bluuebunny/crossref_metadata_2025_split huggingface dataset:
mTOR Kinase Inhibition Causes Feedback-Dependent Biphasic Regulation of AKT Signaling
Authors: Rodrik-Outmezguine Vanessa S. , Chandarlapaty Sarat , Pagano Nen C. , Poulikakos Poulikos I. , Scaltriti Maurizio , Moskatel Elizabeth , Baselga José , Guichard Sylvie , Rosen Neal 
Published: June 2011

Abstract
mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways.
Significance: The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways. Cancer Discovery; 1(3); 248–59. © 2011 AACR.
Read the Commentary on this article by Keniry and Parsons, p. 203
This article is highlighted in the In This Issue feature, p. 189
Acute and Chronic Effects of Epicardial Radiofrequency Applications Delivered on Epicardial Coronary Arteries
Authors: Viles-Gonzalez Juan F. , de Castro Miranda Reynaldo , Scanavacca Mauricio , Sosa Eduardo , d'Avila Andre 
Published: June 2011

Background—
Epicardial coronary injury is by far the most feared complication of epicardial ablation. Little information is available regarding the chronic effects of delivering radiofrequency in the vicinity of large coronary vessels, and the long-term impact of this approach for mapping and ablation on epicardial vessel integrity is poorly understood. Therefore, the aim of this study was to characterize the acute and chronic histopathologic changes produced by in vivo epicardial pulses of radiofrequency ablation on coronary artery of porcine hearts.

Methods and Results—

Seven pigs underwent a left thoracotomy. The catheter was sutured adjacent to the left anterior descending artery and left circumflex artery, and 20 pulses of radiofrequency energy were applied. Radiofrequency lesions located no more than 1 mm of the vessel were used for this analysis. Three animals were euthanized 20 days (acute phase) after the procedure and 4 animals after 70 days (chronic phase). The following parameters were obtained in each vessel analyzed: (1) internal and external perimeter; (2) vessel wall thickness; (3) tunica media thickness, and (4) tunica intima thickness. The presence of adipose tissue around the coronary arteries, the distance between the artery and the epicardium, and the anatomic relationship of the artery with the coronary vein was also documented for each section. Sixteen of 20 (80%) sections analyzed, showed intimal thickening with a mean of 0.18±0.14 mm compared with 0.13±0.16 mm in the acute phase (
P
=0.331). The mean tunica media thickness was 0.25±0.10 mm in the chronic phase animals compared with 0.18±0.03 mm in the acute phase animals (
P
=0.021). A clear protective effect of pericardial fat and coronary veins was also present. A positive correlation between depth of radiofrequency lesion and the degree of vessel injury expressed as intimal and media thickening (
P
=0.001) was present. A negative correlation was identified (
r
=−0.83;
P
=0.002) between intimal thickening and distance between epicardium and coronary artery.

Conclusions—
In this porcine model of in vivo epicardial radiofrequency ablation in proximity to coronary arteries leads to acute and chronic histopathologic changes characterized by tunica intima and media thickening, with replacement of smooth muscle cells with extracellular matrix, but no significant stenosis was observed up to 70 days after the ablation. The absence of acute coronary occlusion or injury does not preclude subsequent significant arterial damage, which frequently occurs when epicardial radiofrequency applications are delivered in close vicinity to the vessels.
Multi-Analyte Profiling Reveals Matrix Metalloproteinase-9 and Monocyte Chemotactic Protein-1 as Plasma Biomarkers of Cardiac Aging
Authors: Chiao Ying Ann , Dai Qiuxia , Zhang Jianhua , Lin Jing , Lopez Elizabeth F. , Ahuja Seema S. , Chou Youn-Min , Lindsey Merry L. , Jin Yu-Fang 
Published: June 2011

Background—
We have previously shown that cardiac sarcopenia occurs with age in C57/BL6J mice. However, underlying mechanisms and plasma biomarkers of cardiac aging have not been identified. Accordingly, the objective of this study was to identify and evaluate plasma biomarkers that reflect cardiac aging phenotypes.

Methods and Results—

Plasma from adult (7.5±0.5 months old, n=27) and senescent (31.7±0.5 months old, n=25) C57/BL6J mice was collected, and levels of 69 markers were measured by multi-analyte profiling. Of these, 26 analytes were significantly increased and 3 were significantly decreased in the senescent group compared with the adult group. The majority of analytes that increased in the senescent group were inflammatory markers associated with macrophage functions, including matrix metalloproteinase-9 (MMP-9) and monocyte chemotactic protein-1 (MCP-1/CCL-2). Immunoblotting (n=12/group) showed higher MMP-9 and MCP-1 levels in the left ventricle (LV) of senescent mice (
P
<0.05), and their expression levels in the LV correlated with plasma levels (ρ=0.50 for MMP-9 and ρ =0.62 for MCP1,
P
<0.05). Further, increased plasma MCP-1 and MMP-9 levels correlated with the increase in end-diastolic dimensions that occurs with senescence. Immunohistochemistry (n=3/group) for Mac-3, a macrophage marker, showed increased macrophage densities in the senescent LV, and dual-labeling immunohistochemistry of Mac-3 and MMP-9 revealed robust colocalization of MMP-9 to the macrophages in the senescent LV sections, indicating that the macrophage is a major contributor of MMP-9 in the senescent LV.

Conclusions—
Our results suggest that MCP-1 and MMP-9 are potential plasma markers for cardiac aging and that augmented MCP-1 and MMP-9 levels and macrophage content in the LV could provide an underlying inflammatory mechanism of cardiac aging.
MicroRNA29a regulates the expression of the nuclear oncogene Ski
Authors: Teichler Sabine , Illmer Thomas , Roemhild Josephine , Ovcharenko Dmitriy , Stiewe Thorsten , Neubauer Andreas 
Published: June 2011

Abstract
MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate growth and differentiation. miRNAs are frequently located at cancer-specific fragile sites in the human genome, such as chromosome 7q. The nuclear oncogene SKI is up-regulated in acute myeloid leukemia (AML) with −7/del7q. Here we asked whether loss of miRNAs on chromosome 7q may explain this up-regulation. miR-29a expression was found to be down-regulated in AML with −7/del7q. Forced expression of miR-29a down-regulated Ski and its target gene, Nr-CAM, whereas miR-29a inhibition induced Ski expression. Luciferase assays validated a functional binding site for miR-29a in the 3′ untranslated region of SKI. Finally, in samples of AML patients, we observed an inverse correlation of Ski and miR-29a expression, respectively. In conclusion, up-regulation of Ski in AML with −7/del7q is caused by loss of miR-29a. miR-29a may therefore function as an important tumor suppressor in AML by restraining expression of the SKI oncogene.
Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia
Authors: Simonsson Bengt , Gedde-Dahl Tobias , Markevärn Berit , Remes Kari , Stentoft Jesper , Almqvist Anders , Björeman Mats , Flogegård Max , Koskenvesa Perttu , Lindblom Anders , Malm Claes , Mustjoki Satu , Myhr-Eriksson Kristina , Ohm Lotta , Räsänen Anu , Sinisalo Marjatta , Själander Anders , Strömberg Ulla , Bjerrum Ole Weiss , Ehrencrona Hans , Gruber Franz , Kairisto Veli , Olsson Karin , Sandin Fredrik , Nagler Arnon , Nielsen Johan Lanng , Hjorth-Hansen Henrik , Porkka Kimmo ,   for the Nordic CML Study Group
Published: June 2011

Abstract
Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-α2b (Peg–IFN-α2b) 50 μg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg–IFN-α2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg–IFN-α2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg–IFN-α2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg–IFN-α2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg–IFN-α2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.
Fibrinogen β–derived Bβ15-42 peptide protects against kidney ischemia/ reperfusion injury
Authors: Krishnamoorthy Aparna , Ajay Amrendra Kumar , Hoffmann Dana , Kim Tae-Min , Ramirez Victoria , Campanholle Gabriela , Bobadilla Norma A. , Waikar Sushrut S. , Vaidya Vishal S. 
Published: June 2011

AbstractIschemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgβ, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgβ chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgβ-derived Bβ15-42 peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.
Immunohistochemical detection and regulation of α5nicotinic acetylcholine receptor (nAChR) subunits by FoxA2 during mouse lung organogenesis
Authors: Porter Jason L , Bukey Benjamin R , Geyer Alex J , Willnauer Charles P , Reynolds Paul R 
Published: June 2011

Abstract

Background
α5 nicotinic acetylcholine receptor (nAChR) subunits structurally stabilize functional nAChRs in many non-neuronal tissue types. The expression of α5 nAChR subunits and cell-specific markers were assessed during lung morphogenesis by co-localizing immunohistochemistry from embryonic day (E) 13.5 to post natal day (PN) 20. Transcriptional control of α5 nAChR expression by FoxA2 and GATA-6 was determined by reporter gene assays.

Results
Steady expression of α5 nAChR subunits was observed in distal lung epithelial cells during development while proximal lung expression significantly alternates between abundant prenatal expression, absence at PN4 and PN10, and a return to intense expression at PN20. α5 expression was most abundant on luminal edges of alveolar type (AT) I and ATII cells, non-ciliated Clara cells, and ciliated cells in the proximal lung at various periods of lung formation. Expression of α5 nAChR subunits correlated with cell differentiation and reporter gene assays suggest expression of α5 is regulated in part by FoxA2, with possible cooperation by GATA-6.

Conclusions
Our data reveal a highly regulated temporal-spatial pattern of α5 nAChR subunit expression during important periods of lung morphogenesis. Due to specific regulation by FoxA2 and distinct identification of α5 in alveolar epithelium and Clara cells, future studies may identify possible mechanisms of cell differentiation and lung homeostasis mediated at least in part by α5-containing nAChRs.
In-silico prediction of disorder content using hybrid sequence representation
Authors: Mizianty Marcin J , Zhang Tuo , Xue Bin , Zhou Yaoqi , Dunker A Keith , Uversky Vladimir N , Kurgan Lukasz 
Published: June 2011

Abstract

Background
Intrinsically disordered proteins play important roles in various cellular activities and their prevalence was implicated in a number of human diseases. The knowledge of the content of the intrinsic disorder in proteins is useful for a variety of studies including estimation of the abundance of disorder in protein families, classes, and complete proteomes, and for the analysis of disorder-related protein functions. The above investigations currently utilize the disorder content derived from the per-residue disorder predictions. We show that these predictions may over-or under-predict the overall amount of disorder, which motivates development of novel tools for direct and accurate sequence-based prediction of the disorder content.

Results
We hypothesize that sequence-level aggregation of input information may provide more accurate content prediction when compared with the content extracted from the local window-based residue-level disorder predictors. We propose a novel predictor, DisCon, that takes advantage of a small set of 29 custom-designed descriptors that aggregate and hybridize information concerning sequence, evolutionary profiles, and predicted secondary structure, solvent accessibility, flexibility, and annotation of globular domains. Using these descriptors and a ridge regression model, DisCon predicts the content with low, 0.05, mean squared error and high, 0.68, Pearson correlation. This is a statistically significant improvement over the content computed from outputs of ten modern disorder predictors on a test dataset with proteins that share low sequence identity with the training sequences. The proposed predictive model is analyzed to discuss factors related to the prediction of the disorder content.

Conclusions
DisCon is a high-quality alternative for high-throughput annotation of the disorder content. We also empirically demonstrate that the DisCon's predictions can be used to improve binary annotations of the disordered residues from the real-value disorder propensities generated by current residue-level disorder predictors. The web server that implements the DisCon is available at http://biomine.ece.ualberta.ca/DisCon/.
Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin
Authors: Carey Robyn M , Blusztajn Jan K , Slack Barbara E 
Published: June 2011

Abstract

Background
The amyloid precursor protein (APP) is cleaved by β- and γ-secretases to generate toxic amyloid β (Aβ) peptides. Alternatively, α-secretases cleave APP within the Aβ domain, precluding Aβ formation and releasing the soluble ectodomain, sAPPα. We previously showed that inhibition of the GTPase dynamin reduced APP internalization and increased release of sAPPα, apparently by prolonging the interaction between APP and α-secretases at the plasma membrane. This was accompanied by a reduction in Aβ generation. In the present study, we investigated whether surface expression of the α-secretase ADAM (a
d isintegrin a nd m etalloprotease)10 is also regulated by dynamin-dependent endocytosis.

Results
Transfection of human embryonic kidney (HEK) cells stably expressing M3 muscarinic receptors with a dominant negative dynamin I mutant (dyn I K44A), increased surface expression of both immature, and mature, catalytically active forms of co-expressed ADAM10. Surface levels of ADAM10 were unaffected by activation of protein kinase C (PKC) or M3 receptors, indicating that receptor-coupled shedding of the ADAM substrate APP is unlikely to be mediated by inhibition of ADAM10 endocytosis in this cell line. Dyn I K44A strongly increased the formation of a C-terminal fragment of ADAM10, consistent with earlier reports that the ADAM10 ectodomain is itself a target for sheddases. The abundance of this fragment was increased in the presence of a γ-secretase inhibitor, but was not affected by M3 receptor activation. The dynamin mutant did not affect the distribution of ADAM10 and its C-terminal fragment between raft and non-raft membrane compartments.

Conclusions
Surface expression and limited proteolysis of ADAM10 are regulated by dynamin-dependent endocytosis, but are unaffected by activation of signaling pathways that upregulate shedding of ADAM substrates such as APP. Modulation of ADAM10 internalization could affect cellular behavior in two ways: by altering the putative signaling activity of the ADAM10 C-terminal fragment, and by regulating the biological function of ADAM10 substrates such as APP and N-cadherin.
Lytic activity of the virion-associated peptidoglycan hydrolase HydH5 of Staphylococcus aureusbacteriophage vB_SauS-phiIPLA88
Authors: Rodríguez Lorena , Martínez Beatriz , Zhou Yuan , Rodríguez Ana , Donovan David M , García Pilar 
Published: June 2011

Abstract

Background

Staphylococcus aureus is a food-borne pathogen and the most common cause of infections in hospitalized patients. The increase in the resistance of this pathogen to antibacterials has made necessary the development of new anti-staphylococcal agents. In this context, bacteriophage lytic enzymes such as endolysins and structural peptidoglycan (PG) hydrolases have received considerable attention as possible antimicrobials against gram-positive bacteria.

Results

S. aureus bacteriophage vB_SauS-phiIPLA88 (phiIPLA88) contains a virion-associated muralytic enzyme (HydH5) encoded by orf58, which is located in the morphogenetic module. Comparative bioinformatic analysis revealed that HydH5 significantly resembled other peptidoglycan hydrolases encoded by staphylococcal phages. The protein consists of 634 amino acid residues. Two putative lytic domains were identified: an N-terminal CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) domain (135 amino acid residues), and a C-terminal LYZ2 (lysozyme subfamily 2) domain (147 amino acid residues). These domains were also found when a predicted three-dimensional structure of HydH5 was made which provided the basis for deletion analysis. The complete HydH5 protein and truncated proteins containing only each catalytic domain were overproduced in E. coli and purified from inclusion bodies by subsequent refolding. Truncated and full-length HydH5 proteins were all able to bind and lyse S. aureus Sa9 cells as shown by binding assays, zymogram analyses and CFU reduction analysis. HydH5 demonstrated high antibiotic activity against early exponential cells, at 45°C and in the absence of divalent cations (Ca2+, Mg2+, Mn2+). Thermostability assays showed that HydH5 retained 72% of its activity after 5 min at 100°C.

Conclusions
The virion-associated PG hydrolase HydH5 has lytic activity against S. aureus, which makes it attractive as antimicrobial for food biopreservation and anti-staphylococcal therapy.
Phylogeography of Francisella tularensis subspecies holarctica from the country of Georgia
Authors: Chanturia Gvantsa , Birdsell Dawn N , Kekelidze Merab , Zhgenti Ekaterine , Babuadze George , Tsertsvadze Nikoloz , Tsanava Shota , Imnadze Paata , Beckstrom-Sternberg Stephen M , Beckstrom-Sternberg James S , Champion Mia D , Sinari Shripad , Gyuranecz Miklos , Farlow Jason , Pettus Amanda H , Kaufman Emily L , Busch Joseph D , Pearson Talima , Foster Jeffrey T , Vogler Amy J , Wagner David M , Keim Paul 
Published: June 2011

AbstractBackgroundFrancisella tularensis, the causative agent of tularemia, displays subspecies-specific differences in virulence, geographic distribution, and genetic diversity.F. tularensissubsp.holarcticais widely distributed throughout the Northern Hemisphere. In Europe,F. tularensissubsp.holarcticaisolates have largely been assigned to two phylogenetic groups that have specific geographic distributions. Most isolates from Western Europe are assigned to the B.Br.FTNF002-00 group, whereas most isolates from Eastern Europe are assigned to numerous lineages within the B.Br.013 group. The eastern geographic extent of the B.Br.013 group is currently unknown due to a lack of phylogenetic knowledge about populations at the European/Asian juncture and in Asia. In this study, we address this knowledge gap by describing the phylogenetic structure ofF. tularensissubsp.holarcticaisolates from the country of Georgia, and by placing these isolates into a global phylogeographic context.ResultsWe identified a new genetic lineage ofF. tularensissubsp.holarcticafrom Georgia that belongs to the B.Br.013 group. This new lineage is genetically and geographically distinct from lineages previously described from the B.Br.013 group from Central-Eastern Europe. Importantly, this new lineage is basal within the B.Br.013 group, indicating the Georgian lineage diverged before the diversification of the other known B.Br.013 lineages. Although two isolates from the Georgian lineage were collected nearby in the Ukrainian region of Crimea, all other global isolates assigned to this lineage were collected in Georgia. This restricted geographic distribution, as well as the high levels of genetic diversity within the lineage, is consistent with a relatively older origin and localized differentiation.ConclusionsWe identified a new lineage ofF. tularensissubsp.holarcticafrom Georgia that appears to have an older origin than any other diversified lineages previously described from the B.Br.013 group. This finding suggests that additional phylogenetic studies ofF. tularensissubsp.holarcticapopulations in Eastern Europe and Asia have the potential to yield important new insights into the evolutionary history and phylogeography of this broadly dispersedF. tularensissubspecies.