tbuckley/cabot-search huggingface dataset:
Unconscious inference and conscious representation: Why primary visual cortex (V1) is directly involved in visual awareness
Authors: Zhicheng Lin
Journal: Behavioral and Brain Sciences (2008)

Abstract The extent to which visual processing can proceed in the visual hierarchy without awareness determines the magnitude of perceptual delay. Increasing data demonstrate that primary visual cortex (V1) is involved in consciousness, constraining the magnitude of visual delay. This makes it possible that visual delay is actually within the optimal lengths to allow sufficient computation; thus it might be unnecessary to compensate for visual delay. The time delay problem – that perception lives slightly in the past as a result of neural conduction – has recently attracted a considerate amount of attention in the context of the flash-lag effect. The effect refers to a visual illusion wherein a brief flash of light and a continuously moving object that physically align in space and time are perceived to be displaced from one another – the flashed stimulus appears to lag behind the moving object (Krekelberg &amp; Lappe 2001). In the target article, Nijhawan compellingly argues that delay compensation could be undertaken by a predictive process in the feedforward pathways in the vision system. Before jumping into the quest for the mechanism of delay compensation, however, I would like to argue that the magnitude of delay has been overestimated, and that it might even be unnecessary to compensate for such a delay.
Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation
Authors: S. Hodge, G. Hodge, M. Holmes, P. N. Reynolds
Journal: European Respiratory Journal (2005)

There is heterogeneity in the propensity of smokers to develop chronic obstructive pulmonary disease (COPD), and improved treatment strategies are hindered by limited understanding of COPD pathogenesis, especially as distinct from the effects of smoking per se . Although apoptosis is essential for tissue homeostasis, increased apoptosis may cause tissue damage and inflammation. This study addressed whether airway T-lymphocytes and airway epithelial cells (AEC) show an increased likelihood of undergoing apoptosis in COPD and if this was related to smoking. Apoptosis (7-amino-actinomycin D, Annexin, single-stranded DNA and caspase), Bcl-2, Bax and p53 were assessed in cells obtained from bronchial bushing and bronchoalveolar lavage from ex- and continuing smokers with COPD, and nonsmoking controls, using flow cytometry. A mean 87% increase in apoptosis of AEC and a 103% increase in T-lymphocyte apoptosis were found in COPD. There were no significant differences in apoptosis of AEC between current and ex-smokers with COPD. Apoptosis may contribute to chronic obstructive pulmonary disease pathogenesis, and continued excess apoptosis after smoking cessation may offer a new target for therapeutic interventions. Whether the persistence of increased apoptosis after smoking cessation results from changes in the pulmonary milleau after years of noxious insult, or whether some individuals have a natural predisposition toward increased apoptosis and possible development of chronic obstructive pulmonary disease remains to be determined.
The determinants of respiratory rate during mechanical ventilation.
Authors: D G Tobert, P M Simon, R W Stroetz, R D Hubmayr
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The independent and interactive effect of feedback related to volume, CO2, inspiratory flow, and arousal state on the regulation of respiratory rate in mechanically ventilated humans is not well characterized. We examined the rate response of eight normal volunteers during both quiet wakefulness and non-rapid-eye-movement (NREM) sleep, while mechanically ventilated through a nasal mask in an assist/control mode with a machine back-up rate of 2 breaths/min. Tidal volume (VT) was set slightly above spontaneous VT and then increased by 0.2 L every 3 min up to 1.8 L or 25 ml/kg. Either an inspiratory flow of 40 L/min or an inspiratory time of 2 s (iso-T(I)) was set, with CO2 added (F(I)CO2 > 0) or F(I)CO2 = 0. Measurements were made during both quiet wakefulness and NREM sleep. We found that as VT increased, the respiratory rate decreased; the rate decline was observed during wakefulness and sleep, and under isocapnic as well as hypocapnic conditions. Increasing inspiratory flow raised the respiratory rate during wakefulness and NREM sleep. During NREM sleep, hypocapnia resulted in wasted ventilator trigger efforts. In summary, both VT and inspiratory flow settings affect the respiratory rate, and depending on state, can affect CO2 homeostasis. Ventilator settings appropriate for wakefulness may cause ventilatory instability during sleep.
Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis
Authors: Dan Rosmarin, Claire Palles, David Church, Enric Domingo, Angela Jones, Elaine Johnstone, Haitao Wang, Sharon Love, Patrick Julier, Claire Scudder, George Nicholson, Anna Gonzalez-Neira, Miguel Martin, Daniel Sargent, Erin Green, Howard McLeod, Ulrich M. Zanger, Matthias Schwab, Michael Braun, Matthew Seymour, Lindsay Thompson, Benjamin Lacas, Valérie Boige, Nuria Ribelles, Shoaib Afzal, Henrik Enghusen, Søren Astrup Jensen, Marie-Christine Etienne-Grimaldi, Gérard Milano, Mia Wadelius, Bengt Glimelius, Hans Garmo, Milena Gusella, Thierry Lecomte, Pierre Laurent-Puig, Eva Martinez-Balibrea, Rohini Sharma, Jesus Garcia-Foncillas, Zdenek Kleibl, Alain Morel, Jean-Pierre Pignon, Rachel Midgley, David Kerr, Ian Tomlinson
Journal: Journal of Clinical Oncology (2014)

Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.
Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells
Authors: Nicole Grabinski, Florian Ewald, Bianca T Hofmann, Katharina Staufer, Udo Schumacher, Björn Nashan, Manfred Jücker
Journal: Molecular Cancer (2012)

Abstract Background Due to the frequent dysregulation of the PI3K/AKT/mTOR signaling pathway, mTOR represents a suitable therapeutic target in hepatocellular carcinoma (HCC). However, emerging data from clinical trials of HCC patients indicate that mTOR inhibition by RAD001 (Everolimus) alone has only moderate antitumor efficacy which may be due to the feedback activation of AKT after mTOR inhibition. In this study, we analyzed the effects of dual inhibition of mTOR and AKT on the proliferation of HCC cell lines. In addition, we measured the feedback activation of each of the AKT isoforms after mTOR inhibition in HCC cell lines and their enzymatic activity in primary samples from HCC patients. Methods The activation status of specific AKT isoforms in human HCC samples and corresponding healthy liver tissue was analyzed using an AKT isoform specific in vitro kinase assay. AKT isoform activation after mTOR inhibition was analyzed in three HCC cell lines (Hep3B, HepG2 and Huh7), and the impact of AKT signaling on proliferation after mTOR inhibition was investigated using the novel AKT inhibitor MK-2206 and AKT isoform specific knockdown cells. Results AKT isoforms become differentially activated during feedback activation following RAD001 treatment. The combination of mTOR inhibition and AKT isoform knockdown showed only a weak synergistic effect on proliferation of HCC cell lines. However, the combinatorial treatment with RAD001 and the pan AKT inhibitor MK-2206 resulted in a strong synergism, both in vitro and in vivo . Moreover, by analyzing primary HCC tissue samples we were able to demonstrate that a hotspot mutation (H1047R) of PI3KCA, the gene encoding the catalytic subunit of PI3K, was associated with increased in vitro kinase activity of all AKT isoforms in comparison to healthy liver tissue of the patient. Conclusion Our results demonstrate that dual targeting of mTOR and AKT by use of RAD001 and the pan AKT inhibitor MK-2206 does effectively inhibit proliferation of HCC cell lines. These data suggest that combined treatment with RAD001 and MK-2206 may be a promising therapy approach in the treatment of hepatocellular carcinoma.
Histone Deacetylase Inhibition Attenuates Transcriptional Activity of Mineralocorticoid Receptor Through Its Acetylation and Prevents Development of Hypertension
Authors: Hae-Ahm Lee, Dong-Youb Lee, Hyun-Min Cho, Sang-Yeob Kim, Yasumasa Iwasaki, In Kyeom Kim
Journal: Circulation Research (2013)

Inhibition of histone deacetylases (HDACs) results in attenuated development of hypertension in deoxycorticosterone acetate-induced hypertensive rats and spontaneously hypertensive rats. However, the molecular mechanism remains elusive.We hypothesized that HDAC inhibition attenuates transcriptional activity of mineralocorticoid receptor (MR) through its acetylation and prevents development of hypertension in deoxycorticosterone acetate-induced hypertensive rats.Expression of MR target genes was measured by quantitative real-time polymerase chain reaction. Recruitment of MR and RNA polymerase II on promoters of target genes was analyzed by chromatin immunoprecipitation assay. Live cell imaging was performed for visualization of nuclear translocation of MR. MR acetylation was determined by Western blot with anti-acetyl-lysine antibody after immunoprecipitation with anti-MR antibody. Transcriptional activity of MR was determined by luciferase assay. For establishment of a hyperaldosteronism animal, Sprague-Dawley rats underwent uninephrectomy and received subcutaneous injection of 40 mg/kg per week of deoxycorticosterone acetate and drinking water containing 1% NaCl. Treatment with a HDAC class I inhibitor resulted in reduced expression of MR target genes in accordance with reduced recruitment of MR and RNA polymerase II on promoters of target genes. HDAC inhibition promoted MR acetylation, leading to decreased transcriptional activity of MR. Knockdown or inhibition of HDAC3 resulted in reduced expression of MR target genes induced by mineralocorticoids.These results indicate that HDAC inhibition attenuates transcriptional activity of MR through its acetylation and prevents development of hypertension in deoxycorticosterone acetate-induced hypertensive rats.
Chronically Depressed Mood and Cancer Risk in Older Persons
Authors: B. W. J. H. Penninx, J. M. Guralnik, R. J. Havlik, M. Pahor, L. Ferrucci, J. R. Cerhan, R. B. Wallace
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Depression has been proposed as a predisposing factor for cancer, but prospective studies have been inconclusive. We examined whether a high level of depressive symptoms, present for a long time, is associated with increased risk of cancer in the elderly. Methods: Data were obtained and analyzed from persons who lived in three communities (Massachusetts, Iowa, and Connecticut) of the Established Populations for Epidemiologic Studies of the Elderly, a prospective cohort study with a mean follow-up of 3.8 years that included 4825 persons (1708 men and 3117 women) aged 71 years and older. Chronically depressed mood was defined as present when the number of depressive symptoms exceeded specific cut points on the Center for Epidemiologic Studies-Depression scale at baseline (1988) and 3 and 6 years before baseline. New cases of cancerwere identified from Medicare hospitalization records and death certificates. Results: Of the 4825 persons studied, 146 (3.0%) were chronicallydepressed. The incidence rate of cancer was 30.5 per 1000 person-years for the 146 persons with chronic depression and 21.9 per 1000 person-years for the4679 nonchronically depressed persons. After adjustment for age, sex, race, disability, hospital admissions, alcohol intake,and smoking, the hazard ratio for cancer associated with chronically depressed mood was 1.88 (95% confidence interval = 1.13–3.14). The excess risk of cancer associated with chronic depression was consistent for most types of cancer and was not specific tocigarette smokers. Conclusion: When present for at least 6 years, depression was associated with a generally increased risk of cancer. [J Natl CancerInst 1998;90:1888-93]
Tofacitinib, a JAK inhibitor, inhibits human B cell activation in vitro
Authors: Sheau-Pey Wang, Shigeru Iwata, Shingo Nakayamada, Kei Sakata, Kunihiro Yamaoka, Yoshiya Tanaka
Journal: Annals of the Rheumatic Diseases (2014)

B cells initiate and perpetuate autoimmune disease processes. Interleukin (IL)-4 and IL-21 produced by follicular helper T cells are required for B cell activation, germinal centre formation, immunoglobulin class switching and plasma cell differentiation.1 ,2 The JAK inhibitor tofacitinib is approved for treatment of rheumatoid arthritis. We recently reported that tofacitinib can suppress IL-17 and interferon-γ production by CD4+ T cells3 and inhibit the T cell stimulatory capacity of human monocyte-derived dendritic cells.4 However, whether this action involves B cell activation remains unclear.

Here we investigated the in vitro effects of tofacitinib on the gene regulatory network that controls B cell class switching and differentiation. Purified CD19+ B cells were stimulated with B cell antigen receptor (BCR), soluble CD40 ligand (sCD40L) and cytokines with/without tofacitinib. Culture medium was replenished on day 3. Cell viability tests revealed that, although B cell survival decreased considerably over time, the possibility of pharmacological toxicity by tofacitinib could be excluded (data not shown).

The expression of AICDA was slightly induced by cytokines or BCR/sCD40L alone, while costimulation with BCR, sCD40L and cytokines, especially IL-4, caused robust gene expression (figure 1A). BCL6 and XBP-1 exhibited similar expression patterns, …
Antiproliferative effect of exemestane in lung cancer cells
Authors: Angelos Koutras, Efstathia Giannopoulou, Ismini Kritikou, Anna Antonacopoulou, TR Jeffry Evans, Athanasios Papavassiliou, Haralabos Kalofonos
Journal: Molecular Cancer (2009)

Recent evidence suggests that estrogen signaling may be involved in the pathogenesis of non-small cell lung cancer (NSCLC). Aromatase is an enzyme complex that catalyses the final step in estrogen synthesis and is present in several tissues, including the lung. In the current study we investigated the activity of the aromatase inhibitor exemestane in human NSCLC cell lines H23 and A549. Aromatase expression was detected in both cell lines. H23 cells showed lower protein and mRNA levels of aromatase, compared to A549 cells. Exemestane decreased cell proliferation and increased apoptosis in both cell lines, 48 h after its application, with A549 exhibiting higher sensitivity than H23 cells. Aromatase protein and mRNA levels were not affected by exemestane in A549 cells, whereas an increase in both protein and mRNA levels was observed in H23 cells, 48 h after exemestane application. Moreover, an increase in cAMP levels was found in both cell lines, 15 min after the administration of exemestane. In addition, we studied the effect of exemestane on epidermal growth factor receptor (EGFR) localization and activation. Exemestane increased EGFR activation 15 min after its application in H23 cells. Furthermore, we demonstrated a translocation of EGFR from cell membrane, 24 h after the addition of exemestane in H23 cells. No changes in EGFR activation or localization were observed in A549 cells. Our findings suggest an antiproliferative effect of exemestane on NSCLC cell lines. Exemestane may be more effective in cells with higher aromatase levels. Further studies are needed to assess the activity of exemestane in NSCLC.
Novel APC-like properties of human NK cells directly regulate T cell activation
Authors: Jacob Hanna, Tsufit Gonen-Gross, Jonathan Fitchett, Tony Rowe, Mark Daniels, Tal I. Arnon, Roi Gazit, Aviva Joseph, Karoline W. Schjetne, Alexander Steinle, Angel Porgador, Dror Mevorach, Debra Goldman-Wohl, Simcha Yagel, Michael J. LaBarre, Jane H. Buckner, Ofer Mandelboim
Journal: Journal of Clinical Investigation (2004)

Initiation of the adaptive immune response is dependent on the priming of naive T cells by APCs. Proteomic analysis of unactivated and activated human NK cell membrane–enriched fractions demonstrated that activated NK cells can efficiently stimulate T cells, since they upregulate MHC class II molecules and multiple ligands for TCR costimulatory molecules. Furthermore, by manipulating antigen administration, we show that NK cells possess multiple independent unique pathways for antigen uptake. These results highlight NK cell–mediated cytotoxicity and specific ligand recognition by cell surface–activating receptors on NK cells as unique mechanisms for antigen capturing and presentation. In addition, we analyzed the T cell–activating potential of human NK cells derived from different clinical conditions, such as inflamed tonsils and noninfected and CMV-infected uterine decidual samples, and from transporter-associated processing antigen 2–deficient patients. This in vivo analysis revealed that proinflammatory, but not immune-suppressive, microenvironmental requirements can selectively dictate upregulation of T cell–activating molecules on NK cells. Taken together, these observations offer new and unexpected insights into the direct interactions between NK and T cells and suggest novel APC-like activating functions for human NK cells.
Morphologic Features of the Liver in Abetalipoproteinemia
Authors: Mark I. Avigan, Kamal G. Ishak, Richard E. Gregg, Jay H. Hoofnagle
Journal: Hepatology (1984)

Liver tissue of a newly diagnosed 30-year-old patient with abetalipoproteinemia was studied by light and electron microscopy. Despite accumulation of large quantities of lipid droplets in hepatocytes, the lobular architecture remained intact, and there was no fibrosis. Acanthocytes were readily identified in sinusoids by scanning electron microscopy. Profiles of rough endoplasmic reticulum, smooth endoplasmic reticulum and Golgi apparatus appeared normal by transmission electron microscopy. Lipid droplets were not bound to membranes and were not associated with the endoplasmic reticulum or Golgi apparatus. In abetalipoproteinemia, these morphological features are consistent with defective apolipoprotein B synthesis. This prevents assembly of lipoproteins that can be secreted through the normal intracellular communicating tubular network and, consequently, fat accumulates in the cytoplasm of the hepatocytes.
Amiloride Potentiation of Differentiation of Human Promyelocytic Cell Line HL-602
Authors: John Carlson, Frederick Dorey, Edward Cragoe, H. Phillip Koeffler
Journal: JNCI Journal of the National Cancer Institute (1984)

Cells of the human acute promyelocytic cell line HL-60 undergo differentiation when exposed to dimethyl sulfoxide (DMSO); in this report, amiloride, an inhibitor of passive intracellular Na+ flux, potentiated the DMSO-induced differentiation of HL-60 cells. This effect was seen at several concentrations of DMSO. Amiloride alone did not affect HL-60 differentiation. Various analogues of amiloride were tested for their ability to potentiate differentiation of HL-60 cells. The synergistic induction of myeloid differentiation by a membrane solvent (DMSO) and an Na+ transport inhibitor (amiloride) suggested membrane cation flux as being important in initiating differentiation.
Exercise at altitude
Authors: Craig Sharp
Journal: British Journal of Sports Medicine (2000)

Bone density in elderly womenEDITOR,-In the article by Rhodes et al 1 "EVects of one year of resistance training on the relation between muscular strength and bone density in elderly women", I was surprised to see no mention of HRT status in the women in the trial.Given the relatively small number of women taking part, surely this is quite an important variable?
P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface
Authors: Arnoldo Padilla, Joel L. Moake, Aubrey Bernardo, Chalmette Ball, Yongtao Wang, Maneesh Arya, Leticia Nolasco, Nancy Turner, Michael C. Berndt, Bahman Anvari, José A. López, Jing-Fei Dong
Journal: Blood (2003)
Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria
Authors: Constanza Solis, Gerardo I. Aizencang, Kenneth H. Astrin, David F. Bishop, Robert J. Desnick
Journal: Journal of Clinical Investigation (2001)

Congenital erythropoietic porphyria, an autosomal recessive inborn error of heme biosynthesis, results from the markedly deficient activity of uroporphyrinogen III synthase. Extensive mutation analyses of 40 unrelated patients only identified approximately 90% of mutant alleles. Sequencing the recently discovered erythroid-specific promoter in six patients with a single undefined allele identified four novel mutations clustered in a 20-bp region: (a) a –70T to C transition in a putative GATA-1 consensus binding element, (b) a –76G to A transition, (c) a –86C to A transversion in three unrelated patients, and (d) a –90C to A transversion in a putative CP2 binding motif. Also, a –224T to C polymorphism was present in approximately 4% of 200 unrelated Caucasian alleles. We inserted these mutant sequences into luciferase reporter constructs. When transfected into K562 erythroid cells, these constructs yielded 3 ± 1, 54 ± 3, 43 ± 6, and 8 ± 1%, respectively, of the reporter activity conferred by the wild-type promoter. Electrophoretic mobility shift assays indicated that the –70C mutation altered GATA1 binding, whereas the adjacent –76A mutation did not. Similarly, the –90C mutation altered CP2 binding, whereas the –86A mutation did not. Thus, these four pathogenic erythroid promoter mutations impaired erythroid-specific transcription, caused CEP, and identified functionally important GATA1 and CP2 transcriptional binding elements for erythroid-specific heme biosynthesis.
Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs
Authors: Martina Krüger, Sebastian Kötter, Anika Grützner, Patrick Lang, Christian Andresen, Margaret M. Redfield, Elke Butt, Cris G. dos Remedios, Wolfgang A. Linke
Journal: Circulation Research (2008)

The sarcomeric titin springs influence myocardial distensibility and passive stiffness. Titin isoform composition and protein kinase (PK)A-dependent titin phosphorylation are variables contributing to diastolic heart function. However, diastolic tone, relaxation speed, and left ventricular extensibility are also altered by PKG activation. We used back-phosphorylation assays to determine whether PKG can phosphorylate titin and affect titin-based stiffness in skinned myofibers and isolated myofibrils. PKG in the presence of 8-pCPT-cGMP (cGMP) phosphorylated the 2 main cardiac titin isoforms, N2BA and N2B, in human and canine left ventricles. In human myofibers/myofibrils dephosphorylated before mechanical analysis, passive stiffness dropped 10% to 20% on application of cGMP-PKG. Autoradiography and anti-phosphoserine blotting of recombinant human I-band titin domains established that PKG phosphorylates the N2-B and N2-A domains of titin. Using site-directed mutagenesis, serine residue S469 near the COOH terminus of the cardiac N2-B–unique sequence (N2-Bus) was identified as a PKG and PKA phosphorylation site. To address the mechanism of the PKG effect on titin stiffness, single-molecule atomic force microscopy force–extension experiments were performed on engineered N2-Bus–containing constructs. The presence of cGMP-PKG increased the bending rigidity of the N2-Bus to a degree that explained the overall PKG-mediated decrease in cardiomyofibrillar stiffness. Thus, the mechanically relevant site of PKG-induced titin phosphorylation is most likely in the N2-Bus; phosphorylation of other titin sites could affect protein–protein interactions. The results suggest that reducing titin stiffness by PKG-dependent phosphorylation of the N2-Bus can benefit diastolic function. Failing human hearts revealed a deficit for basal titin phosphorylation compared to donor hearts, which may contribute to diastolic dysfunction in heart failure.