tbuckley/cabot-search huggingface dataset:
Orai1 and CRAC Channel Dependence of VEGF-Activated Ca <sup>2+</sup> Entry and Endothelial Tube Formation
Authors: Jing Li, Richard M. Cubbon, Lesley A. Wilson, Mohamed S. Amer, Lynn McKeown, Bing Hou, Yasser Majeed, Sarka Tumova, Victoria A.L. Seymour, Hilary Taylor, Martin Stacey, David O'Regan, Richard Foster, Karen E. Porter, Mark T. Kearney, David J. Beech
Journal: Circulation Research (2011)

Orai1 and the associated calcium release-activated calcium (CRAC) channel were discovered in the immune system. Existence also in endothelial cells has been suggested, but the relevance to endothelial biology is mostly unknown.The aim of this study was to investigate the relevance of Orai1 and CRAC channels to vascular endothelial growth factor (VEGF) and endothelial tube formation.In human umbilical vein endothelial cells, Orai1 disruption by short-interfering RNA or dominant-negative mutant Orai1 inhibited calcium release-activated (store-operated) calcium entry, VEGF-evoked calcium entry, cell migration, and in vitro tube formation. Expression of exogenous wild-type Orai1 rescued the tube formation. VEGF receptor-2 and Orai1 partially colocalized. Orai1 disruption also inhibited calcium entry and tube formation in endothelial progenitor cells from human blood. A known blocker of the immune cell CRAC channel (3-fluoropyridine-4-carboxylic acid (2',5'-dimethoxybiphenyl-4-yl)amide) was a strong blocker of store-operated calcium entry in endothelial cells and inhibited calcium entry evoked by VEGF in 3 types of human endothelial cell. The compound lacked effect on VEGF-evoked calcium-release, STIM1 clustering, and 2 types of transient receptor potential channels, TRPC6 and TRPV4. Without effect on cell viability, the compound inhibited human endothelial cell migration and tube formation in vitro and suppressed angiogenesis in vivo in the chick chorioallantoic membrane. The compound showed 100-fold greater potency for endothelial compared with immune cell calcium entry.The data suggest positive roles for Orai1 and CRAC channels in VEGF-evoked calcium entry and new opportunity for chemical modulation of angiogenesis.
IDSA/ATS minor criteria aid pre-intensive care unit resuscitation in severe community-acquired pneumonia
Authors: Hui Fang Lim, Jason Phua, Amartya Mukhopadhyay, Wang Jee Ngerng, Mei Ying Chew, Tiong Beng Sim, Win Sen Kuan, Malcolm Mahadevan, Tow Keang Lim
Journal: European Respiratory Journal (2013)

The effect of employing severity scores to identify severe community-acquired pneumonia (SCAP) cases for early aggressive resuscitation is unknown. Optimising pre-intensive care unit (ICU) care may improve outcomes in patients at risk of SCAP. We conducted a before-and-after study of patients classified into control and intervention groups (January 2004 to December 2007 and January 2008 to December 2010, respectively). Our intervention was two-pronged, using the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) minor criteria to identify SCAP for aggressive emergency department resuscitation. Patients with SCAP, defined as those with three or more IDSA/ATS minor criteria, were targeted. Differences in mortality, triage and compliance with emergency department resuscitation were compared between the groups. The hospital mortality rate was lower in the intervention versus the control group (5.7% versus 23.8%, p&lt;0.001). On multivariate analysis, the intervention group was associated with lower mortality (OR 0.24, 95% CI 0.09–0.67). ICU admission rates decreased from 52.9% to 38.6% (p=0.008) and inappropriately delayed ICU admissions decreased from 32.0% to 14.8% (p&lt;0.001). There was increased compliance with the aggressive resuscitation protocol after the intervention. A combined intervention, using a pneumonia score to identify those at risk of SCAP early and an aggressive pre-ICU resuscitation protocol may reduce mortality and ICU admissions.
Spatially Patterned Gene Delivery for Localized Neuron Survival and Neurite Extension
Authors: Tiffany Houchin-Ray, Kevin J Whittlesey, Lonnie D Shea
Journal: Molecular Therapy (2007)

Natural tissues can have complex architectures, which arise in part from spatial patterns in gene expression. Regenerative strategies for damaged tissue must recreate these architectures to restore function. In this article, we demonstrate spatially controlled gene delivery from a substrate for directing cellular processes. Non-viral vectors were immobilized to substrates in linear patterns using microfluidic techniques, and cells cultured on the surface had localized gene expression within the cell population. Transfection was achieved in pattern widths as low as 100 μm, with efficiencies dependent on the microchannel treatment and vector concentration. The ability of patterned expression to localize cellular processes was investigated using a neuronal co-culture model. Patterned expression of the diffusible neurotrophic factor nerve growth factor initiated neuron survival and neurite out-growth primarily within the pattern, which decreased significantly in regions directly adjacent to the pattern. Primary neurite density was significantly greater on patterned substrates than on surfaces without patterns. This approach demonstrates the basic technology to create patterns of gene expression that can direct tissue formation and could be employed in regenerative strategies to recreate the complex cellular architectures observed in tissues. Natural tissues can have complex architectures, which arise in part from spatial patterns in gene expression. Regenerative strategies for damaged tissue must recreate these architectures to restore function. In this article, we demonstrate spatially controlled gene delivery from a substrate for directing cellular processes. Non-viral vectors were immobilized to substrates in linear patterns using microfluidic techniques, and cells cultured on the surface had localized gene expression within the cell population. Transfection was achieved in pattern widths as low as 100 μm, with efficiencies dependent on the microchannel treatment and vector concentration. The ability of patterned expression to localize cellular processes was investigated using a neuronal co-culture model. Patterned expression of the diffusible neurotrophic factor nerve growth factor initiated neuron survival and neurite out-growth primarily within the pattern, which decreased significantly in regions directly adjacent to the pattern. Primary neurite density was significantly greater on patterned substrates than on surfaces without patterns. This approach demonstrates the basic technology to create patterns of gene expression that can direct tissue formation and could be employed in regenerative strategies to recreate the complex cellular architectures observed in tissues.
Nitric oxide as an inflammatory mediator in autoimmune MRL-lpr/lpr mice.
Authors: J B Weinberg
Journal: Environmental Health Perspectives (1998)

Nitric oxide (.NO) may exhibit proinflammatory features. .NO synthase type 2 (NOS2) is overexpressed and .NO overproduced in rodent models of induced inflammation. Blockage of .NO production by administration of NOS inhibitors prevents or reduces various types of induced inflammation in mice and rats. We have shown that autoimmune MRL-lpr/lpr mice overexpress NOS2 and overproduce .NO in an age-dependent fashion that parallels expression of arthritis, glomerulonephritis, and vasculitis. Blocking .NO production by oral administration of the NOS inhibitor NG-monomethyl-L-arginine reduced the arthritis, glomerulonephritis, and vasculitis, but it did not modify serum anti-DNA antibody levels or glomerular deposition of immune complexes. When mice with genetically disrupted NOS2 were backcrossed to MRL-lpr/lpr mice, the resultant (-/-) mice expressed no NOS2 and produced no .NO, the wild-type (+/+) mice overexpressed NOS2 and overproduced .NO (in comparison to normal, control mice), and the heterozygous (+/-) mice expressed and produced intermediate levels. Nephritis and arthritis in the (-/-) mice were comparable to that in MRL-lpr/lpr mice, but vasculitis was markedly decreased. Levels of anti-DNA antibodies were comparable in all mice, but IgG rheumatoid factor production was markedly reduced in the (-/-) mice. These results of studies in MRL-lpr/lpr mice with genetically disrupted NOS2 highlight the heterogeneity and complexity of the role of NOS2 and .NO in inflammation.
Prevalence and clinical characteristics of TT virus (TTV) in patients with sporadic acute hepatitis of unknown etiology
Authors: Maria del Carmen Parquet, Hiroshi Yatsuhashi, Michiaki Koga, Osami Inoue, Takehiro Matsumoto, Rumiko Hamada, Akira Igarashi, Michitami Yano
Journal: Journal of Hepatology (1999)
Intestinal epithelial restitution. Characterization of a cell culture model and mapping of cytoskeletal elements in migrating cells.
Authors: A Nusrat, C Delp, J L Madara
Journal: Journal of Clinical Investigation (1992)

Closure of superficial wounds in epithelia occurs by migration of cells shouldering the wound. We describe an in vitro model of such restitution using a human intestinal epithelial cell line, T84. T84 cells were grown on novel optically transparent type 1 collagen membranes without underlying filter supports. Monolayers so grown display substantial barrier function (400-500 ohm.cm2; 1.3 +/- 0.4 nmol.h-1.cm-2 mannitol flux). Wounds made with micropipettes were accompanied by a fall in resistance and rise in monolayer permeability to mannitol and inulin. After injury, cells shouldering wounds migrated, by extension of lamellipodia-like processes, to reseal wounds as defined by structural and functional criteria. F actin arcs crossed the base of the lamellipodia-like extensions and F actin microspikes projected from the leading edge of these extensions. Villin, an epithelial-specific cytoskeletal protein with both F actin bundling and severing capacities, was also expressed at the leading edge in a pattern consistent with a regulatory role in the dynamic restructuring of lamellipodia. Lastly, myosin II was predominantly localized to the basal regions of lamellipodia, though occasional staining was seen close to the advancing edge. Myosin I, a recently recognized myosin family member considered to be essential for fibroblast and slime mold motility, was present throughout lamellipodia in punctate fashion, but was not concentrated at the leading edge.
Emotions of “higher” cognition
Authors: Leonid Perlovsky
Journal: Behavioral and Brain Sciences (2012)

Abstract The target article by Lindquist et al. considers discrete emotions. This commentary argues that these are but a minor part of human emotional abilities, unifying us with animals. Uniquely human emotions are aesthetic emotions related to the need for the knowledge of “high” cognition, including emotions of the beautiful, cognitive dissonances, and musical emotions. This commentary touches on their cognitive functions and origins.
cAMP and cGMP Signaling Cross-Talk
Authors: Manuela Zaccolo, Matthew A. Movsesian
Journal: Circulation Research (2007)

Cyclic nucleotide phosphodiesterases regulate cAMP-mediated signaling by controlling intracellular cAMP content. The cAMP-hydrolyzing activity of several families of cyclic nucleotide phosphodiesterases found in human heart is regulated by cGMP. In the case of PDE2, this regulation primarily involves the allosteric stimulation of cAMP hydrolysis by cGMP. For PDE3, cGMP acts as a competitive inhibitor of cAMP hydrolysis. Several cGMP-mediated responses in cardiac cells, including a potentiation of Ca 2+ currents and a diminution of the responsiveness to β-adrenergic receptor agonists, have been shown to result from the effects of cGMP on cAMP hydrolysis. These effects appear to be dependent on the specific spatial distribution of the cGMP-generating and cAMP-hydrolyzing proteins, as well as on the intracellular concentrations of the two cyclic nucleotides. Gaining a more precise understanding of how these cross-talk mechanisms are individually regulated and coordinated is an important direction for future research.
Relationship of Upper and Lower Airway Cytokines to Outcome of Experimental Rhinovirus Infection
Authors: JAMES E. GERN, ROSE VRTIS, KRISTINE A. GRINDLE, CHERI SWENSON, WILLIAM W. BUSSE
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

To test the hypothesis that rhinovirus (RV)-induced immune responses influence the outcome of RV infections, we inoculated 22 subjects with allergic rhinitis or asthma with RV16. Nasal secretions and induced sputum were repeatedly sampled over the next 14 d. RV16 infection increased nasal granulocyte colony-stimulating factor (G-CSF) and interleukin (IL)-8, which was accompanied by neutrophilia in blood and nasal secretions. Nasal G-CSF correlated closely with increased blood neutrophils (rs = 0.69, p < 0.005), whereas nasal neutrophils correlated with both G-CSF (rs = 0.87, p < 0.001) and IL-8 (rs = 0.75, p < 0.001). Although similar relationships were present in sputum, changes in sputum neutrophils and G-CSF with RV16 infection were relatively modest. In addition, virus-induced changes in the sputum interferon- γ -to-IL-5 messenger RNA ratio were inversely related to both peak cold symptoms (rs = − 0.60, p < 0.005) and the time to viral clearance (undetectable picornavirus RNA). These results indicate that airway IL-8 and G-CSF are closely associated with virus-induced neutrophilic inflammation during an experimental RV infection in atopic volunteers. In addition, the balance of airway T-helper cell type 1 (Th1)- and Th2-like cytokines induced by RV infection may help determine the clinical outcome of common cold infections, raising the possibility that the individual subject's immune response, rather than atopic status per se, is important in this regard.
Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy
Authors: Anu Shah, Ling Xia, Elodie A.Y. Masson, Chloe Gui, Abdul Momen, Eric A. Shikatani, Mansoor Husain, Susan Quaggin, Rohan John, I.G. Fantus
Journal: Journal of the American Society of Nephrology (2015)

Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress. We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogen-activated protein kinase phosphorylation, and collagen expression. Here, we investigated the potential role of TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP−/−, and TxNIP+/− mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP−/− mice. Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxNIP−/− mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-β1, collagen IV, and fibrosis only in WT diabetic mice. Additionally, only WT diabetic mice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1β mRNA, F4/80 immunohistochemistry). Expression levels of Nox4-encoded mRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms' tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP−/− mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O2− generation and apoptosis. These data indicate that TxNIP has a critical role in the progression of DN and may be a promising therapeutic target.
The Influence of Maternal Nutrition on Lactation
Authors: Kathleen Maher Rasmussen
Journal: Annual Review of Nutrition (1992)

INTRODUCTION   103 CONCEPTUAL FRAMEWORK   104 EFFECT OF MATERNAL OVERNUTRITION ON LACTATIONAL PERFORMANCE   105 Studies in Experimental Animals   106 Studies in Women   108 EFFECT OF MATERNAL UNDERNUTRITION ON LACTATIONAL PERFORMANCE   109 Studies in Experimental Animals   109 Studies in Women   111 CONCLUSIONS   114
Laser Scanning Tomography of Optic Discs of the Normal Japanese Population in a Population-based Setting
Authors: Haruki Abe, Motohiro Shirakashi, Tae Tsutsumi, Makoto Araie, Atsuo Tomidokoro, Aiko Iwase, Goji Tomita, Tetsuya Yamamoto
Journal: Ophthalmology (2008)
Chemokines, innate and adaptive immunity, and respiratory disease: Table 1—
Authors: I. Sabroe, C.M. Lloyd, M.K.B. Whyte, S.K. Dower, T.J. Williams, J.E. Pease
Journal: European Respiratory Journal (2002)

Selective leukocyte trafficking and recruitment is primarily regulated by a specific family of small proteins called “chemokines”. This extended family shepherds and guides leukocytes through their lives, facilitating their development, regulating their interactions with other leukocyte types, and guiding their recruitment to sites of inflammation. Through the actions of chemokines, allergen sensitization is regulated in atopic asthma, through the controlled migration of dendritic cells, T- and B-lymphocytes, mast cells and basophils. Subsequently, atopic inflammation is driven by chemokine-directed recruitment of eosinophils, basophils and lymphocytes. Diseases from cancer to chronic obstructive pulmonary disease to interstitial fibrosis are all potential targets for chemokine receptor antagonism. Innate immunity (the early pattern-recognition responses to stimuli such as lipopolysaccharide, viral proteins and bacterial DNA) needs to bridge the gap to specific immunity and antibody production and immunological memory. Again, chemokines are likely to be fundamental mediators of these responses. Chemokines are fundamental regulators of leukocyte homeostasis and inflammation, and their antagonism by small molecule chemokine receptor antagonists may be of enormous importance in the future treatment of human respiratory disease.
Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection
Authors: Domenico Mavilio, Gabriella Lombardo, Audrey Kinter, Manuela Fogli, Andrea La Sala, Saida Ortolano, Annahita Farschi, Dean Follmann, Roby Gregg, Colin Kovacs, Emanuela Marcenaro, Daniela Pende, Alessandro Moretta, Anthony S. Fauci
Journal: The Journal of Experimental Medicine (2006)

In this study, we demonstrate that the in vitro interactions between a CD56(neg)/CD16(pos) (CD56(neg)) subset of natural killer (NK) cells and autologous dendritic cells (DCs) from HIV-1-infected viremic but not aviremic individuals are markedly impaired and likely interfere with the development of an effective immune response. Among the defective interactions are abnormalities in the process of reciprocal NK-DC activation and maturation as well as a defect in the NK cell-mediated editing or elimination of immature DCs (iDCs). Notably, the lysis of mature DCs (mDCs) by autologous NK cells was highly impaired even after the complete masking of major histocompatibility complex I molecules, suggesting that the defective elimination of autologous iDCs is at the level of activating NK cell receptors. In this regard, the markedly impaired expression/secretion and function of NKp30 and TNF-related apoptosis-inducing ligand, particularly among the CD56(neg) NK cell subset, largely accounts for the highly defective NK cell-mediated lysis of autologous iDCs. Moreover, mDCs generated from HIV-1 viremic but not aviremic patients are substantially impaired in their ability to secrete interleukin (IL)-10 and -12 and to prime the proliferation of neighboring autologous NK cells, which, in turn, fail to secrete adequate amounts of interferon-gamma.
Economic Evaluation of Fractional Flow Reserve–Guided Percutaneous Coronary Intervention in Patients With Multivessel Disease
Authors: William F. Fearon, Bernhard Bornschein, Pim A.L. Tonino, Raffaella M. Gothe, Bernard De Bruyne, Nico H.J. Pijls, Uwe Siebert
Journal: Circulation (2010)

The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study demonstrated significantly improved health outcomes at 1 year in patients randomized to multivessel percutaneous coronary intervention guided by fractional flow reserve (FFR) compared with percutaneous coronary intervention guided by angiography alone. The economic impact of routine measurement of FFR in this setting is not known.In this study, 1005 patients were randomly assigned to FFR-guided or angiography-guided percutaneous coronary intervention and followed up for 1 year. A prospective cost-utility analysis comparing costs and quality-adjusted life-years was performed with a time horizon of 1 year. Quality-adjusted life-years were calculated with the use of utilities determined by the EuroQuol 5 dimension health survey with US weights. Direct medical costs included those of the index procedure and hospitalization and costs for major adverse cardiac events during follow-up. Confidence intervals for both quality-adjusted life-years and costs were estimated by the bootstrap percentile method. Major adverse cardiac events at 1 year occurred in 13.2% of those in the FFR-guided arm and 18.3% of those in the angiography-guided arm (P=0.02). Quality-adjusted life-years were slightly greater in the FFR-guided arm (0.853 versus 0.838; P=0.2). Mean overall costs at 1 year were significantly less in the FFR-guided arm ($14 315 versus $16 700; P<0.001). Bootstrap simulation indicated that the FFR-guided strategy was cost-saving in 90.74% and cost-effective at a threshold of US $50 000 per quality-adjusted life-years in 99.96%. Sensitivity analyses demonstrated robust results.Economic evaluation of the FAME study reveals that FFR-guided percutaneous coronary intervention in patients with multivessel coronary disease is one of those rare situations in which a new technology not only improves outcomes but also saves resources. Clinical Trial Registration- URL: http://ClinicalTrials.gov. Unique identifier: NCT00267774.
57 SECRETORY LEUKOCYTE PROTEASE INHIBITOR (SLPI) IS A PIVOTAL MEDIATOR OF ANTI-INFLAMMATORY RESPONSES IN ACUTE LIVER FAILURE
Authors: C. Antoniades, W. Khamri, R. Abeles, A. O'Brien, L. Possamai, W. Bernal, C. Starling, R. Mitry, G. Auzinger, D. Gilroy, M. Heneghan, N. Heaton, A. Quaglia, D. Vergani, J. Wendon, M. Thursz
Journal: Journal of Hepatology (2013)