tbuckley/cabot-search huggingface dataset:
High-throughput RNA interference screening using pooled shRNA libraries and next generation sequencing
Authors: David Sims, Ana M Mendes-Pereira, Jessica Frankum, Darren Burgess, Maria-Antonietta Cerone, Cristina Lombardelli, Costas Mitsopoulos, Jarle Hakas, Nirupa Murugaesu, Clare M Isacke, Kerry Fenwick, Ioannis Assiotis, Iwanka Kozarewa, Marketa Zvelebil, Alan Ashworth, Christopher J Lord
Journal: Genome biology (2011)

Abstract RNA interference (RNAi) screening is a state-of-the-art technology that enables the dissection of biological processes and disease-related phenotypes. The commercial availability of genome-wide, short hairpin RNA (shRNA) libraries has fueled interest in this area but the generation and analysis of these complex data remain a challenge. Here, we describe complete experimental protocols and novel open source computational methodologies, shALIGN and shRNAseq, that allow RNAi screens to be rapidly deconvoluted using next generation sequencing. Our computational pipeline offers efficient screen analysis and the flexibility and scalability to quickly incorporate future developments in shRNA library technology.
Magnetic resonance imaging of cardiac transplants: the evaluation of rejection of cardiac allografts with and without immunosuppression.
Authors: T Aherne, D Tscholakoff, W Finkbeiner, U Sechtem, N Derugin, E Yee, C B Higgins
Journal: Circulation (1986)

The purpose of this study was to evaluate the potential of magnetic resonance imaging (MRI) in vivo for the characterization of tissue changes associated with acute myocardial rejection after cardiac transplantation. Of 15 dogs that underwent heterotopic cardiac transplantation, six served as untreated controls, and nine received immunosuppressive therapy (25 mg/kg/day cyclosporine, 1 mg/kg/day prednisone). Serial electrocardiographically gated MRI (spin-echo technique) and histologic examinations of allograft biopsy samples were performed for each dog at 2 to 3, 7 to 10, 14 to 17, and 26 to 29 days after transplantation and immediately after animals were killed. Untreated allografts showed a significant increase (p less than .01) in T2 (spin-spin) relaxation time (T2 = 66 +/- 8 msec) and intensity values compared with values in the native hearts (T2 = 44 +/- 6 msec) as early as 1 week after transplantation. The significant difference in T2 values could be observed in vivo as well as on postmortem examination and corresponded to histologic progression of the rejection process. There was no significant difference in T1, T2, or intensity values in cyclosporine-treated allografts and native hearts except in two dogs in which T2 relaxation times and signal intensity in the transplanted hearts increased simultaneously with histologic evidence of rejection, indicating failure of immunosuppressive therapy. There was a significant correlation between histologic grading of severity of rejection and T2 relaxation times of the cardiac transplants (r = .72). Likewise, there was a significant linear relationship between T2 values in vivo and percent water content when the differences between native hearts and allografts were compared (r = .92, p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Abnormal Lipoprotein Lipase in Familial Exogenous Hypertriglyceridemia
Authors: Paul H. Schreibman, Daniel L. Arons, Christopher D. Saudek, Ronald A. Arky
Journal: Journal of Clinical Investigation (1973)

A 5-yr old male proband and his sister have had hypertriglyceridemia and hepatosplenomegaly since birth. When studied on a metabolic ward, they demonstrated rapid decreases in serum triglycerides on 3 g fat/day diets. Oral glucose tolerance tests were normal. Postheparin lipolytic activity (PHLA) against chylomicrons was virtually absent in both children whereas the mother and a normolipemic sister had levels approximately 50% normal. However, all four had a normal PHLA against commercial triglyceride emulsion (Intralipid). Two unrelated children from different kindreds of typical type 1 hyperlipoproteinemia and two patients with acquired type V hyperlipoproteinemia had deficient PHLA against both substrates. No inhibitors of PHLA could be demonstrated in the proband's plasma, and his own PHLA could not be enhanced by either normal concentrated plasma or pooled d > 1.063 lipoprotein fraction. The proband's postheparin plasma required almost 20 times the normal chylomicron-triglyceride concentration to reach one-half maximal lipase velocity. Both affected siblings showed heavy pre-beta lipoprotein electrophoretic bands plus chylomicrons in their fasting plasmas while ingesting a 33% carbohydrate, 30% fat diet. Incubation of their postheparin plasma with S(f) > 400 chylomicrons in vitro produced a smaller S(f) 20-400 "remnant" with pre-beta electrophoretic mobility that was not seen under the same conditions when normal postheparin plasma was used. Postheparin monoglyceridase and phospholipase activities were either normal or only moderately decreased when determined with appropriate artificial substrates. These data are consistent with either (a) a mutant gene producing a lipoprotein lipase with unusual substrate specificities or (b) an absolute deficiency of normal lipoprotein lipase with a compensatory increase in some other postheparin triglyceridase.
Effects of Cortisone Administration on the Metabolism and Localization of 25-Hydroxycholecalciferol in the Rat
Authors: Murray J. Favus, Daniel V. Kimberg, Gail N. Millar, Elaine Gershon
Journal: Journal of Clinical Investigation (1973)

Glucocorticoid administration is known to decrease calcium absorption in vivo and the vitamin D-dependent active transport of calcium by rat duodenum in vitro. The basis for this antivitamin D-like effect of glucocorticoids is unclear. Previous studies in the rat failed to demonstrate an effect of glucocorticoid treatment on the hepatic conversion of the parent vitamin to 25-hydroxycholecalciferol (25-HCC). Moreover, pharmacologic doses of 25-HCC did not restore intestinal calcium transport to normal. The results of these experiments suggested that if indeed glucocorticoids interfere with the metabolism of vitamin D, the step involved must be subsequent to 25-hydroxylation. The present studies demonstrate that the administration of cortisone to vitamin D-deficient rats does not affect the rate of conversion of a physiologic dose of [(3)H]25-HCC to the biologically important metabolite, 1,25-dihydroxycholecalciferol (1,25-DHCC). Furthermore, pretreatment with glucocorticoids affects neither the tissue distribution nor the subcellular localization on or in intestinal mucosal cell nuclei of 1,25-DHCC. Of note is the fact that 1,25-DHCC is currently considered to be the "tissue-active" form of the vitamin in the intestine. Whereas tissues from cortisone-treated animals had increased concentrations of the biologically less active 24,25-DHCC, the physiologic significance of this observation remains unclear. The results of the present studies strongly support the concept that the antivitamin D-like effects of glucocorticoids in the intestine are due to hormonal influences on the biochemical reactions responsible for calcium transport. While the effects of these hormones are opposite in direction to those of vitamin D, they occur by a mechanism that is independent of a direct interaction with either the vitamin or its biologically active metabolites.
The Biological Basis and Measurement of Thresholds
Authors: W N Aldridge
Journal: The Annual Review of Pharmacology and Toxicology (1986)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Extracellular adenosine levels and cellular energy metabolism in ischemically preconditioned rat heart
Authors: Glenn J. Harrison, Roger J. Willis, John P. Headrick
Journal: Cardiovascular Research (1998)

Objective: Microdialysis and 31P-NMR spectroscopy were used to test opposing hypotheses that ischemic preconditioning inhibits adenine nucleotide degradation and purine efflux, or that preconditioning activates cardiovascular adenosine formation to provide enhanced cardioprotection. Methods:31P-NMR spectra and matching interstitial fluid (ISF) or venous effluent samples were obtained from Langendorff perfused rat hearts. Control hearts (n=9) underwent 30 min of global normothermic ischemia and 30 min reperfusion. Preconditioned hearts (n=6) were subjected to a 5 min ischemic episode and 10 min reflow prior to 30 min ischemia and 30 min reperfusion. Effects of repetitive ischemia–reperfusion (3×5 min ischemic episodes) on adenosine levels and energy metabolism were also assessed (n=8). Results: Preconditioning improved post-ischemic recovery of heart rate x left ventricular developed pressure (71±5 vs 43±8%, P<0.05) and end-diastolic pressure (14±3 vs 29±4 mmHg, P<0.05) compared with control hearts, respectively. Preconditioning did not alter intracellular ATP, phosphocreatine (PCr), inorganic phosphate (Pi), H+ or free Mg2+ during global ischemia, but improved recoveries of PCr, Pi, and ΔGATP on reperfusion. ISF adenosine increased more than 20-fold during 30 min ischemia. The 5 min preconditioning episode increased ISF adenosine 3-fold, and reduced ISF adenosine and inosine during subsequent prolonged ischemia by up to 75%. Venous purine levels during reperfusion were also reduced by preconditioning. Accumulation of adenosine in ISF and venous effluent during repetitive ischemia was progressively reduced despite comparable changes in substrate for adenosine formation via 5′-nucleotidase (5′-AMP), and in allosteric modulators of this enzyme (Mg2+, H+, Pi, ADP, ATP). Conclusions: (i) Ischemic preconditioning reduces interstitial and vascular adenosine levels during ischemia–reperfusion, (ii) reduced ISF adenosine during ischemia is not due to reduced ischemic depletion of adenine nucleotides in preconditioned rat hearts, (iii) preconditioning may inhibit adenosine formation via 5′-nucleotidase in ischemic rat hearts, and (iv) improved functional recovery with preconditioning is unrelated to metabolic/bioenergetic changes during the ischemic insult, but may be related to improved post-ischemic recovery of [Pi] and ΔGATP in this model.
Influenza Viruses and Cell Membranes
Authors: J. J. Skehel, D. C. Wiley
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Influenza viruses are spherical, about 1000 À in diameter, and consist of an as yet undefined central structure containing the eight negative-sense RNA molecules of the genome (1) in association with the transcriptase required for mRNA synthesis, an abundant nucleoprotein, and an equally abundant matrix protein. This core is surrounded by a membrane derived from the cell surface in a budding process by which newly formed viruses are released from the infected cell. During infection cell membranes are modified by the incorporation of newly synthesized virus membrane proteins, and the finally released viruses contain exclusively two different types of virus-specified glycoprotein, hemagglutinin and neuraminidase, and a proton channel protein, M2. All three of these molecules have been studied extensively, particularly the glycoproteins, and in this paper information on their structures and functions will be summarized and related to modifications in cellular membranes that occur during virus infection. Skehel JJ, Wiley DC. Influenza viruses and cell membranes.
Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1
Authors: Nils Schallner, Rambhau Pandit, Robert LeBlanc, Ajith J. Thomas, Christopher S. Ogilvy, Brian S. Zuckerbraun, David Gallo, Leo E. Otterbein, Khalid A. Hanafy
Journal: Journal of Clinical Investigation (2015)

Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.
Safety of medicine and the use of animals in research
Authors: Kathy Archibald, Anthony D Baxter, Kelly BéruBé, David Bunton, Margaret Clotworthy, Bob Coleman, Christopher S Foster, Chris Hillier, Morag McFarlane, Anup Patel, Barbara Pierscionek, James Root, Gerry Thomas, Katya Tsaioun, J Malcolm Wilkinson, Ian Wilmut, Karen L Wright
Journal: The Lancet (2011)
The role of transcription factor PAX-5 (BSAP) in asthma severity and in the activity of allergic inflammation
Authors: Valeriy Mineev, Lada Sorokina, Michael Nyoma, Georgiy Lipkin, Valeria Lim, Anna Eremeeva, Yulia Malfygina, Vasiliy Ivanov, Vasiliy Trofimov
Journal: European Respiratory Journal (2012)

PAX-5 is transcription factor of B-cell, which is crucial in asthma pathogenesis.  The aim is to evaluate PAX-5 role in allergic (AA) and non-allergic asthma (NAA).  Materials and methods. Peripheral blood lymphocytes from 107 asthma patients and 22 healthy were examined. Part of lymphocytes was analyzed after 24h incubation with and without IL-4 10 ng/ml. To estimate PAX-5 and CHe (constant parts of IgE heavy chains) mRNA semi-quantitive RT-PCR was performed.  Results: PAX-5 mRNA levels were significantly increased in patients with NAA in comparison with healthy (p=0,018) and AA patients (p=0,03) (U-crit.). We revealed important positive correlations of PAX-5 with CHe which were stronger in patients with normal and low serum IgE (≤150 MU/ml) than in patients with high serum IgE levels (>150 MU/ml) (r=0,543; p  Significant decrease of mRNA PAX-5 was registered in lymphocytes from AA patients after 24h IL-4 action (p=0,046; n=13, W-crit.). This decrease was not significant in healthy (p=0,345; n=5, W-crit.).  Conclusion: We revealed the association of PAX-5 and NAA development. It may be explained by fact of PAX-5 prolonging B-cell life and its functioning as antigen-presenting cell. In patients with AA PAX-5 may be considered as protective factor. IL-4 may influence PAX-5 expression through the pathways which are involved in asthma pathogenesis (e.g. STAT6 signaling).  The work was supported by Saint-Petersburg government grant (No. 4/04-05/1-A).
Circulating Immune Complexes in 50-Year-Old Men as a Strong and Independent Risk Factor for Myocardial Infarction
Authors: Awder Mustafa, Soniya Nityanand, Lars Berglund, Hans Lithell, Ann Kari Lefvert
Journal: Circulation (2000)

Background —Circulating immune complexes (CICs) and autoantibodies against oxidatively modified LDLs (oxLDLs) and cardiolipin occur in patients with atherosclerosis and myocardial infarction (MI). The ability of such CICs and antibodies to predict myocardial infarction (MI) was investigated in a prospective nested case-control study in which healthy 50-year-old men were followed for 20 years. Methods and Results —Two hundred fifty-seven men were included in the study, and 119 developed MI (39 died) between 50 and 70 years of age. One hundred thirty-eight randomly chosen men who did not develop MI up to 70 years of age served as controls. The prevalence of elevated levels of CICs and the concentration of CICs in men who developed MI were higher than in those who remained healthy. The concentration of CICs at age 50 was associated with a marked increased risk for MI, and this risk was independent of other conventionally recognized risk factors. There was a positive correlation between the levels of CIC and IgG antibodies to cardiolipin in men who developed MI. The level of IgG antibodies and the prevalence of elevated IgG and IgM antibodies to cardiolipin were higher in those who developed MI and had CICs than in those without CICs. Among men homozygous for C4 null alleles, those who developed MI had higher concentrations of CICs than did those who remained healthy. Conclusions —This prospective study shows that CICs alone or in combination with autoantibodies against cardiolipin in healthy males at 50 years of age predict subsequent MI between the age of and 70 years.
Immunologic Phenomena in Burn Injuries
Authors: J. Wesley Alexander
Journal: JAMA (1967)

Bacterial infections continue to cause more deaths following severe thermal injury than any other single factor, and a depression of the defense mechanism is felt by many to contribute significantly to this apparent increased susceptibility to infection. An important part of the overall host defense mechanism is the ability to produce specific antibody in response to an antigenic stimulus. This aspect has been studied incompletely following thermal injury, even though both active and passive immunity to certain bacteria have been shown to prevent progressive bacterial invasion in burn wounds and surgical wounds of experimental animals. Alexander and co-workers<sup>1</sup>have been able to induce good protection against infection by<i>Pseudomonas aeruginosa</i>by immunization with a purified extract of the organism. Feller et al,<sup>2</sup>Walker et al,<sup>3</sup>and McMeel et al<sup>4</sup>obtained similar protection with whole cell vaccines to a single strain of<i>Pseudomonas</i>. Jones and Luwbury<sup>5</sup>
The origin of language as a product of the evolution of double-scope blending
Authors: Gilles Fauconnier, Mark Turner
Journal: Behavioral and Brain Sciences (2008)

Abstract Meaning construction through language requires advanced mental operations also necessary for other higher-order, specifically human behaviors. Biological evolution slowly improved conceptual mapping capacities until human beings reached the level of double-scope blending, perhaps 50 to 80 thousand years ago, at which point language, along with other higher-order human behaviors, became possible. Languages are optimized to be driven by the principles and powers of double-scope blending.
The role of p27kip1 protein expression on the biological behavior of intrahepatic cholangiocarcinoma
Authors: Ken-Ichi Taguchi, Shin-Ichi Aishima, Yoshiki Asayama, Kiyoshi Kajiyama, Naoko Kinukawa, Mitsuo Shimada, Keizo Sugimachi, Masazumi Tsuneyoshi
Journal: Hepatology (2001)

Recent studies have reported that a decreased p27kip1 protein (p27) expression is associated with aggressive tumor behavior in several human malignancies. In this study, we examined the role of p27 expression in intrahepatic cholangiocarcinoma (ICC) and the noncancerous intrahepatic bile duct epithelium and assessed its association with clinicopathologic features, especially the influence of decreased p27 expression by the tumor on its prognosis as determined by immunohistochemistry. Almost all noncancerous bile duct epithelia show positive nuclear staining and reveal a faintly positive reaction in the cytoplasm. In 62 surgically resected ICCs, a variable degree of positive p27 nuclear staining is recognized. A subset (13 of 62 cases; 21.0%) of the carcinomas displayed cytoplasmic staining. We classified 62 cases into 2 groups, a low expression group (< 50% of p27 nuclear positive cells) and a high expression group (> or = 50% of p27 nuclear positive cells), and tested for the association between positive expression and clinicopathologic features. We found that a low expression of nuclear p27 was correlated with positive vascular invasion (P < .05). The survival curve of the group with low p27 nuclear expression was significantly lower than that of the group with high p27 nuclear expression (P < .005). According to the multivariate analyses, low p27 expression can be considered an independent prognostic factor whose occurrence indicates a worse prognosis. We conclude that a decreased p27 expression adds an independent parameter that can be used when determining the prognosis of patients with ICC.
Fusion genes with<i>ALK</i>as recurrent partner in ependymoma-like gliomas: a new brain tumor entity?
Authors: Thale Kristin Olsen, Ioannis Panagopoulos, Torstein R. Meling, Francesca Micci, Ludmila Gorunova, Jim Thorsen, Bernt Due-Tønnessen, David Scheie, Marius Lund-Iversen, Bård Krossnes, Cathrine Saxhaug, Sverre Heim, Petter Brandal
Journal: Neuro-Oncology (2015)

BackgroundWe have previously characterized 19 ependymal tumors using Giemsa banding and high-resolution comparative genomic hybridization. The aim of this study was to analyze these tumors searching for fusion genes.
Randomized, Placebo-Controlled Trial of Olanzapine as Maintenance Therapy in Patients With Bipolar I Disorder Responding to Acute Treatment With Olanzapine
Authors: Mauricio Tohen, Joseph R. Calabrese, Gary S. Sachs, Michael D. Banov, Holland C. Detke, Richard Risser, Robert W. Baker, James C.-Y. Chou, Charles L. Bowden
Journal: American Journal of Psychiatry (2006)

In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder.Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score < or =12 and 21-item Hamilton Depression Rating Scale [HAM-D] score <or =8) at two consecutive weekly visits following 6-12 weeks of open-label acute treatment with 5-20 mg/day of olanzapine were randomly assigned to double-blind maintenance treatment with olanzapine (N=225) or placebo (N=136) for up to 48 weeks. The primary measure of efficacy was time to symptomatic relapse into any mood episode (YMRS score > or =15, HAM-D score > or =15, or hospitalization).Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2).Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.