tbuckley/cabot-search huggingface dataset:
Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry
Authors: Deepak Shukla, Patricia G. Spear
Journal: Journal of Clinical Investigation (2001)

Heparan sulfate proteoglycansGlycosaminoglycan chains on cell surface proteoglycans provide initial docking sites for the binding to eukaryotic cells of various viruses and other microorganisms.The ubiquitously expressed glycosaminoglycan heparan sulfate is particularly important in this regard, at least for viruses.Often, binding of a viral protein to heparan sulfate is only the first step in a cascade of interactions between virus and cell that is required for viral entry into the cell and the initiation of infection.The steps that occur after binding of virus to heparan sulfate may require the interaction of other viral proteins with other cell surface molecules.Several of the human herpesviruses, the focus of this Perspective, can make their initial contact with cells by binding to cell surface heparan sulfate.One member of this group, herpes simplex virus type 1 (HSV-1), can also bind to specific sites in heparan sulfate to trigger the fusion between viral envelope and cell membrane that is required for viral entry.
Endothelium-Specific Interference With Peroxisome Proliferator Activated Receptor Gamma Causes Cerebral Vascular Dysfunction in Response to a High-Fat Diet
Authors: Andreas M. Beyer, Willem J. de Lange, Carmen M. Halabi, Mary L. Modrick, Henry L. Keen, Frank M. Faraci, Curt D. Sigmund
Journal: Circulation Research (2008)

The ligand-activated transcription factor peroxisome proliferator activated receptor gamma (PPARγ) is expressed in vascular endothelium where it exerts anti-inflammatory and antioxidant effects. However, its role in regulating vascular function remains undefined. We examined endothelial function in transgenic mice expressing dominant-negative mutants of PPARγ under the control of an endothelial-specific promoter to test the hypothesis that endothelial PPARγ plays a protective role in the vasculature. Under baseline conditions, responses to the endothelium-dependent agonist acetylcholine were not affected in either aorta or the basilar artery in vitro. In response to feeding a high-fat diet for 12 weeks, acetylcholine produced dilation that was markedly impaired in the basilar artery of mice expressing dominant-negative mutants, but not in mice expressing wild-type PPARγ controlled by the same promoter. Unlike basilar artery, 12 weeks of a high-fat diet was not sufficient to cause endothelial dysfunction in the aorta of mice expressing dominant-negative PPARγ, although aortic dysfunction became evident after 25 weeks. The responses to acetylcholine in basilar artery were restored to normal after treatment with a scavenger of superoxide. Baseline blood pressure was only slightly elevated in the transgenic mice, but the pressor response to angiotensin II was augmented. Thus, interference with PPARγ in the endothelium produces endothelial dysfunction in the cerebral circulation through a mechanism involving oxidative stress. Consistent with its role as a fatty acid sensor, these findings provide genetic evidence that endothelial PPARγ plays a critical role in protecting blood vessels in response to a high-fat diet.
On gradience and optionality in non-native grammars
Authors: Antonella Sorace
Journal: Behavioral and Brain Sciences (1996)

Abstract Epstein et al.'s “full access to Universal Grammar” position is conceptually and empirically problematic. Its shortcomings are illustrated through a brief discussion of the following issues: (1) initial versus final states of grammatical knowledge in a second language, (2) knowledge of gradience of grainmaticality, (3) optionality and retention in non-native grammars, and (4) the empirical measurement of syntactic knowledge.
Combination of pan-RAF and MEK inhibitors in NRAS mutant melanoma
Authors: Mohammad Atefi, Bjoern Titz, Earl Avramis, Charles Ng, Deborah JL Wong, Amanda Lassen, Michael Cerniglia, Helena Escuin-Ordinas, David Foulad, Begonya Comin-Anduix, Thomas G Graeber, Antoni Ribas
Journal: Molecular Cancer (2015)

Approximately 20% of melanomas contain a mutation in NRAS. However no direct inhibitor of NRAS is available. One of the main signaling pathways downstream of NRAS is the MAPK pathway. In this study we investigated the possibility of blocking oncogenic signaling of NRAS by inhibiting two signaling points in the MAPK pathway. Fourteen NRAS mutated human melanoma cell lines were treated with a pan-RAF inhibitor (PRi, Amgen Compd A), a MEK inhibitor (MEKi, trametinib) or their combination and the effects on proliferation, cell cycle progression, apoptosis, transcription profile and signaling of the cells were investigated. The majority of the cell lines showed a significant growth inhibition, with high levels of synergism of the PRi and MEKi combination. Sensitive cell lines showed induction of apoptosis by the combination treatment and there was a correlation between p-MEK levels and synergistic effect of the combination treatment. Proliferation of sensitive cell lines was blocked by the inhibition of the MAPK pathway, which also blocked expression of cyclin D1. However, in resistant cell lines, proliferation was blocked by combined inhibition of the MAPK pathway and cyclin D3, which is not regulated by the MAPK pathway. Resistant cell lines also showed higher levels of p-GSK3β and less perturbation of the apoptotic profile upon the treatment in comparison with the sensitive cell lines. The combination of PRi + MEKi can be an effective regimen for blocking proliferation of NRAS mutant melanomas when there is higher activity of the MAPK pathway and dependence of proliferation and survival on this pathway.
Understanding What We See: How We Derive Meaning From Vision
Authors: Alex Clarke, Lorraine K. Tyler
Journal: Trends in Cognitive Sciences (2015)

TrendsWe view object recognition as a dynamic process of transformation from low-level visual analyses through superordinate category to basic-level conceptual representations.Understanding this process is facilitated by using semantic cognitive models that can capture feature-based statistical regularities between concepts, providing both superordinate category and basic-level information.We highlight research using fMRI, MEG, and neuropsychological and behavioural testing to show how feature-based cognitive models can relate to object semantic representations in the ventral visual pathway.The posterior fusiform and perirhinal cortex are shown to process complementary aspects of object semantics.The temporal coordination between these regions is also highlighted, while superordinate category information precedes basic-level semantic information in time.AbstractRecognising objects goes beyond vision, and requires models that incorporate different aspects of meaning. Most models focus on superordinate categories (e.g., animals, tools) which do not capture the richness of conceptual knowledge. We argue that object recognition must be seen as a dynamic process of transformation from low-level visual input through categorical organisation to specific conceptual representations. Cognitive models based on large normative datasets are well-suited to capture statistical regularities within and between concepts, providing both category structure and basic-level individuation. We highlight recent research showing how such models capture important properties of the ventral visual pathway. This research demonstrates that significant advances in understanding conceptual representations can be made by shifting the focus from studying superordinate categories to basic-level concepts.
Lymphoid tumors displaying rearrangements of both immunoglobulin and T cell receptor genes.
Authors: P G Pelicci, D M Knowles, R Dalla Favera
Journal: The Journal of Experimental Medicine (1985)

Ig and T beta gene rearrangements can be used as genetic markers of lineage and clonality in the study of B and T cell populations. We have addressed the issue of the respective B and T lineage specificity of these rearrangements by analyzing a panel of 63 lymphoid tumors representative of the various clinicopathologic categories of both B and T neoplasias. We report that approximately 10% of the cases tested displayed rearrangements of both Ig and T beta genes. Despite their dual genotypic pattern, these tumors retain a pure immunophenotype, i.e. they display either B or T cell lineage-restricted cell surface antigens. The implications of these findings for both normal and neoplastic lymphoid differentiation are discussed.
Propagation of dendritic cell progenitors from normal mouse liver using granulocyte/macrophage colony-stimulating factor and their maturational development in the presence of type-1 collagen.
Authors: L Lu, J Woo, A S Rao, Y Li, S C Watkins, S Qian, T E Starzl, A J Demetris, A W Thomson
Journal: The Journal of Experimental Medicine (1994)

Within 1 wk of liquid culture in granulocyte/macrophage colony-stimulating factor (GM-CSF), normal B10 BR (H-2k I-E+) mouse liver nonparenchymal cells (NPC) formed loosely adherent myeloid cell clusters that have been shown to contain dendritic cell (DC) progenitors in similar studies of mouse blood or bone marrow. Mononuclear cell progeny released from these clusters at and beyond 4 d exhibited distinct dendritic morphology and were actively phagocytic. After 6-10 d of culture, these cells strongly expressed CD45, CD11b, heat stable antigen, and CD44. However, the intensity of expression of the DC-restricted markers NLDC 145, 33D1, and N418, and the macrophage marker F4/80, intercellular adhesion molecule 1, and Fc gamma RII was low to moderate, whereas the cells were negative for CD3, CD45RA, and NK1.1. Splenocytes prepared in the same way also had a similar range and intensity of expression of these immunophenotypic markers. Unlike the splenic DC, however, most of the GM-CSF-propagated putative liver DC harvested at 6-10 d expressed only a low level of major histocompatibility complex (MHC) class II (I-Ek), and they failed to induce primary allogeneic responses in naive T cells, even when propagated additionally in GM-CSF and tumor necrosis alpha and/or interferon gamma-supplemented medium. However, when 7-d cultured GM-CSF-stimulated liver cells were maintained additionally for three or more days on type-1 collagen-coated plates in the continued presence of GM-CSF, they exhibited characteristics of mature DC: MHC class II expression was markedly upregulated, mixed leukocyte reaction stimulatory activity was increased, and phagocytic function was decreased. Similar observations were made when Ia+ cells were depleted from the GM-CSF-propagated cells before exposure to collagen. Further evidence that the GM-CSF-stimulated class IIdim or class II-depleted hepatic NPC were immature DC was obtained by injecting them into allogeneic B10 (H-2b I-E-) recipients. They "homed" to T cell-dependent areas of lymph nodes and spleen where they strongly expressed donor MHC class II antigen 1-5 d later. These observations provide insight into the regulation of DC maturation, and are congruent with the possibility that the migration of immature DC from normal liver and perhaps other organ allografts may help explain their inherent tolerogenicity.
Sporadic adenoma in ulcerative colitis: endoscopic resection is an adequate treatment
Authors: M Vieth
Journal: Gut (2005)

In studies with small numbers of cases, it has been shown that endoscopic resection of adenomas in ulcerative colitis represents adequate treatment. In a larger study cohort with more prolonged follow up, we assessed the reliability of this finding.Between 1988 and 2002, 148 consecutive patients, mainly from private gastroenterologists' practices, with ulcerative colitis were diagnosed as having an adenoma. In 60 patients, histological diagnosis was established in biopsies and in 87 patients in polypectomy specimens; one patient underwent proctocolectomy following diagnosis. The outcome of these patients was analysed after a mean follow up period of 6.0 (3.63) years.Among 60 patients, surprisingly without endoscopic treatment, 48.3% developed ulcerative colitis associated neoplasia in the same colon segment (23.3% low grade intraepithelial neoplasia; 8.3% high grade intraepithelial neoplasia; 16.7% carcinoma). Among 87 patients undergoing polypectomy of the adenoma, follow up revealed colitis associated neoplasia in other segments of colon in 4.6% of cases.Development of adenocarcinomas in a total of 6.7% of the overall patient group, and in 2.3% of those undergoing polypectomy, indicates that biopsy based diagnosis of an adenoma in ulcerative colitis must be considered to mandate endoscopic resection of the lesion; 40% of affected patients did not receive any form of endoscopic removal of the lesion. This shows that the most recent guidelines are not followed in a considerable number of patients with ulcerative colitis in private practice in Germany. Although polypectomy of the adenoma represents adequate therapy, further regular follow up examinations are nevertheless necessary.
Towards an operational definition of sports concussion: identifying a limitation in the 2012 Zurich consensus statement and suggesting solutions
Authors: Kenneth Lincoln Quarrie, Ian Robert Murphy
Journal: British Journal of Sports Medicine (2014)

A fundamental precept in managing injury risks1 and preventing injuries2 ,3 is that the size of the injury issue needs to be well established. The size, or importance, of the particular injury issue depends on factors such as the injury incidence (how many injuries occur per participant per unit of exposure) and severity (eg, typical degree and duration of impairment; costs associated with the injury).3 The most common means of measuring the size of an injury issue is via an injury surveillance system, by which all injuries meeting some predetermined criteria are counted.

To understand the size of an injury issue, the injury being counted needs to be well defined. Theoretical definitions of injury specify what injuries ‘are’4; operational definitions of injury specify which injuries become cases, that is, how injuries can, or will, be counted in a given context.5–7

Although controversies remain about exactly what does and does not fall within a good theoretical definition of an injury,4 most definitions include some reference to an abnormal transfer of energy, and the resulting outcome(s). Theoretical definitions of injury are helpful in providing a conceptual framework by which to consider injuries, however, they leave open the question of operationalising the definition for the purposes of injury surveillance, and subsequent risk management and injury prevention initiatives. It is for this reason that various sports medicine groups have produced ‘injury definitions’ guidelines specifying which events meet the criteria for inclusion in injury counts.6 ,8

The Zurich Consensus Statement on Concussion (hereafter referred to as the Zurich Guidelines) provides a relatively clear theoretical definition of concussion.9 The concept of a transfer of injury resulting in some physical change is reflected in the Zurich Guidelines. To paraphrase, the Zurich Guidelines specify that concussion is …
Prediction of Type 2 Diabetes Using Alternate Anthropometric Measures in a Multi-Ethnic Cohort
Authors: Meredith F. MacKay, Steven M. Haffner, Lynne E. Wagenknecht, Ralph B. D'Agostino, Anthony J.G. Hanley
Journal: Diabetes Care (2009)

OBJECTIVE To compare different anthropometric measures in terms of their ability to predict type 2 diabetes and to determine whether predictive ability was modified by ethnicity. RESEARCH DESIGN AND METHODS Anthropometry was measured at baseline for 1,073 non-Hispanic white (nHW), African American (AA), and Hispanic (HA) subjects, of whom 146 developed type 2 diabetes after 5.2 years. Logistic regression models were used with areas under the receiver operator characteristic curve (AROCs) comparing the prediction of models. RESULTS Waist-to-height ratio (AROC 0.678) was the most predictive measure, followed by BMI (AROC 0.674). Results were similar in nHW and HA subjects, although in AA subjects, central adiposity measures appeared to best predict type 2 diabetes. CONCLUSIONS Measures of central and overall adiposity predicted type 2 diabetes to a similar degree, except in AA subjects, for whom results suggested that central measures were more predictive.
PIPKIγ Regulates β-Catenin Transcriptional Activity Downstream of Growth Factor Receptor Signaling
Authors: Mark Schramp, Narendra Thapa, Jessica Heck, Richard Anderson
Journal: Cancer Research (2011)

Increased β-catenin transcriptional activity downstream of the Wnt/Wingless signaling pathway has been observed in many human tumors, most notably colorectal carcinomas. However, β-catenin activation is also observed in many human malignancies with no observable Wnt activity. Wnt-independent pathways that activate β-catenin remain undefined, yet have the potential to play a significant role during tumorigenesis. Here, we report that phosphotidylinositol phosphate kinase Iγ (PIPKIγ), an enzyme that generates phosphoinositide messengers in vivo, directly associates with β-catenin and increases β-catenin activity downstream of growth factor stimulation. PIPKIγ expression and kinase activity enhance β-catenin phosphorylation on residues that promote nuclear importation and transcriptional activity. Lastly, we show that β-catenin is required for PIPKIγ-dependent increased cell proliferation. These results reveal a novel mechanism in which PIPKIγ expression and catalytic activity enhance β-catenin nuclear translocation and expression of its target genes to promote tumorigenic phenotypes.
RED CELL STROMA PROTEIN RICH IN VITAMIN B12 DURING ACTIVE REGENERATION
Authors: G. H. Whipple, F. S. Robscheit-Robbins, W. F. Bale
Journal: The Journal of Experimental Medicine (1955)

During active blood regeneration in anemia in dogs an increase occurs in the stroma protein of the red cells. When vitamin B(12) with radioactive cobalt is given at the start of this blood regeneration one finds concentration of labeledB(12)in the stroma protein but not in the hemoglobin. After the acute phase of red cell regeneration is ended the concentration of B(12) in stroma protein falls rapidly to very low levels within 2 weeks. Subsequent episodes of red blood cell regeneration seems not to cause remobilization of radioactive cobalt into red cells from other body stores. It appears that the vitamin B(12) is a factor of importance in the first steps of stroma protein formation in the first few days of the life of the red cell in the dog. This response in dogs and the response in pernicious anemia to vitamin B(12) may have some points in common. Distribution of the B(12)-radioactive cobalt in the organs and tissues at autopsy has been recorded. Some very suggestive localizations were noted and some variation 1 week and 7 weeks after B(12) injections. Radioactive cobalt escapes in the urine during the weeks following B(12) injections.
Acute neurological toxicity (NT) and long-term outcomes in high-grade glioma RTOG trials.
Authors: Y. R. Lawrence, M. Wang, A. Dicker, D. W. Andrews, W. J. Curran, J. M. Michalski, L. Souhami, W. A. Yung, M. P. Mehta
Journal: Journal of Clinical Oncology (2010)

2037 Background: Treatment of high-grade glioma consists of fractionated radiation therapy (RT) ± chemotherapy. The incidence/significance of NT in this disease is not known. We evaluated the relationship between acute and chronic NT, and ultimate outcome, as well as risk factors for NT from the RTOG database. Methods: Acute (≤ 90 days of RT start) and late (> 90 days) NT events ≥ grade 3 were analyzed amongst 2,761 patients from 14 RTOG RT glioma studies, accrued from 1983-2003. Scoring schema used were RTOG Acute Morbidity Scoring Criteria, RTOG/EORTC Late Radiation Morbidity Scoring Schema and NCI–CTC version 2.0. The incidence of acute and late NT, the risk factors for these, correlation between acute and late NT, and eventual outcome were analyzed. Statistical methods included Chi squared test, McNemar's test, logistic regression, and Cox proportional hazards model. Two sided test was used, significance level 0.05. Results: Of 2610 analyzable patients 86% had glioblastoma, and 10% anaplastic astrocytoma. All received a systemic agent during RT (78% BCNU, 5% thalidomide, 5% tirapazamine, 12% other agents). Median RT dose: 60 Gy. There were 182 acute and 83 late NT events. On univariate analysis age > 50, poor performance status, more aggressive surgery, poor neurological function, poor mental function and twice daily RT were associated with increased acute NT. All these variables, except age, were also associated with acute NT on multivariate analysis. There was a statistically significant correlation between acute and chronic NT (p < 0.0001). In a step-wise logistic regression model considering once daily RT, use of chemotherapy, total RT dose (BED) and acute NT, the occurrence of acute NT was significantly associated with late NT (OR = 2.48; 95% CI = 1.2-5.0; p = 0.01). The presence of acute NT (HR = 1.43; 95% CI [1.2, 1.7]; p < 0.0001) was also found to predict poor overall survival, independent of RPA class (median survival 7.8 vs. 11.8 months). Conclusions: Acute NT is significantly associated with both chronic NT and overall survival. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from the NCI. This abstract's contents are the sole responsibility of the authors and do not necessarily represent the official views of the NCI. No significant financial relationships to disclose.
Fluorescently labeled mesenchymal stem cells (MSCs) maintain multilineage potential and can be detected following implantation into articular cartilage defects
Authors: Joseph Quintavalla, Susan Uziel-Fusi, Jianyun Yin, Ernst Boehnlein, Gary Pastor, Vincent Blancuzzi, Hem N Singh, Karl H Kraus, Elizabeth O’Byrne, Theodore C Pellas
Journal: Biomaterials (2002)
Blue Journal Conference. Aging and Susceptibility to Lung Disease
Authors: Victor J. Thannickal, Mahadev Murthy, William E. Balch, Navdeep S. Chandel, Silke Meiners, Oliver Eickelberg, Moisés Selman, Annie Pardo, Eric S. White, Bruce D. Levy, Paula J. Busse, Rubin M. Tuder, Veena B. Antony, Jacob I. Sznajder, G. R. Scott Budinger
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

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