tbuckley/cabot-search huggingface dataset:
Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer’s disease
Authors: Véréna Landel, Kévin Baranger, Isabelle Virard, Béatrice Loriod, Michel Khrestchatisky, Santiago Rivera, Philippe Benech, François Féron
Journal: Molecular Neurodegeneration (2014)

The 5XFAD early onset mouse model of Alzheimer's disease (AD) is gaining momentum. Behavioral, electrophysiological and anatomical studies have identified age-dependent alterations that can be reminiscent of human AD. However, transcriptional changes during disease progression have not yet been investigated. To this end, we carried out a transcriptomic analysis on RNAs from the neocortex and the hippocampus of 5XFAD female mice at the ages of one, four, six and nine months (M1, M4, M6, M9).Our results show a clear shift in gene expression patterns between M1 and M4. At M1, 5XFAD animals exhibit region-specific variations in gene expression patterns whereas M4 to M9 mice share a larger proportion of differentially expressed genes (DEGs) that are common to both regions. Analysis of DEGs from M4 to M9 underlines the predominance of inflammatory and immune processes in this AD mouse model. The rise in inflammation, sustained by the overexpression of genes from the complement and integrin families, is accompanied by an increased expression of transcripts involved in the NADPH oxidase complex, phagocytic processes and IFN-γ related pathways.Overall, our data suggest that, from M4 to M9, sustained microglial activation becomes the predominant feature and point out that both detrimental and neuroprotective mechanisms appear to be at play in this model. Furthermore, our study identifies a number of genes already known to be altered in human AD, thus confirming the use of the 5XFAD strain as a valid model for understanding AD pathogenesis and for screening potential therapeutic molecules.
Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90
Authors: Byoung Heon Kang, Janet Plescia, Ho Young Song, Massimiliano Meli, Giorgio Colombo, Kristin Beebe, Bradley Scroggins, Len Neckers, Dario C. Altieri
Journal: Journal of Clinical Investigation (2009)

Although therapeutically targeting a single signaling pathway that drives tumor development and/or progression has been effective for a number of cancers, in many cases this approach has not been successful. Targeting networks of signaling pathways, instead of isolated pathways, may overcome this problem, which is probably due to the extreme heterogeneity of human tumors. However, the possibility that such networks may be spatially arranged in specialized subcellular compartments is not often considered in pathway-oriented drug discovery and may influence the design of new agents. Hsp90 is a chaperone protein that controls the folding of proteins in multiple signaling networks that drive tumor development and progression. Here, we report the synthesis and properties of Gamitrinibs, a class of small molecules designed to selectively target Hsp90 in human tumor mitochondria. Gamitrinibs were shown to accumulate in the mitochondria of human tumor cell lines and to inhibit Hsp90 activity by acting as ATPase antagonists. Unlike Hsp90 antagonists not targeted to mitochondria, Gamitrinibs exhibited a "mitochondriotoxic" mechanism of action, causing rapid tumor cell death and inhibiting the growth of xenografted human tumor cell lines in mice. Importantly, Gamitrinibs were not toxic to normal cells or tissues and did not affect Hsp90 homeostasis in cellular compartments other than mitochondria. Therefore, combinatorial drug design, whereby inhibitors of signaling networks are targeted to specific subcellular compartments, may generate effective anticancer drugs with novel mechanisms of action.
Effect of extended cold ischaemia with UW solution on graft function after liver transplantation
Authors: R. Adam, H. Bismuth, T. Diamond, M. Morino, I. Astarcioglu, M. Johann, D. Azoulay, L. Chiche, Y.M. Bao, D. Castaing, B. Ducot
Journal: The Lancet (1992)
Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation
Authors: Joseph Khoury, Juan C. Ibla, Andrew S. Neish, Sean P. Colgan
Journal: Journal of Clinical Investigation (2007)

A major adaptive pathway for hypoxia is hypoxic preconditioning (HPC), a form of endogenous protection that renders cells tolerant to severe challenges of hypoxia. We sought to define the antiinflammatory properties of HPC. cDNA microarray analysis of lung tissue from mice subjected to hypoxia or HPC identified a cluster of NF-κB–regulated genes whose expression is attenuated by HPC. Studies using an NF-κB luciferase reporter assay confirmed a significant suppression of NF-κB activation during HPC. HPC-elicited activity was conferrable, as a soluble supernatant from HPC-treated cells, and the active fraction was purified and identified as adenosine (Ado). Guided by recent studies demonstrating bacterial inhibition of NF-κB through cullin-1 (Cul-1) deneddylation, we found a dose-dependent deneddylation of Cul-1 by Ado receptor stimulation predominantly mediated by the Ado A2B receptor subtype. Further, siRNA-mediated repression of CSN5, a subunit of the COP9 signalosome responsible for deneddylation of Cul-1, partially reversed HPC-mediated inhibition of NF-κB. Cul-1 deneddylation was evident in a murine model of HPC and lost in animals lacking extracellular Ado (Cd73–/– mice). Taken together, these results demonstrate that HPC induces extracellular accumulation of Ado and suppresses NF-κB activity through deneddylation of Cul-1. These results define a molecular regulatory pathway by which Ado provides potent antiinflammatory properties.
Effect of urodilatin on cGMP accumulation in the kidney.
Authors: J Koike, H Nonoguchi, Y Terada, K Tomita, F Marumo
Journal: Journal of the American Society of Nephrology (1993)

Urodilatin is found in the urine and is thought to be produced in the kidney. The effect of urodilatin on cGMP accumulation in the kidney was investigated. cGMP accumulation by urodilatin and atrial natriuretic peptide (ANP) were compared with tubule suspensions from renal cortex, outer medulla, inner medulla, and microdissected nephron segments. Urodilatin-stimulated cGMP accumulation was higher in tubule suspensions from the inner medulla than in those from the cortex and outer medulla. The highest accumulation stimulated by 10(-6) M urodilatin among nephron segments was observed in glomeruli and inner medullary collecting ducts (IMCD). Small accumulations were seen in proximal convoluted tubules and medullary thick ascending limbs. Urodilatin-stimulated cGMP accumulation was almost equal to that stimulated by the same concentrations of ANP in these nephron segments. Urodilatin (10(-8) M) did not stimulate cGMP accumulation in glomeruli, but it stimulated cGMP accumulation in IMCD by threefold. This pattern was quite similar to that with ANP. It was concluded that urodilatin has a similar ability to ANP in stimulating cGMP synthesis and that the main target sites are glomeruli and IMCD.
Reference Ranges for Exhaled Nitric Oxide Derived from a Random Community Survey of Adults
Authors: Justin Travers, Suzanne Marsh, Sarah Aldington, Mathew Williams, Philippa Shirtcliffe, Alison Pritchard, Mark Weatherall, Richard Beasley
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Measurement of the fraction of nitric oxide in exhaled breath (Fe(NO)) has been proposed as a noninvasive marker of airway inflammation. Before the widespread use of this test, there is a need to develop reference ranges to allow clinicians to interpret Fe(NO) measurements.To derive reference ranges for Fe(NO) and to determine which factors in health and disease influence Fe(NO) levels.Subjects aged between 25 and 75 years were drawn from a random sample of the predominantly white population of Wellington, New Zealand.Fe(NO) was measured using an online nitric oxide monitor in accordance with international guidelines. A detailed respiratory questionnaire and pulmonary function tests were performed. The geometric mean Fe(NO) was 17.9 parts per billion (ppb) with a 90% confidence interval for an individual prediction (reference range) for normal subjects of 7.8 to 41.1 ppb. Sex, atopy, and smoking status significantly affected Fe(NO) levels, and several reference ranges are presented adjusting for these factors. Asthma and allergic rhinitis were associated with higher Fe(NO). Measurement of Fe(NO) had poor discriminant ability to identify steroid-naive subjects with asthma.The reference ranges presented may be used to assist in the interpretation of Fe(NO) measurements in white adults.
NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans
Authors: Travis L Dickendesher, Katherine T Baldwin, Yevgeniya A Mironova, Yoshiki Koriyama, Stephen J Raiker, Kim L Askew, Andrew Wood, Cédric G Geoffroy, Binhai Zheng, Claire D Liepmann, Yasuhiro Katagiri, Larry I Benowitz, Herbert M Geller, Roman J Giger
Journal: Nature Neuroscience (2012)
Oncogene's point mutation produces cancer
Authors: T. Hager
Journal: JAMA (1982)

What turns a normal cell into a cancer cell? Scientists have long suspected that the answer lies somewhere in the chromosomal material. This is based on the observation that once a normal cell becomes cancerous, through a process called malignant transformation, it passes its tumor characteristics on to progeny in a stable manner. In addition, most carcinogens have also been shown in the laboratory to damage DNA. The recent finding that certain single genes present in normal cell DNA, called cellular oncogenes, have the potential to trigger cell transformation has given researchers a new focus for study (<i>JAMA</i>1982; 247:178-181;1098-1103). Some of these genes appear to play an active role in normal cell function. Yet in tumor cells they have somehow been altered in a way that results in cancer. What sort of DNA changes are involved in this alteration? For at least one type of oncogene, researchers now have
P134 Validating structured light plethysmography (SLP) as a non-invasive method of measuring lung function when compared to Spirometry
Authors: S. Alimohamed, K. Prosser, C. Weerasuriya, R. Iles, J. Cameron, J. Lasenby, C. Fogarty
Journal: Thorax (2011)

<h3>Background</h3> Structured Light Plethysmography (SLP) is a recently developed technology for non-invasive and entirely non-contact monitoring of lung (respiratory) function. The system projects a structured light grid onto the thoraco-abdominal surface of the subject, which is imaged by two cameras giving a dynamic 3D reconstruction of the surface as the subject breathes. From this data we can infer changes in chest/abdomen volume over time, allowing us to extract parameters and generate curves (eg, Volume-Time, Flow-Time, Flow-Volume curves) directly comparable to conventional spirometry. SLP therefore hopes to provide an inexpensive replacement for conventional spirometry, which is an invasive methodology unusable in a number of patient classes (eg, neonates, young children, intensive care patients etc). This study tests the validity of SLP in terms of reproducibility, repeatability and position dependence, as compared to conventional spirometry (Pneumatach); by comparison of ventilation parameters extracted from both technologies. <h3>Methods</h3> SLP and Pneumatach spirometry were used simultaneously to capture 120 datasets from 10 randomly chosen adult subjects. Each complete dataset contained tidal breathing and forced expiratory manoeuvres, in both sitting and standing positions. Operator-dependence (reproducibility) was tested by collecting data sets from each subject using three different operators. Repeatability was tested by collecting the data from each subject once, and then again after a 40 min break. Tidal Inspiratory Time (TI) parameters were extracted from the results and the data analysed using the paired Student t test. <h3>Results</h3> There was no significant difference between TI values obtained from SLP compared to conventional spirometry throughout the study (n=120; p=0.8556). SLP comparisons of pooled mean TI before, and after a 40 min break were not significant (1.5589 vs 1.5595; p=0.9938); similarly, readings in different positions (sitting or standing) were not significantly different. SLP comparison of all three operator pairs (1vs2, 1vs3 and 2vs3), were not significant (p=0.7361, p=0.9765, p=0.7343, respectively). <h3>Conclusions</h3> SLP measurements are not operator, time or position dependant. Therefore SLP shows a high degree of reproducibility and repeatability; and represents a promising, viable and non-invasive alternative to conventional spirometry.
Alterations in electrical activity and membrane currents induced by intracellular oxygen-derived free radical stress in guinea pig ventricular myocytes.
Authors: R I Jabr, W C Cole
Journal: Circulation Research (1993)

Oxygen-derived free radicals (O-Rs) are thought to induce alterations in cardiac electrical activity; however, the underlying membrane ionic currents affected by O-Rs and the mechanisms by which O-Rs induce their effects on ion channels in the heart are not well defined. In this study, we investigated the time-dependent changes in resting membrane potential and action potential configuration and changes in steady-state membrane currents in guinea pig ventricular myocytes after intracellular application of an O-R-generating system. O-Rs were generated from the combination of dihydroxyfumaric acid (3 mM) and FeCl3:ADP (0.05:0.5 mM) added to the pipette solution that was used to record membrane potential and currents via the whole-cell variant of the patch-clamp technique. Intracellular exposure of myocytes to the O-R-generating solution induced three stages of changes: 1) an early depolarization (5-10 mV) and an increase in action potential duration accompanied by a decrease in resting inward rectifying K+ current conductance, 2) delayed afterdepolarizations and triggered activity caused by the activation of transient inward current mediated by Na(+)-Ca2+ exchange, with failure to repolarize and sustained depolarization between -35 and -20 mV, reflecting the stimulation of nonselective cation current, and 3) a late stage of marked decline in action potential duration, hyperpolarization, and loss of excitability accompanied by activation of the outward current through ATP-sensitive K+ channels. These alterations in electrical activity and membrane currents could be prevented by pretreatment with N-(2-mercaptopropionyl)glycine (500 microM), a scavenger of hydroxyl free radicals. The alterations associated with stages 1 and 2 but not stage 3 were completely abolished on intracellular Ca2+ chelation (5 mM EGTA in the pipette solution) or disruption of sarcoplasmic reticulum Ca2+ handling with ryanodine (10 microM). This study shows that intracellular O-R stress causes specific alterations in membrane ionic currents, leading to changes in resting membrane potential and action potential configuration. Moreover, the data indicate that an elevation in intracellular Ca2+ due to abnormal Ca2+ handling by the sarcoplasmic reticulum is a cause of some of the alterations in membrane currents during O-R stress.
Paracetamol in osteoarthritis of the knee
Authors: C Miceli-Richard
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> Paracetamol is a recommended symptomatic treatment of osteoarthritis (OA), but in clinical trials sample sizes have been relatively small and variable daily doses of paracetamol have been used. <b>Objectives:</b> To determine the therapeutic efficacy of paracetamol in OA of the knee and identify predictive factors of clinical response to treatment. <b>Methods:</b> A double blind, parallel group, placebo controlled trial of analgesic efficacy and safety of paracetamol versus placebo including 779 patients with OA of the knee. Patients were randomly assigned to receive paracetamol 4 g/day (n = 405) or placebo (n = 374) for 6 weeks. Symptomatic OA of the knee was required at inclusion with global pain intensity of the knee during physical activities for the past 24 hours of ⩾30 mm on a 100 mm visual analogue scale. The primary end point was a 30% decrease of global pain intensity of the knee. Intention to treat analyses were performed. <b>Results:</b> The percentage of responders did not differ significantly between groups: 52.6% and 51.9% in paracetamol and placebo groups, respectively (p = 0.840). In a subgroup of patients with chronic mechanical knee pain without signs of inflammation (n = 123), the mean change in pain intensity from baseline was 25.2 mm <i>v</i> 15.2 mm, in the paracetamol (n = 63) and placebo (n = 60) groups, respectively—mean difference 10.0 mm; 95% CI 1.0 to 19.0; p = 0.0294. No serious adverse events were attributable to treatment. <b>Conclusion:</b> A statistically significant symptomatic effect of oral paracetamol 4 g/day over placebo was not found, suggesting that paracetamol use in symptomatic OA of the knee should be further explored. The tolerability and safety of paracetamol, at the recommended maximum dose of 4 g/day, was confirmed over 6 weeks.
Simultaneous bone marrow and intestine transplantation promotes marrow-derived hematopoietic stem cell engraftment and chimerism
Authors: Atsunori Nakao, Hideyoshi Toyokawa, Kei Kimizuka, Michael A. Nalesnik, Isao Nozaki, Robert J. Bailey, Anthony J. Demetris, Thomas E. Starzl, Noriko Murase
Journal: Blood (2006)
Management of postnatal depression
Authors: C. Musters, E. McDonald, I. Jones
Journal: BMJ (2008)

Depression is common in the postpartum period.It can be severe and may have serious consequences for the woman and her child.The term postnatal depression, however, is often applied indiscriminately to all occurrences of psychological distress after childbirth.It is important to identify and to treat postnatal depression-recently published National Institute for Health and Clinical Excellence (NICE) guidance supports a range of effective psychological and pharmacological interventions. 1 Here, we discuss current thinking on the clinical features, aetiology, and management of postnatal depression.
The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease
Authors: Y-C Lee, A M-F Yen, J J Tai, S-H Chang, J-T Lin, H-M Chiu, H-P Wang, M-S Wu, T H-H Chen
Journal: Gut (2008)

The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease (GORD), which remains elusive, was quantified.The population included 3669 subjects undergoing repeated upper endoscopy. Data were analysed using a three-state Markov model to estimate transition rates (according to the Los Angeles classification) regarding the natural course of the disease. Individual risk score together with the kinetic curve was derived by identifying significant factors responsible for the net force between progression and regression.During three consecutive study periods, 12.2, 14.9 and 17.9% of subjects, respectively, progressed from non-erosive to erosive disease, whereas 42.5, 37.3 and 34.6%, respectively, regressed to the non-erosive stage. The annual transition rate from non-erosive to class A-B disease was 0.151 per person year (95% CI 0.136 to 0.165) and from class A-B to C-D was 0.079 per person year (95% CI 0.063 to 0.094). The regression rate from class A-B to non-erosive disease was 0.481 per person year (95% CI 0.425 to 0.536). Class C-D, however, appeared to be an absorbing state when not properly treated. Being male (relative risk (RR) 4.31; 95% CI 3.22 to 5.75), smoking (RR 1.20; 95% CI 1.03 to 1.39) or having metabolic syndrome (RR 1.75; 95% CI 1.29 to 2.38) independently increased the likelihood of progressing from a non-erosive to an erosive stage of disease and/or lowered the likelihood of disease regression. The short-term use of acid suppressants (RR 0.54; 95% CI 0.39 to 0.75) raised the likelihood of regression from erosive to non-erosive disease.Intraoesophageal damage is a dynamic and migratory process in which the metabolic syndrome is associated with accelerated progression to or attenuated regression from erosive states. These findings have important implications for the design of effective prevention and screening strategies.
TGF-β1–Mediated Inhibition of HK-2 Cell Migration
Authors: Ya-Chung Tian, Aled O. Phillips
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Restoration of proximal tubular cell (PTC) integrity and function after ischemic injury involves cell proliferation and migration. Hypoxia is a known stimulus for PTC TGF-β1 synthesis. This study examines the effect of TGF-β1 on PTC migration. A model of PTC injury was used consisting of mechanically wounding a monolayer of HK2 cells followed by repopulation of the denuded area by time lapse photomicroscopy. Repopulation was the result of cell migration but not proliferation. Addition of TGF-β1 led to a marked inhibition of cell migration increased expression of paxillin and vincullin and their incorporation into dense focal adhesion plaques. This was associated with increased association of focal adhesion components with the f-actin cytoskeleton. There was also increased β3 integrin expression and increased synthesis of the matrix component fibronectin. The effect on migration and focal adhesion reorganisation was abrogated by inhibitors of the RhoA downstream target ROCK, suggesting that signaling events resulting from altered β3 integrin expression initiate the TGF-β1 response. These results suggest that, by inhibition of cell migration, increased expression of TGF-β1 after ischemia delays recovery of proximal tubule structure and function. We speculate that this may contribute to permanent alteration in renal tubular function after severe ischemic injury. E-mail: [email protected]
Amylin: Pharmacology, Physiology, and Clinical Potential
Authors: Debbie L. Hay, Steve Chen, Thomas A. Lutz, David G. Parkes, Jonathan D. Roth
Journal: Pharmacological Reviews (2015)

Amylin is a pancreatic <i>β</i>-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein–coupled receptors resulting from the coexpression of a core receptor protein with receptor activity–modifying proteins, resulting in multiple receptor subtypes. Amylin's major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease. Other amylin actions have also been reported, such as on the cardiovascular system or on bone. Amylin acts principally in the circumventricular organs of the central nervous system and functionally interacts with other metabolically active hormones such as cholecystokinin, leptin, and estradiol. The amylin-based peptide, pramlintide, is used clinically to treat type 1 and type 2 diabetes. Clinical studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents.