tbuckley/cabot-search huggingface dataset:
Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor α Degradation
Authors: Valérie Lallemand-Breitenbach, Jun Zhu, Francine Puvion, Marcel Koken, Nicole Honoré, Alexandre Doubeikovsky, Estelle Duprez, Pier Paolo Pandolfi, Edmond Puvion, Paul Freemont, Hugues de Thé
Journal: The Journal of Experimental Medicine (2001)

Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PML nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) α expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (As2O3) restore them. PML is conjugated by the ubiquitin-related peptide SUMO-1, a process enhanced by As2O3 and proposed to target PML to the nuclear matrix. We demonstrate that As2O3 triggers the proteasome-dependent degradation of PML and PML/RARα and that this process requires a specific sumolation site in PML, K160. PML sumolation is dispensable for its As2O3-induced matrix targeting and formation of primary nuclear aggregates, but is required for the formation of secondary shell-like NBs. Interestingly, only these mature NBs harbor 11S proteasome components, which are further recruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only likely accounts for the failure of PML-K160R to be degraded. Therefore, studying the basis of As2O3-induced PML/RARα degradation we show that PML sumolation directly or indirectly promotes its catabolism, suggesting that mature NBs could be sites of intranuclear proteolysis and opening new insights into NB alterations found in viral infections or transformation.
Temporal correlation of pathology and DNA damage with gene expression in a choline-deficient model of rat liver injury
Authors: Christine L. Powell, Oksana Kosyk, Blair U. Bradford, Joel S. Parker, Edward K. Lobenhofer, Ayumi Denda, Fumiyuki Uematsu, Dai Nakae, Ivan Rusyn
Journal: Hepatology (2005)

Abstract Hepatocellular carcinoma (HCC) is the terminal event in chronic liver diseases with repeated cycles of cellular injury and regeneration. Although much is known about the cellular pathogenesis and etiological agents leading to HCC, the molecular events are not well understood. The choline-deficient (CD) model of rodent HCC involves the consecutive emergence of a fatty liver, apoptosis, compensatory proliferation, fibrosis, and cirrhosis that is markedly similar to the sequence of events typified by human HCC. Moreover, oxidative stress is thought to play a pivotal role in the progression of the disease. Here, we hypothesize that gene expression profiling can temporally mirror the histopathology and oxidative DNA damage observed with this model. We show that clusters of highly co-regulated genes representing distinct cellular pathways for lipid biosynthesis and metabolism, apoptosis, cell proliferation, and tissue remodeling temporally correlate with the well-defined sequential emergence of pathological alterations in the progression of liver disease. Additionally, an oxidative stress signature was observed that was corroborated in a time-dependent manner with increases in oxidized purines and abasic sites in DNA. Collectively, expression patterns were strongly driven by pathology, demonstrating that patterns of gene expression in advanced stages of liver disease are primarily driven by histopathological changes and to a much lesser degree by the original etiological agent. In conclusion , gene expression profiling coupled with the CD model of HCC provides a unique opportunity to unveil the molecular events associated with various stages of liver injury and carcinogenesis and to distinguish between causal and consecutive changes. Supplementary material for this article can be found on the Hepatologywebsite ( http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html ). (Hepatology 2005;42:1137–1147.)
Impact of Recent Increase in Incidence on Future Diabetes Burden
Authors: K.M. Venkat Narayan, James P. Boyle, Linda S. Geiss, Jinan B. Saaddine, Theodore J. Thompson
Journal: Diabetes Care (2006)

n an earlier study, we had forecasted 39 million with diagnosed diabetes in 2050 in the U.S. (1,2).However, since then, national diabetes incidence increased (3) and the relative risk of death among people with diabetes declined (4,5).These changes will impact future forecasts.Incorporating these changes, we now project 48.3 million people with diagnosed diabetes in the U.S. in 2050.We also present age-, sex-, and race/ethnicityspecific forecasts, with Bayesian CIs, of the number of people with diagnosed diabetes through 2050. RESEARCH DESIGN AND METHODS-We used a discretetime (1-year intervals), incidence-based Markov model with three states (no diagnosed diabetes, diagnosed diabetes, and death) (1).In each cycle of the model, projections are developed for 808 population subgroups defined by age, sex, and race/ethnicity.We estimated the age-, sex-, and race/ ethnicity-specific prevalence and incidence of diabetes from the U.S. National Health Interview Survey (6 -9) and modeled data for 1984 -2004 to improve the precision of 2004 estimates.Models were fit using Bayesian methods with improper flat priors applied to logistic regression.We assessed adequacy of model fit using posterior predictive P values (10).Estimated prevalence of diagnosed diabetes for 2000 and 2004 were
The Role of Limited Joint Mobility in Diabetic Patients With an At-Risk Foot
Authors: Stefan Zimny, Helmut Schatz, Martin Pfohl
Journal: Diabetes Care (2004)

To assess the role of limited joint mobility (LJM) in causing abnormal high plantar pressures in the forefoot of diabetic patients with an at-risk foot.A total of 70 type 1 or type 2 diabetic patients and 30 control subjects participated in this cross-sectional study. Thirty-five diabetic patients with an at-risk foot, defined as a foot with neuropathy but without ulceration or previous ulceration, and 35 diabetic control subjects without neuropathy were selected for the subgroups. Joint mobility was assessed in the foot at the ankle and metatarsophalangeal I (first MTP) joints. Using the FastScan plantar pressure analyzer, the pressure-time integrals (PTIs) as dynamic variables were measured in each foot. The clinical assessment included standard measures of peripheral neuropathy.The mobility at the ankle and first MTP joint were significantly reduced in the foot-at-risk group compared with the diabetic control group and the control subjects (P < 0.0001). The PTIs were significantly higher in the foot-at-risk group compared with the two other groups (P < 0.0001). There was a strong inverse correlation between the mobility of the ankle or first MTP joint and the PTI of the diabetic patients (r = -0.67, P < 0.0001, and r = -0.71, P < 0.0001, respectively). The vibration perception threshold was positively correlated with the PTI of the diabetic patients (r = 0.44, P = 0.0001).Diabetic patients with an at-risk foot have reduced joint mobility and elevated PTIs on the plantar forefoot, placing them at risk for subsequent ulceration. Therefore, LJM may be a possible factor in causing high plantar pressures and may contribute to foot ulceration in the susceptible neuropathic at-risk foot.
Very Low-Calorie Diets for Obesity
Authors: Gordon D. Kaplan
Journal: JAMA (1994)

<h3>To the Editor.</h3> —We applaud the National Institutes of Health National Task Force on the Prevention and Treatment of Obesity<sup>1</sup>for its well-balanced presentation of very low-calorie diets (VLCDs). An important point not made by the authors concerns appropriate criteria for evaluating the effectiveness of VLCDs. They were designed as a procedure for weight loss; as such, they have repeatedly been demonstrated to be effective.<sup>2</sup>Since VLCDs are, by definition, used short term, they are not useful for maintenance of long-term weight loss. Thus, it should come as no surprise that obese patients who have been successful on a VLCD would regain weight without continued support for a change in lifestyle. Poor long-term weight control data speak to the ineffectiveness of treatment models and program content. In addition, as stated by the authors, averages can hide successful groups of individuals. A two-year follow-up of three samples of patients
Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism
Authors: Tara C. Brennan-Speranza, Holger Henneicke, Sylvia J. Gasparini, Katharina I. Blankenstein, Uta Heinevetter, Victoria C. Cogger, Dmitri Svistounov, Yaqing Zhang, Gregory J. Cooney, Frank Buttgereit, Colin R. Dunstan, Caren Gundberg, Hong Zhou, Markus J. Seibel
Journal: Journal of Clinical Investigation (2012)

Long-term glucocorticoid treatment is associated with numerous adverse outcomes, including weight gain, insulin resistance, and diabetes; however, the pathogenesis of these side effects remains obscure. Glucocorticoids also suppress osteoblast function, including osteocalcin synthesis. Osteocalcin is an osteoblast-specific peptide that is reported to be involved in normal murine fuel metabolism. We now demonstrate that osteoblasts play a pivotal role in the pathogenesis of glucocorticoid-induced dysmetabolism. Osteoblast-targeted disruption of glucocorticoid signaling significantly attenuated the suppression of osteocalcin synthesis and prevented the development of insulin resistance, glucose intolerance, and abnormal weight gain in corticosterone-treated mice. Nearly identical effects were observed in glucocorticoid-treated animals following heterotopic (hepatic) expression of both carboxylated and uncarboxylated osteocalcin through gene therapy, which additionally led to a reduction in hepatic lipid deposition and improved phosphorylation of the insulin receptor. These data suggest that the effects of exogenous high-dose glucocorticoids on insulin target tissues and systemic energy metabolism are mediated, at least in part, through the skeleton.
Increased leucocyte adhesiveness/aggregation is a most useful indicator of disease activity in patients with inflammatory bowel disease.
Authors: N Arber, S Berliner, A Hallak, Y Bujanover, I Dotan, E Liberman, M Santo, M Moshkowitz, J Ratan, G Dotan
Journal: Gut (1995)

The aim of the study was to determine the comparative usefulness of inflammatory markers, in evaluating disease activity in patients with inflammatory bowel disease. Disease activity was assessed by the Mayo Clinic score for ulcerative colitis, and Harvey-Bradshaw score for Crohn's disease. Five hundred normal blood donors who had no underlying inflammatory condition served as controls. The erythrocyte sedimentation rate, platelet and white blood cell count, C reactive protein, and the leucocyte adhesiveness/aggregation test (LAAT) were determined in each patient. One hundred and twenty four patients with inflammatory bowel disease were tested while in remission and 128 in relapse. Their mean (SD) per cent of aggregated white blood cells in the peripheral blood was 8 (5) and 17 (10) respectively compared with controls 6 (4) (p < 0.0001). Moreover, the LAAT could effectively discriminate between various grades of disease activity, the values in patients with active disease being 13 (6)% in mild, 17 (10)% in moderate, and 26 (10)% in severe disease (p < 0.0001). Other acute phase reactants including the erythrocyte sedimentation rate, the white blood cell count, the platelet count, neutrophil count, as well as, the C reactive protein concentration did not differentiate as well between the various groups. Using logistic regression analysis to differentiate between inflammatory bowel disease patients in remission or relapse, the LAAT was the single best indicator. The addition of any other test did not contribute to the discrimination. Among the different laboratory variables tested only the LAAT significantly discriminated between the five different subgroups of controls, remission and mild, moderate or severe disease activity.
Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na <sup>+</sup> Channel
Authors: Marieke W. Veldkamp, Prakash C. Viswanathan, Connie Bezzina, Antonius Baartscheer, Arthur A. M. Wilde, Jeffrey R. Balser
Journal: Circulation Research (2000)

Abstract —The congenital long-QT syndrome (LQT3) and the Brugada syndrome are distinct, life-threatening rhythm disorders linked to autosomal dominant mutations in SCN5A , the gene encoding the human cardiac Na + channel. It is believed that these two syndromes result from opposite molecular effects: LQT3 mutations induce a gain of function, whereas Brugada syndrome mutations reduce Na + channel function. Paradoxically, an inherited C-terminal SCN5A mutation causes affected individuals to manifest electrocardiographic features of both syndromes: QT-interval prolongation (LQT3) at slow heart rates and distinctive ST-segment elevations (Brugada syndrome) with exercise. In the present study, we show that the insertion of the amino acid 1795insD has opposite effects on two distinct kinetic components of Na + channel gating (fast and slow inactivation) that render unique, simultaneous effects on cardiac excitability. The mutation disrupts fast inactivation, causing sustained Na + current throughout the action potential plateau and prolonging cardiac repolarization at slow heart rates. At the same time, 1795insD augments slow inactivation, delaying recovery of Na + channel availability between stimuli and reducing the Na + current at rapid heart rates. Our findings reveal a novel molecular mechanism for the Brugada syndrome and identify a new dual mechanism whereby single SCN5A mutations may evoke multiple cardiac arrhythmia syndromes by influencing diverse components of Na + channel gating function. The full text of this article is available at http://www.circresaha.org.
Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus
Authors: Gisela Orozco, Steve Eyre, Anne Hinks, John Bowes, Ann W Morgan, Anthony G Wilson, Paul Wordsworth, Sophia Steer, Lynne Hocking, Wendy Thomson, Jane Worthington, Anne Barton
Journal: Annals of the Rheumatic Diseases (2010)

Background Evidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases. Objective To investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls. Methods 3962 patients with RA and 9275 controls were included in the study. Eleven SNPs mapping to confirmed SLE loci were investigated. These mapped to the TNFSF4 , BANK1 , TNIP1 , PTTG1 , UHRF1BP1 , ATG5 , JAZF1 , BLK , KIAA1542 , ITGAM and UBE2L3 loci. Genotype frequencies were compared between patients with RA and controls using the trend test. Results The SNPs mapping to the BLK and UBE2L3 loci showed significant evidence for association with RA. Two other SNPs, mapping to ATG5 and KIAA1542 , showed nominal evidence for association with RA (p=0.02 and p=0.02, respectively) but these were not significant after applying a Bonferroni correction. Additionally, a significant global enrichment in carriage of SLE alleles in patients with RA compared with controls (p=9.1×10 −7 ) was found. Meta-analysis of this and previous studies confirmed the association of the BLK and UBE2L3 gene with RA at genome-wide significance levels (p&lt;5×10 −8 ). Together, the authors estimate that the SLE and RA overlapping loci, excluding HLA-DRB1 alleles, identified so far explain ∼5.8% of the genetic susceptibility to RA as a whole. Conclusion The findings confirm the association of the BLK and UBE2L3 loci with RA, thus adding to the list of loci showing overlap between RA and SLE.
Enrichment of antigen-specific B lymphocytes by the direct removal of B cells not bearing specificity for the antigen.
Authors: S M Walker, G C Meinke, W O Weigle
Journal: The Journal of Experimental Medicine (1977)

Antigen-specific B cells (ASC) were purified from other B cells by prior incubation with specific antigen followed by rosetting with erythrocytes conjugated with anti-mouse Ig and sedimenting on Ficoll-Isopaque. This procedure allowed the removal of most of the B cells, while those speicifc for the antigen used in incubation were retained. Relative to the B-cell content, ASC were enriched 64- to 132-fold. The method is highly specific in that B cells primed to two different antigens, turkey gamma globulin and sheep erythrocytes, could be separated from each other. The advantages of this indirect purification procedure over purification procedures which obtain ASC directly are the simplicity of obtaining the ASC and the ability of the ASC of respond to antigen without the addition of other cells.
Intracellular pH regulation in isolated rat bile duct epithelial cells.
Authors: M Strazzabosco, A Mennone, J L Boyer
Journal: Journal of Clinical Investigation (1991)

To evaluate ion transport mechanisms in bile duct epithelium (BDE), BDE cells were isolated from bile duct-ligated rats. After short-term culture pHi was measured with a single cell microfluorimetric set-up using the fluorescent pHi indicator BCECF, and calibrated with nigericin in high K+ concentration buffer. Major contaminants were identified using vital markers. In HCO3(-)-free media, baseline pHi (7.03 +/- 0.12) decreased by 0.45 +/- 0.18 pH units after Na+ removal and by 0.12 +/- .04 after amiloride administration (1 mM). After acid loading (20 mM NH4Cl) pHi recovery was inhibited by both Na+ removal and amiloride (JH+ = 0.74 +/- 1.1, and JH+ = 2.28 +/- 0.8, respectively, vs. 5.47 +/- 1.97 and 5.97 +/- 1.76 mM/min, in controls, respectively). In HCO3- containing media baseline pHi was higher (7.16 +/- 0.1, n = 36, P less than 0.05) and was decreased by Na+ substitution but not by amiloride. Na+ removal inhibited pHi recovery after an intracellular acid load (0.27 +/- 0.26, vs. 7.7 +/- 4.1 mM/min, in controls), whereas amiloride reduced JH+ only by 27%. pH recovery was inhibited by DIDS (0.5-1 mM), but not by Cl- depletion. Finally, acute Cl- removal increased pHi by 0.18 pH units in the absence but not presence of DIDS. These data indicate that BDE cells possess mechanisms for Na+/H+ exchange, Na+:HCO3- symport and Cl-/HCO3 exchange. Therefore BDE may be capable of transepithelial H+/HCO3- transport.
Apoptosis and Proinflammatory Cytokine Responses of Primary Mouse Microglia and Astrocytes Induced by Human H1N1 and Avian H5N1 Influenza Viruses
Authors: Gefei Wang, Juan Zhang, Weizhong Li, Gang Xin, Yun Su, Yuanli Gao, Heng Zhang, Guimei Lin, Xiaoyang Jiao, Kangsheng Li
Journal: Cellular and Molecular Immunology (2008)
Molecular evolution of the zinc-containing long-chain alcohol dehydrogenase genes.
Authors: S Yokoyama, R Yokoyama, C S Kinlaw, D E Harry
Journal: Molecular Biology and Evolution (1990)

Phylogenetic relationships and rates of nucleotide substitution were studied for alcohol dehydrogenase (ADH) genes by using DNA sequences from mammals and plants. Mammalian ADH sequences include the three class I genes and a class II gene from humans and one gene each from baboon, rat, and mouse. Plant sequences include two ADH genes each from maize and rice, three genes from barley, and one gene each from wheat and two dicots, Arabidopsis and pea. Phylogenetic trees show that relationships among ADH genes are generally consistent with taxonomic relationships: mammalian and plant ADH genes are classified into two distinct groups; primate class I genes are clustered; and two dicot sequences are clustered separately from monocot sequences. Accelerated evolution has been detected among the duplicated ADH genes in plants, in which synonymous substitutions occurred more often within the coenzyme-binding domain than within the catalytic domains.
Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice
Authors: Paolo E. Porporato, Nicoletta Filigheddu, Simone Reano, Michele Ferrara, Elia Angelino, Viola F. Gnocchi, Flavia Prodam, Giulia Ronchi, Sharmila Fagoonee, Michele Fornaro, Federica Chianale, Gianluca Baldanzi, Nicola Surico, Fabiola Sinigaglia, Isabelle Perroteau, Roy G. Smith, Yuxiang Sun, Stefano Geuna, Andrea Graziani
Journal: Journal of Clinical Investigation (2013)

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a–independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a–independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a–mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.
Permissive Hypercapnia Impairs Pulmonary Gas Exchange in the Acute Respiratory Distress Syndrome
Authors: FRANÇOIS FEIHL, PHILIPPE ECKERT, SERGE BRIMIOULLE, OLIVIER JACOBS, MARIE-DENISE SCHALLER, CHRISTIAN MÉLOT, ROBERT NAEIJE
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Current recommendations for mechanical ventilation in the acute respiratory distress syndrome (ARDS) include the use of small tidal volumes (VT), even at the cost of respiratory acidosis. We evaluated the effects of this permissive hypercapnia on pulmonary gas exchange with the multiple inert gas elimination technique (MIGET) in eight patients with ARDS. After making baseline measurements, we induced permissive hypercapnia by reducing VT from 10 +/- 2 ml/kg to 6 +/- 1 ml/kg (mean +/- SEM) at constant positive end-expiratory pressure. After restoration of initial VT, we infused dobutamine to increase cardiac output (Q) by the same amount as with hypercapnia. Permissive hypercapnia increased Q by an average of 1.4 L. min(-)(1). m(2), decreased arterial oxygen tension from 109 +/- 10 mm Hg to 92 +/- 11 mm Hg (p < 0.05), markedly increased true shunt (Q S/Q T), from 32 +/- 6% to 48 +/- 5% (p < 0.0001), and had no effect on the dispersion of VA/Q.VA/Q. On reinstatement of baseline V T with maintenance of a high Q, Q S/Q T remained increased, to 38 +/- 6% (p < 0.05), and Pa(O(2 ))remained decreased, to 93 +/- 4 mm Hg (p < 0. 05). These results agreed with effects of changes in VT and Q predicted by the mathematical lung model of the MIGET. We conclude that permissive hypercapnia increases pulmonary shunt, and that deterioration in gas exchange is explained by the combined effects of increased Q and decreased alveolar ventilation.
A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53 -Defective Tumors to Chemotherapy
Authors: Ian G. Cannell, Karl A. Merrick, Sandra Morandell, Chang-Qi Zhu, Christian J. Braun, Robert A. Grant, Eleanor R. Cameron, Ming-Sound Tsao, Michael T. Hemann, Michael B. Yaffe
Journal: Cancer Cell (2015)