectin and with increased secretion of several cytokines and chemokines including interleukin (IL)-6, IL-8, and MCP-1. MCP-1 has been shown to play an important role for the associated recruitment of macrophages into the adipose tissue. The increased release of cytokines leads to an impaired differentiation of the preadipocytes with reduced lipid accumulation and induction of adiponectin, thus promoting ectopic lipid storage. In particular tumor necrosis factor (TNF) α, but also IL-6, has been shown to induce these effects in preadipocytes and this is associated with an increased Wnt signaling maintaining the cells in an undifferentiated and proinflammatory state. The proinflammatory state in the adipose tissue also leads to a local insulin resistance including an impaired inhibitory effect of insulin on FFA release. The insulin resistance further supports the proinflammatory state because insulin, by itself, is both antilipolytic and antiinflammatory by antagonizing cytokine-induced activation of STAT signaling.
Nuclear Redox-Signaling Is Essential for Apoptosis Inhibition in Endothelial Cells—Important Role for Nuclear Thioredoxin-1
Authors: Schroeder Peter , Popp Ruediger , Wiegand Barbara , Altschmied Joachim , Haendeler Judith
Published: September 2007

Objective—

The redox regulator thioredoxin-1 (Trx) is a potent antioxidative enzyme and exerts important cellular functions. Physiological concentrations of reactive oxygen species (ROS) and of nitric oxide (NO) act as second messengers. Previously, we demonstrated that ROS and NO reduced apoptosis in a Trx-dependent manner. The aim of this study was to determine the underlying mechanisms.

Methods and Results—

First, we investigated the localization of Trx after H
2
O
2
and NO. Both induced nuclear import of Trx, which required karyopherin-α. siRNA against karyopherin-α inhibited nuclear import of Trx. Analysis of the Trx amino acid sequence and subsequent immunoprecipitation studies revealed that Trx(K81/82E) is not imported into the nucleus under H
2
O
2
treatment and Trx(K81/82/85E) was retained in the cytosol and induced cell death. Trx(K81/82E) abolished the antiapoptotic capacity of H
2
O
2
. Glutathione S-transferase P1 (GST-P1) was identified as one major target regulated by H
2
O
2
. siRNA against GST-P1 abolished the antiapoptotic effect of H
2
O
2
. Cysteine 69, but not cysteines 32 and 35, which are all required for the complete antiapoptotic function of Trx, is not imported into the nucleus.

Conclusion—

H
2
O
2
-induced nuclear import of Trx depends on karyopherin-α and NO. Trx-dependent induction of GST-P1 expression is required for apoptosis inhibition in endothelial cells.
Successive Action of Meprin A and Neprilysin Catabolizes B-Type Natriuretic Peptide
Authors: Pankow Kristin , Wang Yong , Gembardt Florian , Krause Eberhard , Sun Xiaoou , Krause Gerd , Schultheiss Heinz-Peter , Siems Wolf-Eberhard , Walther Thomas
Published: September 2007

Natriuretic peptides such as B-type natriuretic peptide (BNP) are important cardioprotective hormones with essential functions in sodium excretion, water balance and blood pressure regulation. Consequently, the catabolism of these peptides is in the focus of clinical research. In previous studies, we demonstrated that BNP, in contrast to the structurally related atrial and C-type natriuretic peptide, was not hydrolyzed by neprilysin (NEP). Because membrane preparations of several organs of NEP-knockout mice rapidly degrade BNP, the aim of this study was to identify BNP-catabolizing peptidases responsible for this fast clearance. Using kidney membranes of wild-type and NEP-knockout mice, as well as several peptidase inhibitors, we monitored the catabolism of BNP and analyzed its degradation products. We identified meprin A, a multimeric metalloprotease expressed in the brush borders of kidney proximal tubules, to initially truncate mouse BNP in the N terminus to mBNP7-32, a BNP metabolite with conserved biological activity. Consequently, in vivo experiments with the meprin inhibitor actinonin successfully elevated plasma BNP concentration in rats. We further demonstrated that the generation of mBNP7-32 is the prerequisite to catabolize BNP and identified NEP as the peptidase degrading the truncated BNP. Thus, the cooperative, successive action of the 2 transmembranal peptidases meprin A and NEP is crucial for rapid renal BNP inactivation. Therefore, the inhibition of meprin A could be a potent tool for increasing circulating BNP levels.
STAT3-Dependent Mouse Embryonic Stem Cell Differentiation Into Cardiomyocytes
Authors: Rajasingh Johnson , Bord Evelyn , Hamada Hiromichi , Lambers Erin , Qin Gangjian , Losordo Douglas W. , Kishore Raj
Published: September 2007

Pluripotent embryonic stem (ES) cell therapy may be an attractive source for postinfarction myocardial repair and regeneration. However, the specific stimuli and signal pathways that may control ES cell–mediated cardiomyogenesis remains to be completely defined. The aim of the present study was to investigate (1) the effect and underlying signal transduction pathways of leukemia inhibitory factor (LIF) and bone-morphogenic protein-2 (BMP-2)-induced mouse ES cell (mES-D3 line) differentiation into cardiomyocytes (CMC) and (2) the efficacy of CMC precommitted mES cells for functional and anatomical cardiac repair in surgically-induced mouse acute myocardial infarction (AMI) model. Various doses of LIF and BMP-2 and their inhibitors or blocking antibodies were tested for mES differentiation to CMC in vitro. CMC differentiation was assessed by mRNA and protein expression of CMC-specific markers, Connexin-43, CTI, CTT, Mef2c, Tbx5, Nkx2.5, GATA-4, and αMHC. LIF and BMP-2 synergistically induced the expression of CMC markers as early as 2 to 4 days in culture. Signaling studies identified STAT3 and MAP kinase (ERK1/2) as specific signaling components of LIF+BMP-2–mediated CMC differentiation. Inhibition of either STAT3 or MAPK activation by specific inhibitors drastically suppressed LIF+BMP-2–mediated CMC differentiation. Moreover, in mouse AMI, transplantation of lentivirus-GFP–transduced, LIF+BMP-2 precommitted mES cells, improved post-MI left ventricular functions, and enhanced capillary density. Transplanted cells engrafted in myocardium and differentiated into CMC and endothelial cells. Our data suggest that LIF and BMP-2 may synergistically enhance CMC differentiation of transplanted stem cells. Thus augmentation of LIF/BMP-2 downstream signaling components or cell type specific precommitment may facilitate the effects of ES cell–based therapies for post-MI myocardial repair and regeneration.
Impaired Angiogenesis After Hindlimb Ischemia in Type 2 Diabetes Mellitus
Authors: Hazarika Surovi , Dokun Ayotunde O. , Li Yongjun , Popel Aleksander S. , Kontos Christopher D. , Annex Brian H.
Published: September 2007

Deficient angiogenesis after ischemia may contribute to worse outcomes of peripheral arterial disease in patients with diabetes mellitus (DM). Vascular endothelial growth factor (VEGF) and its receptors promote angiogenesis. We hypothesized that in peripheral arterial disease, maladaptive changes in VEGF ligand/receptor expression could account for impaired angiogenesis in DM. Skeletal muscle from diet-induced, type 2 diabetic (DM) and age-matched normal chow (NC)-fed mice was collected at baseline and 3 and 10 days after hindlimb ischemia and analyzed for expression of VEGF (n=10 per group), full-length VEGF receptor (VEGFR)-1, soluble VEGFR-1, and markers of downstream VEGF signaling (n=20 per group) using ELISA, reverse transcriptase-polymerase chain reaction, and Western blots. In the absence of ischemia, DM mice had increased VEGF (NC versus DM: 26.6±2.6 versus 53.5±8.8 pg/mg protein;
P
<0.05), decreased soluble and membrane-bound VEGFR-1 (NC versus DM: 1.44±0.30 versus 0.85±0.08 and 1.03±0.10 versus 0.72±0.10, respectively;
P
<0.05), decreased phospho-AKT/AKT and phospho–endothelial NO synthase/endothelial NO synthase (NC versus DM: 0.76±0.2 versus 0.38±0.1 and 0.36±0.06 versus 0.25±0.04, respectively;
P
<0.05), and no change in VEGFR-2. After ischemia, both DM and NC had comparable increases in VEGF-A. VEGFR-1 and soluble VEGFR-1 expression increased in both groups, but the fold increase was significantly greater in DM. These data demonstrate that soluble VEGFR-1, an angiogenesis inhibitor, is regulated in skeletal muscle by type 2 DM and ischemia. In the absence of ischemia, despite reductions in both soluble VEGFR-1 and VEGFR-1, VEGF ligand signaling is lower in DM compared with controls. After ischemia, maladaptive upregulation of these receptors further reduces the capacity of VEGF to induce an angiogenic response, which may provide a novel target for therapy.
DXA, Health Beliefs, and Osteoporosis Prevention Behaviors
Authors: Sedlak Carol A. , Doheny Margaret O. , Estok Patricia J. , Zeller Richard A. , Winchell Janice
Published: September 2007

Objective: This experimental longitudinal study was designed to examine the relationship between having a bone density through dual energy X ray absorptiometry (DXA) and osteoporosis preventing behaviors (OPB) among healthy postmenopausal women. Methods: Subjects were 203 healthy community-based women 50-65 years of age. Mediating variables were general knowledge of osteoporosis and revised health belief model variables. Treatment group women ( n = 101) had a DXA screen and control group women ( n = 102) did not. Study questionnaires were completed at three time points; initially and at 6 months and 12 months. Results: Repeated measures ANOVA revealed treatment group women scored significantly higher on perceived susceptibility and calcium intake. Wilks's Lambda F revealed a significant difference in use of osteoporosis preventing medications. Discussion: Personal knowledge gained from DXAs increased perceived susceptibility to osteoporosis, calcium intake, and use of osteoporosis preventing medications and appears to be an effective intervention in promoting OPB in younger postmenopausal women.
HGAL, a lymphoma prognostic biomarker, interacts with the cytoskeleton and mediates the effects of IL-6 on cell migration
Authors: Lu Xiaoqing , Chen Jun , Malumbres Raquel , Cubedo Gil Elena , Helfman David M. , Lossos Izidore S.
Published: September 2007

HGAL is a newly identified germinal center (GC)–specific gene whose expression by the tumor cells correlates with a favorable prognosis in patients with diffuse large B-cell and classical Hodgkin lymphomas. The function of HGAL is unknown. Previous studies demonstrated that HGAL is dispensable for GC formation, immunoglobulin gene class-switch recombination, and somatic hypermutation. Herein, we identify a role for HGAL in the regulation of cell motility. We demonstrate that IL-6 induces the phosphorylation of the C-terminal tyrosine residue of the HGAL protein via the Lyn kinase, and promotes its relocalization from the cytoplasm to podosome-like structures. Further, IL-6–induced HGAL phosphorylation increases its interaction with myosin II and is associated with inhibition of cell migration. Knockdown of endogenous HGAL ameliorates IL-6–induced inhibition of cell migration, whereas overexpression of HGAL imparts inhibitory effects of IL-6 on cell migration. Taken together, our results suggest that HGAL is involved in negative regulation of lymphocyte migration, thus constraining lymphocytes to the GC. Inhibition of lymphocyte migration might contribute to the less aggressive clinical behavior of HGAL-expressing lymphomas.
The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells
Authors: Bae Jong-Sup , Yang Likui , Manithody Chandrashekhara , Rezaie Alireza R.
Published: September 2007

Recent studies have indicated that activated protein C (APC) may exert its cytoprotective and anti-inflammatory activities through the endothelial protein C receptor (EPCR)-dependent cleavage of protease-activated receptor 1 (PAR-1) on vascular endothelial cells. Noting that (1) the activation of protein C on endothelial cells requires thrombin, (2) relative to APC, thrombin cleaves PAR-1 with approximately 3 to 4 orders of magnitude higher catalytic efficiency, and (3) PAR-1 is a target for the proinflammatory activity of thrombin, it is not understood how APC can elicit a protective signaling response through the cleavage of PAR-1 when thrombin is present. In this study, we demonstrate that EPCR is associated with caveolin-1 in lipid rafts of endothelial cells and that its occupancy by the γ-carboxyglutamic acid (Gla) domain of protein C/APC leads to its dissociation from caveolin-1 and recruitment of PAR-1 to a protective signaling pathway through coupling of PAR-1 to the pertussis toxin–sensitive Gi-protein. Thus, when EPCR is bound by protein C, the PAR-1 cleavage-dependent protective signaling responses in endothelial cells can be mediated by either thrombin or APC. These results provide a new paradigm for understanding how PAR-1 and EPCR participate in protective signaling events in endothelial cells.
Milk fermentation products of L. helveticus R389 activate calcineurin as a signal to promote gut mucosal immunity
Authors: Vinderola Gabriel , Matar Chantal , Perdigón Gabriela
Published: September 2007

Background

Fermented milks containing probiotic bacteria are a way of delivering bioactive constituents to targets in the gastrointestinal tract. We reported previously that the fermentation of milk at constant pH 6 byL. helveticusR389 increased its content of peptide fractions, and the oral administration of the non-bacterial fraction (FMSpH6) to mice increased total secretory IgA in the intestinal lumen and enhanced the number of IgA and various cytokines producing cells as well as the secretion of IL-6 by small intestine epithelial cells. We also demonstrated that this FMSpH6 was effective for the prevention ofSalmonella typhimuriuminfection in mice. In this work, we studied in mice the impact of the oral administration of the supernatant of milk fermented byL. helveticusR389 on the gut physiology by measuring parameters such as calcium channels and E-cadherin expression, the activation of the biological signal calcineurin and mast and goblet cells, as a way to determine some mechanisms involved in the immunomodulating effects of the milk fermentation products, observed in previous studies. We analyzed the impact of the supernatant of milk fermented byL. helveticusR389 at pH6-controlled on the expression of calcineurin and on the reinforcement of the ephitelial barrier, measuring parameters such as calcium channels and E-cadherin expression and in the reinforcement of the non-specific immunity determining mast cells and goblet cells associated to the gut.

Results

We observed an enhanced expression of TRPV6 channels in the duodenum, indicating an improved capacity for dietary Ca2+ uptake. We demonstrated an enhanced expression of calcineurin in the small intestine, able to upregulate immune parameters such as IL-2 and TNF production, with an increase in the number of these cytokines secreting cells. We determined an increase in the number of mucosal mast cells and goblet cells, which would mean an improved state of mucosal surveillance at sites of infection.

Conclusion

The oral administration of the supernatant of milk fermented byL. helveticusR389 enhanced the gut mucosal immunity by improving the mechanisms that reinforce the epithelial and non-specific barriers and the gut functioning at sites of infection, with an improvement in the expression of the enzyme calcineurin, an important signal in the network that activates the gut immune system. The results of this work contribute to revealing the mechanisms underlying the immunomodulation of the gut immune function by fermented milks with probiotic bacteria.
Dying from cardiac tamponade
Authors: Swaminathan Aravind , Kandaswamy Karikalan , Powari Manish , Mathew Joseph
Published: September 2007

Background

To determine the causes of cardiac tamponade (CT), focussing especially on haemopericardium (HP), as a terminal mode of death, within a 430,000 rural English population.

Methods

Our hospital mortuary register and, all postmortem reports between 1995 and 2004 inclusive, were interrogated for patients dying of CT or HP. The causes of CT/HP and selected morphological characteristics were then determined.

Results

14,368 postmortems were performed in this period: of these, 461 patients died of CT. Three cases were due to non-haemorrhagic pericardial effusion. HP accounted for the remaining 458 cases of which, five were post-traumatic, 311 followed rupture of an acute myocardial infarction (RAMI), 138 after intra-pericardial rupture of dissecting ascending aortic aneurysms (RD3A) and four were due to miscellaneous causes.

HP was more commonly due to RAMI. Men tended to die from RAMI or RD3A earlier than women. RAMI or RD3A were commoner in men <70 yrs, but more frequent in women after this.

Two thirds of RAMI were associated with coronary artery thrombosis. Anterior free wall rupture was commonest overall, and in women, but posterior free wall rupture was commoner in men.

The volume of intrapericardial blood in RAMI (mean = 440 ml) and RD3A (mean = 498 ml) varied between 150 and 1000 ml: intrapericardial blood volume was greater in men than in women dying from either RAMI or RD3A.

Conclusion

At postmortem, CT is most often related to HP, attributable to either RAMI or intrapericardial RD3A. Post-traumatic and other causes of CT are infrequent.
Limited-Stage Small-Cell Lung Cancer: The Current Status of Combined-Modality Therapy
Authors: Socinski Mark A. , Bogart Jeffrey A.
Published: September 2007

Limited-stage (LS) small-cell lung cancer (SCLC) remains a therapeutic challenge to medical and radiation oncologists. The treatment of LS-SCLC has evolved significantly over the last two decades with combined-modality therapy now the standard of care. The addition of thoracic radiotherapy (TRT) to standard chemotherapy has led to improvements in long-term survival in this population. However, many questions remain about the optimal way to deliver chemoradiotherapy. In a landmark trial, twice-daily TRT to a dose of 45 Gy increased 5-year survival by 10% compared with once-daily TRT administered to the same dose. This suggests that more intensive TRT regimens may lead to further survival gains, assuming they can be delivered safely in this setting. Strategies currently under investigation include higher total daily doses delivered once daily or novel concurrent boost techniques allowing more intensive treatments over shorter periods of time. Several trials and meta-analyses have evaluated the timing of TRT with chemotherapy, with the weight of evidence suggesting that early and concurrent TRT with chemotherapy is optimal. Novel cytotoxic chemotherapy combinations have failed thus far to provide an advantage over standard etoposide-cisplatin combinations. Prophylactic cranial irradiation in near or complete responders to induction chemoradiotherapy has also been shown to improve long-term survival rates. LS-SCLC has been a model cancer in terms of the potential benefit of combined chemoradiotherapy strategies in improving patient outcomes.
Inhibition of Histone Deacetylation: A Strategy for Tumor Radiosensitization
Authors: Camphausen Kevin , Tofilon Philip J.
Published: September 2007

Recently, strategies to enhance tumor radiosensitivity have begun to focus on targeting the molecules and processes that regulate cellular radioresponse. A molecular target that has begun to receive considerable attention is histone acetylation. Histone acetylation is determined by the dynamic interaction of two families of enzymes: histone acetylases and histone deacetylases (HDACs). Histone acetylation plays a role in regulating chromatin structure and gene expression—two parameters that have long been considered determinants of radioresponse. As a means of modifying histone acetylation status, considerable effort has been put into the development of inhibitors of HDAC activity. This has led to the generation of a relatively large number of structurally diverse compounds that can inhibit HDAC activity resulting in histone hyperacetylation. Many of the newer HDAC inhibitor compounds have been designed with better bioavailability or pharmacology than the first-generation compounds. Whereas a number of these second-generation HDAC inhibitors have antitumor activity in preclinical cancer models when delivered as single agents, early clinical data demonstrate only cytostasis when used as monotherapy. However, recent preclinical studies have indicated that HDAC inhibitors from structurally diverse classes can enhance both the in vitro and in vivo radiosensitivity of human tumor cell lines generated from a spectrum of solid tumors. HDAC inhibitors are in clinical trials as single modalities, in combination with chemotherapeutic agents, and recently, in combination with radiotherapy.
Diffusion Magnetic Resonance Imaging: A Biomarker for Treatment Response in Oncology
Authors: Hamstra Daniel A. , Rehemtulla Alnawaz , Ross Brian D.
Published: September 2007

Imaging of response to oncology treatments, either on clinical protocol or as part of standard practice, is a complicated process that has evolved during the last 10 years due to the improvement of existing imaging technologies and the introduction of newer modalities. Diffusion magnetic resonance imaging is a technique that measures the mobility of water within tissues and, as such, may function as a surrogate marker for both tissue cellularity and response to treatment that occur earlier than usual measures of tumor response. This review highlights the development of this technique and the state of current clinical understanding of its utility.
Definitive Chemoradiation for the Treatment of Locally Advanced Non–Small-Cell Lung Cancer
Authors: Blackstock A. William , Govindan Ramaswamy
Published: September 2007

A third of patients with newly diagnosed non–small-cell lung cancer (NSCLC) have locally advanced disease not amenable for curative resection. Addition of chemotherapy to thoracic radiation improves survival in patients with locally advanced NSCLC when compared with thoracic radiation alone. Over the past two decades, we have made slow but steady progress in improving the outcomes of therapy in this subset of patients. This review summarizes the past two decades of research and outlines the direction we need to pursue to significantly enhance the outcomes. The widespread use of positron emission tomography (identifying those with occult distant metastatic disease and sparing them combined-modality therapy), improved radiation techniques, and better supportive care resulting in improved chemotherapy delivery have resulted in improved outcomes. There is considerable interest in studying the role of higher doses of thoracic radiation (74 Gy) in this disease, and this is the subject of an ongoing intergroup study. Despite some recent setbacks, molecularly targeted therapies need to be studied carefully in combination with chemoradiotherapy. There is an urgent need to develop regimens that incorporate chemotherapy agents that can be administered at doses that are systemically active and yet tolerable.
Estradiol Enhances Cholecystokinin-Dependent Lipid-Induced Satiation and Activates Estrogen Receptor-α-Expressing Cells in the Nucleus Tractus Solitarius of Ovariectomized Rats
Authors: Asarian Lori , Geary Nori
Published: September 2007

Part of the mechanism through which estradiol, acting via estrogen receptor (ERα) signaling, inhibits feeding in rats and mice is increasing the satiating potency of cholecystokinin (CCK) acting on peripheral CCK-1 receptors. Ingested lipid is a principal secretagogue of intestinal CCK, and intraduodenal lipid infusions elicit CCK-mediated satiation in animals and humans. Here we tested whether estradiol affects the satiating potency of intraduodenal lipid infusions in ovariectomized rats and, using c-Fos immunocytochemistry, searched for potential brain sites of ERα involved. Food-deprived ovariectomized rats with open gastric cannulas sham fed 0.8 m sucrose 2 d after estradiol (estradiol benzoate, 10 μg, sc) or vehicle injection. Estradiol markedly increased the satiating potency of intraduodenal infusions of Intralipid but not the satiating potency of L-phenylalanine (10 min infusions, 0.44 ml/min, 0.13 kcal/ml), which in male rats satiates via a CCK-independent mechanism. Estradiol had no significant effect in rats pretreated with the CCK-1 receptor antagonist Devazepide (1 mg/kg, ip). The effect of estradiol on intraduodenal Intralipid-induced satiation was mirrored by selective increases in the number of cells expressing c-Fos immunoreactivity in a circumscribed region of the nucleus tractus solitarius (NTS), just caudal to the area postrema (cNTS) but not elsewhere in the NTS or the hypothalamic paraventricular or arcuate nuclei. In addition, a significant proportion of cNTS c-Fos-positive cells also expressed ERα. These data provide behavioral and cellular evidence that estradiol-ERα signaling in cNTS neurons increases the satiating potency of endogenous CCK released in response to ingested lipid.
The Matricellular Protein CYR61 Inhibits Osteoclastogenesis by a Mechanism Independent of αvβ3 and αvβ5
Authors: Crockett Julie C. , Schütze Norbert , Tosh Denise , Jatzke Susanne , Duthie Angela , Jakob Franz , Rogers Michael J.
Published: September 2007

Cysteine-rich protein 61 (CYR61/CCN1) belongs to the family of CCN matricellular proteins. Most of the known effects of CCN proteins appear to be due to binding to extracellular growth factors or integrins, including αvβ3 and αvβ5. Although CYR61 can stimulate osteoblast differentiation, until now the effect of CYR61 on osteoclasts was unknown. We demonstrate that recombinant human CYR61 inhibits the formation of multinucleated, αvβ3-positive, or tartrate-resistant acid phosphatase-positive human, mouse, and rabbit osteoclasts in vitro. CYR61 markedly reduced the expression of the osteoclast phenotypic markers tartrate-resistant acid phosphatase, matrix metalloproteinase-9, calcitonin receptor, and cathepsin K. However, CYR61 did not affect the formation of multinucleated osteoclasts when added to osteoclast precursors prior to fusion or affect the number or resorptive activity of osteoclasts cultured on dentine discs, indicating that CYR61 affects early osteoclast precursors but not mature osteoclasts. CYR61 did not affect receptor activator of nuclear factor-κB (RANK) ligand-induced phosphorylation of p38 or ERK1/2 in human macrophages and did not affect RANK ligand-induced activation of nuclear factor-κB, indicating that CYR61 does not appear to inhibit osteoclastogenesis by affecting RANK signaling. Furthermore, a mutant form of CYR61 defective in binding to αvβ3 also inhibited osteoclastogenesis, and CYR61 inhibited osteoclastogenesis similarly in cultures of mouse wild-type or β5−/− macrophages. Thus, CYR61 does not appear to inhibit osteoclast formation by interacting with αvβ3 or αvβ5. These observations demonstrate that CYR61 is a hitherto unrecognized inhibitor of osteoclast formation, although the exact mechanism of inhibition remains to be determined. Given that CYR61 also stimulates osteoblasts, CYR61 could represent an important bifunctional local regulator of bone remodeling.
Expression of Transgenic FLIP on Thyroid Epithelial Cells Inhibits Induction and Promotes Resolution of Granulomatous Experimental Autoimmune Thyroiditis in CBA/J Mice
Authors: Fang Yujiang , DeMarco Vincent G. , Sharp Gordon C. , Braley-Mullen Helen
Published: September 2007

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by transfer of thyroglobulin-primed in vitro activated splenocytes. Thyroid lesions reach maximal severity 20 d later, and inflammation resolves or progresses to fibrosis by d 60, depending on the extent of thyroid damage at d 20. Depletion of CD8+ T cells inhibits G-EAT resolution. We showed that expression of Fas-associated death domain-like IL-1β-converting enzyme inhibitory protein (FLIP) transgene (Tg) on thyroid epithelial cells (TECs) of DBA/1 mice had no effect on G-EAT induction but promoted earlier resolution of G-EAT. However, when CBA/J wild-type donor cells were transferred to transgenic CBA/J mice expressing FLIP on TECs, they developed less severe G-EAT than FLIP Tg− littermates. Both strains expressed similar levels of the FLIP Tg, but endogenous FLIP was up-regulated to a greater extent on infiltrating T cells during G-EAT development in DBA/1 compared with CBA/J mice. After transient depletion of CD8+ T cells, FLIP Tg+ and Tg− CBA/J recipients both developed severe G-EAT at d 20. Thyroid lesions in CD8-depleted Tg+ recipients were resolving by d 60, whereas lesions in Tg− littermates did not resolve, and most were fibrotic. FLIP Tg+ recipients had increased apoptosis of CD3+ T cells compared with Tg− recipients. The results indicate that transgenic FLIP expressed on TECs in CBA/J mice promotes G-EAT resolution, but induction of G-EAT is inhibited unless CD8+ T cells are transiently depleted.
Hypoglycemia with Enhanced Hepatic Glycogen Synthesis in Recombinant Mice Lacking Hexose-6-Phosphate Dehydrogenase
Authors: Lavery Gareth G. , Hauton David , Hewitt Kylie N. , Brice Sophie M. , Sherlock Mark , Walker Elizabeth A. , Stewart Paul M.
Published: September 2007

Hexose-6-phosphate dehydrogenase (H6PDH) knockout (KO) mice have reduced generation of nicotinamide adenine dinucleotide phosphate (reduced) within the endoplasmic reticulum. As a consequence, 11β-hydroxysteroid dehydrogenase type 1 enzyme activity switches from a reductase to a dehydrogenase leading to glucocorticoid inactivation. 11β-Hydroxysteroid dehydrogenase type 1 has emerged as an important factor in regulating hepatic glucose output; therefore, we examined aspects of glucose homeostasis in KO mice. Compared with wild-type mice, KO mice reduced weight gain, displayed peripheral fasting hypoglycemia, improved glucose tolerance, and elevated plasma corticosterone concentrations. Plasma insulin levels in fed and fasted KO mice are normal; however, insulin and plasma glucose levels are reduced 4 h after fasted animals are refed, indicating improved insulin sensitivity. There is preserved induction and activity of the glucocorticoid-responsive gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in fasted KO mice. Glycogen storage is elevated in fed KO liver, with fed glycogenesis rates increased in KO mice. There is normal flux of lactate through gluconeogenesis recovered as plasma glucose, coupled with increased glycogen derived from lactate. These data suggest partial retention of glucocorticoid sensitivity at the level of the liver. We therefore postulate that increased glycogen synthesis may reflect increased flux of glucose-6-phosphate (H6PDH substrate) through to glycogen in the absence of H6PDH mediated metabolism.