bluuebunny/crossref_metadata_2025_split huggingface dataset:
Src family kinases are necessary for cell migration induced by extracellular HMGB1
Authors: Palumbo Roberta , De Marchis Francesco , Pusterla Tobias , Conti Antonio , Alessio Massimo , Bianchi Marco E 
Published: April 2009

Abstract
The signaling pathways activated by extracellular HMGB1 to mediate cell migration include Src and related kinases, which target cystoskeletal proteins directly.
HMGB1 is a nuclear protein that signals tissue damage, as it is released by cells dying traumatically or secreted by activated innate immunity cells. Extracellular HMGB1 elicits the migration to the site of tissue damage of several cell types, including inflammatory cells and stem cells. The identity of the signaling pathways activated by extracellular HMGB1 is not known completely: We reported previously that ERK and NF-κB pathways are involved, and we report here that Src is also activated. The ablation of Src or inhibition with the kinase inhibitor PP2 blocks migration toward HMGB1. Src associates to and mediates the phosphorylation of FAK and the formation of focal adhesions.
AGE–modified albumin containing infusion solutions boosts septicaemia and inflammation in experimental peritonitis
Authors: Humpert Per M , Lukic Ivan K , Thorpe Suzanne R , Hofer Stefan , Awad Ezzat M , Andrassy Martin , Deemer Elizabeth K , Kasper Michael , Schleicher Erwin , Schwaninger Markus , Weigand Markus A , Nawroth Peter P , Bierhaus Angelika 
Published: April 2009

Abstract
Advanced glycation endproducts (AGEs) act as potential contaminants of infusion solutions boosting inflammation in experimental sepsis.
HSA preparations for i.v. use are administered in critically ill patients. Although increasing intravascular osmotic pressure seems to be a pathophysiologically orientated treatment, clinical trials do not indicate a benefit for mortality in HSA–treated patients. Instead, there is evidence for inflammatory reactions upon infusion of different HSA batches. A neglected issue concerning the safety and quality of these therapeutics is processing–related post–transcriptional protein modifications, such as AGEs. We therefore tested the hypothesis that commercially available infusion solutions contain AGEs and studied whether these protein modifications influence outcome and inflammation in a murine model of sepsis induced by CLP. Screening of different HSA and Ig preparations in this study revealed an up to approximate tenfold difference in the amount of AGE modifications. Application of clinically relevant concentrations of CML–modified HSA in CLP led to increased inflammation and enhanced mortality in wild–type mice but not in mice lacking the RAGE. Lethality was paralleled by increased activation of the proinflammatory transcription factor NF–κB, NF–κB–dependent gene expression, and infiltration of inflammatory cells in the peritoneal cavity. This study implies that infusion solutions containing a high load of the AGE–modified protein have the potential to activate RAGE/NF–κB–mediated inflammatory reactions, causing increased mortality in experimental peritonitis.
T cell suppression by naturally occurring HLA-G-expressing regulatory CD4+ T cells is IL-10-dependent and reversible
Authors: Huang Yu-Hwa , Zozulya Alla L , Weidenfeller Christian , Schwab Nicholas , Wiendl Heinz 
Published: April 2009

Abstract
HLA-Gpos Treg-mediated suppression is critically dependent on the secretion of IL-10 but not TGF-β.
CD4+ T cells constitutively expressing the immune-tolerogenic HLA-G have been described recently as a new type of nTreg (HLA-Gpos Treg) in humans. HLA-Gpos Treg accumulate at sites of inflammation and are potent suppressors of T cell proliferation in vitro, suggesting their role in immune regulation. We here characterize the mechanism of how CD4+ HLA-Gpos Treg influence autologous HLA-Gneg Tresp function. Using a suppression system free of APC, we demonstrate a T–T cell interaction, resulting in suppression of HLA-Gneg Tresp, which is facilitated by TCR engagement on HLA-Gpos Treg. Suppression is independent of cell–cell contact and is reversible, as the removal of HLA-Gpos Treg from the established coculture restored the proliferative capability of responder cells. Further, HLA-Gpos Treg-mediated suppression critically depends on the secretion of IL-10 but not TGF-β.
Ca2+-dependent mast cell death induced by Ag (I) via cardiolipin oxidation and ATP depletion
Authors: Inoue Toshio , Suzuki Yoshihiro , Yoshimaru Tetsuro , Ra Chisei 
Published: April 2009

Abstract
Ag (I) induction leads to a unique necrotic death pathway in which Ca2+-dependent cardiolipin oxidation and ATP depletion play critical roles.
In genetically susceptible humans and/or experimental animals, ions of heavy metals, Hg (II), Au (III), and Ag (I) have been shown to strongly induce autoimmunity, in which mast cells have been implicated to play a role. Here, we demonstrate that Ag (I) application results in mast cell death through a unique Ca2+- and mitochondria-dependent pathway. As cellular susceptibilities to Ag (I) cytotoxicity varied considerably, we analyzed the cell death pathway in the low and high responding cells. In the low responding cells, long application (e.g., 20 h) of Ag (I) at concentrations (≥30 μM) induced cell death, which was accompanied by mitochondrial membrane depolarization, cyt c release, and caspase-3/7 activation but was not prevented by selective inhibitors of caspase-3/7 and the mitochondrial permeability transition. The cell death was preceded by elevations in the cytoplasmic and mitochondrial Ca2+ levels, and Ca2+ responses and cell death were prevented by thiol reagents, including DTT, N-acetylcysteine, and reduced glutathione monoethyl ester. In the high responding cells, Ag (I) evoked considerable cell death by necrosis within 1 h, without inducing caspase activation, and this cell death was reduced significantly by depleting extracellular but not intracellular Ca2+. Moreover, Ag (I) strongly induced Ca2+-dependent CL oxidation and intracellular ATP depletion, both of which were blocked by thiol reagents. These results suggest that Ag (I) activates thiol-dependent Ca2+ channels, thereby promoting Ca2+-dependent CL oxidation, cyt c release, and ATP depletion. This necrotic cell death may play roles in Ag-induced inflammation and autoimmune disorders.
Lethal pulmonary infection with Francisella novicida is associated with severe sepsis
Authors: Sharma Jyotika , Li Qun , Mishra Bibhuti B , Pena Christopher , Teale Judy M 
Published: April 2009

Abstract
Excessive host inflammatory responses negatively impact the disease outcome in pneumonic tularemia.
The bacterial or host determinants of lethality associated with respiratory Francisella infections are currently unknown. No exo– or endotoxins that contribute to the severity of this disease have been identified. However, a deregulated host immune response upon infection is characterized by an initial 36– to 48–h delay followed by a rapid and excessive inflammatory response prior to death at 72–120 h. Here, we extend these findings by comparing host immune responses between sublethal and lethal respiratory infections of mice with an attenuated transposon mutant (Mut) of F. novicida (F.n.) strain U112 (sublethal) versus the wild–type (WT) strain (lethal). Infection with WT bacteria, but not the Mut, was characterized by sustained bacteremia and systemic dissemination of the pathogen with temporal increases in bacterial burdens in liver and spleen. Severe pathology with large foci of infiltrates associated with extensive tissue damage was evident in WT–infected lungs, and Mut–infected mice displayed much reduced pathology with intact lung architecture. Similar to other experimental models of severe sepsis, WT– but not the Mut–infected mice exhibited a robust increase in numbers of Gr1+ and CD11b+ cells, while displaying a significant depletion of αβ T cells. Further, a dramatic up–regulation of multiple cytokines and chemokines was observed only in lethal WT infection. In addition, an earlier and larger increased expression of S100A9, a known mediator of sepsis, was observed in WT–infected mice. Taken together, these results show that a hyperinflammatory host immune response, culminating in severe sepsis, is responsible for the lethal outcome of respiratory tularemia.
Morphometric Vertebral Fractures in Postmenopausal Women with Primary Hyperparathyroidism
Authors: Vignali Edda , Viccica Giuseppe , Diacinti Daniele , Cetani Filomena , Cianferotti Luisella , Ambrogini Elena , Banti Chiara , Del Fiacco Romano , Bilezikian John P. , Pinchera Aldo , Marcocci Claudio 
Published: April 2009

Context: An increased risk of fracture in patients with primary hyperparathyroidism (PHPT) compared to the general population has been reported, but available data are controversial.
Objective: The aim of the study was to evaluate the rate of vertebral fractures (VFs) by dual-energy x-ray absorptiometry in postmenopausal women with sporadic PHPT and compare the results with a control group.
Design and Setting: A case-control study was performed at a referral center.
Participants: A total of 150 consecutive patients and 300 healthy women matched for age and menopausal age participated in the study.
Results: VFs were detected in 37 of 150 (24.6%) patients and 12 of 300 (4.0%) controls (P &lt; 0.0001). The majority of VFs were mild. Stepwise multiple logistic regression analysis showed that in PHPT patients lumbar spine bone mineral density was the only variable independently associated with the prevalence of VFs (P = 0.003). The rate of fracture was higher in symptomatic (34.1%) than asymptomatic (21.1%) patients, but this difference was not statistically significant (P = 0.15). Among asymptomatic patients, fracture rate was significantly higher in those who met the criteria for parathyroidectomy (28.1%) than in those who did not (11.1%) (P = 0.03). Compared to controls, the fracture rate was significantly higher in patients with symptomatic and asymptomatic PHPT who met the criteria for surgery (P &lt; 0.0001), but not in those who did not meet the criteria (P = 0.06).
Conclusions: VF rate is increased in postmenopausal women with PHPT compared to controls, independently of whether they are classified as symptomatic or asymptomatic. The question of whether the finding of mild morphometric VFs in the latter represents an indication for parathyroid surgery remains to be established.
Identification and Characterization of Two Novel Truncated but Functional Isoforms of the Somatostatin Receptor Subtype 5 Differentially Present in Pituitary Tumors
Authors: Durán-Prado Mario , Gahete Manuel D. , Martínez-Fuentes Antonio J. , Luque Raúl M. , Quintero Ana , Webb Susan M. , Benito-López Pedro , Leal Alfonso , Schulz Stefan , Gracia-Navarro F. , Malagón María M. , Castaño Justo P. 
Published: April 2009

Context: Somatostatin and its related peptide cortistatin exert multiple actions on normal and tumoral tissue targets through a family of receptors termed somatostatin receptor (sst)1-5. Despite the considerable advances in the knowledge on these receptors and their (patho)physiological roles, there is still evidence that additional receptors for these peptides should exist to fully explain their actions.Objective: The growing number of spliced variants found in similar receptor families, often present in tumors, and results from our group obtained on sst5 from other species (pig) led us to explore the existence of new human sst5 isoforms.Design and Results: A rapid amplification of cDNA ends PCR approach on samples from a human pituitary tumor and a cell line enabled identification of two novel alternatively spliced sst5 receptor variants. The sequences obtained encode putative proteins that correspond to truncated isoforms of five and four transmembrane domains (TMDs), accordingly named sst5TMD5 and sst5TMD4, respectively. Both novel receptors show a differential expression pattern in normal tissues and are also present in pituitary tumors of diverse etiology including nonfunctioning adenomas, corticotropinomas, somatotropinomas, and a prolactinoma. In contrast to the predominant plasma membrane localization of full-length sst5, both sst5TMD5 and sst5TMD4 show a preferentially intracellular localization. Despite their truncated nature, both receptors are functional, as shown by their ability to mediate selective, ligand-induced rises in free cytosolic calcium concentration. Specifically, whereas sst5TMD5 is selectivity activated by somatostatin compared with cortistatin, cells transfected with sst5TMD4 almost exclusively respond to cortistatin and not to somatostatin.Conclusions: Our results demonstrate the existence of two previously unidentified sst5 spliced variants with distinct distribution in normal tissues and pituitary tumors, unique ligand-selective signaling properties, and subcellular distribution, which could contribute to somatostatin and cortistatin signaling in normal and tumoral cells.
Hypothyroidism Secondary to Hypothalamic-Pituitary Dysfunction May Be Part of the Phenotype in Klinefelter Syndrome: A Case-Control Study
Authors: Bjørn Anne-Mette Bay , Bojesen Anders , Gravholt Claus H. , Laurberg Peter 
Published: April 2009

Context: Klinefelter syndrome (KS) may involve a number of abnormalities besides the characteristic testicular insufficiency. Some studies have suggested that thyroid abnormalities may be common, but this has not been clarified.Design: A case-control study of men with KS (n = 75) compared with age-matched men from the general population (n = 75) was organized, and thyroid function, thyroid volume by ultrasonography, and thyroid antibodies were examined.Results: Men with KS were on average taller and heavier and tended to have a higher body mass index than the men in the control group. Serum free T4 (fT4) was lower in men with KS than controls [mean (sd): 16.3 (2.35) vs. 17.6 (1.75) pmol/liter; P &lt; 0.001], with clustering in or just below the lower part of the reference range for the assay. The ratio fT4 to free T3 was low in KS (P &lt; 0.001), whereas no differences between groups were observed in TSH, free T3, TSH to fT4 ratio, thyroid volume, or the prevalence of thyroid antibodies. No difference in any of the variables were observed between testosterone-treated and untreated KS men. Adjustment for differences in height, weight, and concomitant disease in multivariate models did not alter the results.Conclusions: Men with KS had a general shift toward lower values in distribution of serum fT4 with no compensatory increase in serum TSH. The most likely mechanism is a decrease or change in set point of thyrotroph control of thyroid function.
The Szilard Hypothesis on the Nature of Aging Revisited
Authors: Zetterberg Henrik , Båth Magnus , Zetterberg Madeleine , Bernhardt Peter , Hammarsten Ola 
Published: April 2009

AbstractThis year marks the 50th anniversary of a nearly forgotten hypothesis on aging by Leo Szilard, best known for his pioneering work in nuclear physics, his participation in the Manhattan Project during World War II, his opposition to the nuclear arms race in the postwar era, and his pioneering ideas in biology. Given a specific set of assumptions, Szilard hypothesized that the major reason for the phenomenon of aging was aging hits, e.g., by ionizing radiation, to the gene-bearing chromosomes and presented a mathematical target-hit model enabling the calculation of the average and maximum life span of a species, as well as the influence of increased exposure to DNA-damaging factors on life expectancy. While many new findings have cast doubt on the specific features of the model, this was the first serious effort to posit accumulated genetic damage as a cause of senescence. Here, we review Szilard's assumptions in the light of current knowledge on aging and reassess his mathematical model in an attempt to reach a conclusion on the relevance of Szilard's aging hypothesis today.
Allometric Growth in Hatchery-Reared Gilthead Seabream
Authors: Çoban Deniz , Kamaci H Okan , Suzer Cüneyt , Saka Şahin , Firat Kürşat 
Published: April 2009

Abstract
Morphological development and allometric growth were investigated in the gilthead seabream Sparus aurata during larval development until the end of the weaning period on day 41. Fertilized eggs had a diameter of 1.01 ± 0.02 mm (mean ± SE) and a lipid vesicle diameter of 0.227 ± 0.021 mm. Mean total length (TL) was 2.68 ± 0.04 mm for newly hatched larvae and 3.57 ± 0.09 mm at the onset of feeding (4 d after hatching [DAH]). At 10 DAH, initial swim bladder inflation occurred, mean TL was 4.19 ± 0.08 mm, and notochord length (NL) was 4.00 ± 0.07 mm. At 16 DAH, the swim bladder became more elongated, TL was 5.13 ± 0.09 mm, and NL was 4.94 ± 0.07 mm. Notochord flexion occurred at 6.46 ± 0.11 mm TL on 23 DAH, and the complement of the flexion occurred at 8.67 ± 0.109 mm TL on 35 DAH. At the end of the weaning period (at 41 DAH), larvae were 10.85 ± 0.116 mm TL. The majority of all allometric changes from the inflection point were expressed during the larval stage and integrated with the metamorphosis stage. Inflections in body proportion changes occurred mainly at 4.19 and 7.04 mm TL, corresponding to initial swim bladder inflation and the notochord flexion period, respectively.
Gene expression analysis in zebrafish embryos: A potential approach to predict effect concentrations in the fish early life stage test
Authors: Weil Mirco , Scholz Stefan , Zimmer Michaela , Sacher Frank , Duis Karen 
Published: April 2009

Abstract
Based on the hypothesis that analysis of gene expression could be used to predict chronic fish toxicity, the zebrafish (Danio rerio) embryo test (DarT), developed as a replacement method for the acute fish test, was expanded to a gene expression D. rerio embryo test (Gene-DarT). The effects of 14 substances on lethal and sublethal endpoints of the DarT and on expression of potential marker genes were investigated: the aryl hydrocarbon receptor 2, cytochrome P450 1A (cypla), heat shock protein 70, fizzy-related protein 1, the transcription factors v-maf musculoaponeurotic fibrosarcoma oncogene family protein g (avian) 1 and NF-E2-p45-related factor, and heme oxygenase 1 (hmox1). After exposure of zebrafish embryos for 48 h, differential gene expression was evaluated using reverse transcriptase-polymerase chain reaction, gel electrophoresis, and densitometric analysis of the gels. All tested compounds significantly affected the expression of at least one potential marker gene, with cyp1a and hmox1 being most sensitive. Lowest-observed-effect concentrations (LOECs) for gene expression were below concentrations resulting in 10% lethal effects in the DarT. For 10 (3,4- and 3,5-dichloroaniline, 1,4-dichlorobenzene, 2,4-dinitrophenol, atrazine, parathion-ethyl, chlorotoluron, genistein, 4-nitroquinoline-1-oxide, and cadmium) out of the 14 tested substances, LOEC values derived with the Gene-DarT differ by a factor of less than 10 from LOEC values of fish early life stage tests with zebrafish. For pentachloroaniline and pentachlorobenzene, the Gene-DarT showed a 23- and 153-fold higher sensitivity, respectively, while for lindane, it showed a 13-fold lower sensitivity. For ivermectin, the Gene-DarT was by a factor of more than 1,000 less sensitive than the acute fish test. The results of the present study indicate that gene expression analysis in zebrafish embryos could principally be used to predict effect concentrations in the fish early life stage test.
The Productivity of a Well with a Vertical Infinite-Conductivity Fracture in a Rectangular Closed Reservoir
Authors: Hagoort Jacques 
Published: April 2009

Summary
In this work, we have evaluated the productivity index (PI) of a well with a vertical, infinite-conductivity fracture in a closed rectangular reservoir for a wide range of fracture lengths, reservoir aspect ratios, and fracture eccentricities. The reported PIs are based on a rigorous analytical solution for the semi-steady-state pressure distribution created by a uniform-flux fracture in combination with Muskat’s method to convert the uniform-flux to a uniform-pressure solution. The PIs based on Earlougher’s shape factors are too optimistic. The equivalent-pressure (EP) method works very well at small fracture lengths but overestimates the PI at medium and large fracture lengths. The average-pressure (AP) method is too pessimistic at all fracture lengths.
Lack of Type VIII Collagen in Mice Ameliorates Diabetic Nephropathy
Authors: Hopfer Ulrike , Hopfer Helmut , Meyer-Schwesinger Catherine , Loeffler Ivonne , Fukai Naomi , Olsen Bjorn R. , Stahl Rolf A.K. , Wolf Gunter 
Published: April 2009

OBJECTIVE
Key features of diabetic nephropathy include the accumulation of extracellular matrix proteins. In recent studies, increased expression of type VIII collagen in the glomeruli and tubulointerstitium of diabetic kidneys has been noted. The objectives of this study were to assess whether type VIII collagen affects the development of diabetic nephropathy and to determine type VIII collagen–dependent pathways in diabetic nephropathy in the mouse model of streptozotocin (STZ)-induced diabetes.

RESEARCH DESIGN AND METHODS
Diabetes was induced by STZ injections in collagen VIII–deficient or wild-type mice. Functional and histological analyses were performed 40 days after induction of diabetes. Type VIII collagen expression was assessed by Northern blots, immunohistochemistry, and real-time PCR. Proliferation of primary mesangial cells was measured by thymidine incorporation and direct cell counting. Expression of phosphorylated extracellular signal–regulated kinase (ERK1/2) and p27Kip1 was assessed by Western blots. Finally, Col8a1 was stably overexpressed in mesangial cells.

RESULTS
Diabetic wild-type mice showed a strong renal induction of type VIII collagen. Diabetic Col8a1−/Col8a2− animals revealed reduced mesangial expansion and cellularity and extracellular matrix expansion compared with the wild type. These were associated with less albuminuria. High-glucose medium as well as various cytokines induced Col8a1 in cultured mesangial cells. Col8a1−/Col8a2− mesangial cells revealed decreased proliferation, less phosphorylation of Erk1/2, and increased p27Kip1 expression. Overexpression of Col8a1 in mesangial cells induced proliferation.

CONCLUSIONS
Lack of type VIII collagen confers renoprotection in diabetic nephropathy. One possible mechanism is that type VIII collagen permits and/or fosters mesangial cell proliferation in early diabetic nephropathy.