tbuckley/cabot-search huggingface dataset:
In vivo alterations of IFN regulatory factor-1 and PIAS1 protein levels in cystic fibrosis epithelium
Authors: Thomas J. Kelley, Heather L. Elmer
Journal: Journal of Clinical Investigation (2000)

Inducible nitric oxide synthase-2 (NOS2) expression has been shown to be reduced in cystic fibrosis (CF) epithelial cells. Reduced NOS2 expression is unexpected, given the inflammatory nature of CF airway disease, and is an indication that cell-signaling mechanisms necessary for proper NOS2 regulation are probably altered in CF epithelium. Therefore, we examined the expression levels of regulatory factors necessary for NOS2 expression in CF epithelium and showed that IFN regulatory factor-1 (IRF-1) is necessary for full NOS2 expression. Mice lacking IRF-1 expression have diminished epithelial NOS2 expression, as well as reduced NO-dependent chloride transport across the nasal epithelia. Furthermore, IRF-1 protein expression is reduced in nasal and intestinal epithelial cells from CF mice, suggesting a possible mechanism for the CF-related reduction of epithelial NOS2 expression. Active signal transducer and activator of transcription-1 (Stat1) is necessary for both NOS2 and IRF-1 expression. We found that protein levels of Stat1 were increased in CF cells, but that the active phosphorylated form of Stat1 was bound to the protein inhibitor of activated Stat1 (PIAS1). We propose that increased levels of PIAS1 diminish certain cell-signaling pathways, resulting in reduced IRF-1 and NOS2 expression in CF epithelial cells.
Increasing Lung Cancer Death Rates Among Young Women in Southern and Midwestern States
Authors: Ahmedin Jemal, Jiemin Ma, Philip S. Rosenberg, Rebecca Siegel, William F. Anderson
Journal: Journal of Clinical Oncology (2012)

Purpose Previous studies reported that declines in age-specific lung cancer death rates among women in the United States abruptly slowed in women younger than age 50 years (ie, women born after the 1950s). However, in view of substantial geographic differences in antitobacco measures and sociodemographic factors that affect smoking prevalence, it is unknown whether this change in the trend was similar across all states. Methods We examined female age-specific lung cancer death rates (1973 through 2007) by year of death and birth in each state by using age-period-cohort models. Cohort relative risks adjusted for age and period effects were used to compare the lung cancer death rate for a given birth cohort to a referent birth cohort (ie, the 1933 cohort herein). Results Age-specific lung cancer death rates declined continuously in white women in California, but the rates declined less quickly or even increased in the remaining states among women younger than age 50 years and women born after the 1950s, especially in several southern and midwestern states. For example, in some southern states (eg, Alabama), lung cancer death rates among women born in the 1960s were approximately double those of women born in the 1930s. Conclusion The unfavorable lung cancer trend in white women born after circa 1950 in southern and midwestern states underscores the need for additional interventions to promote smoking cessation in these high-risk populations, which could lead to more favorable future mortality trends for lung cancer and other smoking-related diseases.
Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial
Authors: Craig S Anderson, Yining Huang, Ji Guang Wang, Hisatomi Arima, Bruce Neal, Bin Peng, Emma Heeley, Christian Skulina, Mark W Parsons, Jong Sung Kim, Qing Ling Tao, Yue Chun Li, Jian Dong Jiang, Li Wen Tai, Jin Li Zhang, En Xu, Yan Cheng, Stephane Heritier, Lewis B Morgenstern, John Chalmers
Journal: The Lancet Neurology (2008)
Airways in cystic fibrosis are acidified: detection by exhaled breath condensate
Authors: S Tate
Journal: Thorax (2002)

<b>Background:</b> The loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride conductance does not fully explain the diverse pathologies evident in patients with cystic fibrosis (CF). Bicarbonate (HCO<sub>3</sub><sup>−</sup>) secretion is also impaired in CFTR expressing tissues and CFTR is thought to regulate HCO<sub>3</sub><sup>−</sup> secretion at the apical membrane of epithelial cells. We hypothesised that the epithelial lining fluid (ELF) of patients with CF would be acidified and that this may be worsened during an infective exacerbation due to the increased inflammatory burden. <b>Methods:</b> pH and nitrite levels in exhaled breath condensate (EBC) from 12 healthy non-smoking controls and 30 patients with CF (11 of whom were in an infective exacerbation) were measured. A further nine patients were studied before and after intravenous antibiotic treatment for an exacerbation of CF. <b>Results:</b> The pH of EBC was significantly lower in patients with stable CF than in controls (5.88 (0.32) <i>v</i> 6.15 (0.16), p=0.017), and was further reduced in CF patients with an exacerbation (5.32 (0.38), p=0.001) compared with stable CF patients. EBC pH increased significantly following antibiotic treatment from 5.27 (0.42) to 5.71 (0.42), p=0.049). Nitrite levels in EBC were increased in CF patients with an exacerbation compared with control subjects (4.4 (4.0) μm <i>v</i> 1.6 (1.6) μm p=0.047). No correlation was found between EBC pH and nitrite levels. <b>Conclusions:</b> These findings support the hypothesis that airway acidification occurs in CF. This acidity is in part a function of inflammation as the pH of the EBC of patients increased significantly with treatment of an exacerbation, although not to control levels. Acidic pH of the ELF may play a role in the pathophysiology of CF lung disease and requires further investigation.
Spontaneous resolution of acute gouty arthritis is associated with rapid induction of the anti-inflammatory factors TGF 1, IL-10 and soluble TNF receptors and the intracellular cytokine negative regulators CIS and SOCS3
Authors: Y.-H. Chen, S.-C. Hsieh, W.-Y. Chen, K.-J. Li, C.-H. Wu, P.-C. Wu, C.-Y. Tsai, C.-L. Yu
Journal: Annals of the Rheumatic Diseases (2011)

The molecular basis for spontaneous resolution of acute gouty arthritis (GA) remains unclear. The hypothesis that extracellular and intracellular mechanisms play roles in resolving acute GA was tested.Synovial fluid (SF) levels of transforming growth factor β1 (TGFβ1), interleukin 1 (IL-1) receptor antagonist (IL-1ra), IL-10 and soluble tumour necrosis factor (TNF) receptor I (sTNFRI) and II (sTNFRII) were measured by ELISA in patients with acute GA and osteoarthritis (OA). Monosodium urate (MSU) crystal-stimulated RAW264.7 mouse macrophages were analysed for cytokine inducible SH2-containing protein (CIS) and suppressors of cytokine signalling (SOCS)1-7 mRNA expression by reverse transcription (RT)-PCR. Immunohistochemical analysis, quantitative PCR and immunoblotting were performed to detect CIS and SOCS3 expression in synovial tissue, SF mononuclear cells (SFMCs) from patients with GA and MSU crystal-stimulated monocyte-derived macrophages from healthy donors. CIS overexpression and small interfering RNA-mediated knockdown in RAW264.7 cells were used to investigate the role of CIS in resolving MSU crystal-induced acute inflammation.SF levels of anti-inflammatory molecules TGFβ1, IL-1ra, IL-10 and sTNFR-I/II were significantly elevated in GA compared to OA. CIS and SOCS3 were upregulated in the synovium and SFMCs from acute GA and MSU crystal-stimulated monocyte-derived macrophages and RAW264.7 cells. CIS overexpression in RAW264.7 cells attenuated MSU crystal-induced IL-1β and TNFα but enhanced TGFβ1 production via increased binding of signal transducer and activator of transcription 3 (STAT3) to the TGFβ1 promoter. Conversely, CIS knockdown reversed the effect of CIS overexpression, resulting in enhanced IL-1β and TNFα but reduced TGFβ1 production in MSU crystal-stimulated RAW264.7 cells.Increased production of TGFβ1, IL-1ra, IL-10 and sTNFR-I/II and upregulation of intracellular CIS and SOCS3 expression are associated with spontaneous resolution of acute GA.
Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice
Authors: Tokio Matsuzaki, Takehiko Matsushita, Koji Takayama, Tomoyuki Matsumoto, Kotaro Nishida, Ryosuke Kuroda, Masahiro Kurosaka
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Important roles for SIRT1 are implicated in ageing and age-related diseases. The role of SIRT1 in osteoarthritis (OA), however, remains partially unknown. To investigate the role of SIRT1 in chondrocytes in vivo, cartilage-specific <i>Sirt1-</i>conditional knockout (CKO) mice were analysed using an experimental OA model. <h3>Methods</h3> OA was surgically induced in 8-week-old C57BL6/J (wild-type) mice and <i>Sirt1</i>-CKO (<i>Sirt1</i><sup>flox</sup>/<sup>flox</sup>; <i>Col2a1-Cre</i>) mice generated using the Cre-<i>lox</i>P system. We examined changes in Sirt1 protein during the development of surgically-induced OA and during ageing in wild-type mice. OA progression in <i>Sirt1</i>-CKO mice was evaluated histologically at 2, 4 and 8 weeks after surgery, and at 1 year of age without surgery compared with control (<i>Sirt1</i><sup>flox</sup>/<sup>flox</sup>) mice. <h3>Results</h3> The number of Sirt1-positive chondrocytes decreased during ageing, and although it was increased at 2 weeks after surgery, then gradually decreased to the presurgical level during the progression of OA in wild-type mice. <i>Sirt1</i>-CKO mice showed no obvious skeletal abnormalities. The histological OA score was significantly higher in 1-year-old <i>Sirt1</i>-CKO mice than in control mice. <i>Sirt1</i>-CKO mice showed accelerated OA progression at 2 and 4 (but not 8) weeks compared with control mice. Immunohistochemical analysis revealed increases in type X collagen, matrix metalloproteinase 13, a disintegrin and metalloproteinase with thrombospondin motifs-5, apoptotic markers, and acetylated nuclear factor-κB p65 in <i>Sirt1</i>-CKO mice compared with control mice 2 weeks after surgery. <h3>Conclusions</h3> Loss of Sirt1 in chondrocytes led to the accelerated development of OA in mice. Our observations suggest that SIRT1 has a preventive role against the development of OA.
Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice
Authors: Margarete Mehrabian, Hooman Allayee, Jack Wong, Weibin Shih, Xu-Ping Wang, Zory Shaposhnik, Colin D. Funk, Aldons J. Lusis
Journal: Circulation Research (2002)

We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor-null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined. The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor-null (LDLR(-/-)) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold; P<0.0005) in aortic lesion development, similar to the CON6 mice. Immunohistochemistry revealed that 5-LO was abundantly expressed in atherosclerotic lesions of apoE(-/-) and LDLR(-/-) deficient mice, appearing to colocalize with a subset of macrophages but not with all macrophage-staining regions. When bone marrow from 5-LO(+/-) mice was transplanted into LDLR(-/-), there was a significant reduction in atherogenesis, suggesting that macrophage 5-LO is responsible, at least in part, for the effect on atherosclerosis. These results indicate that 5-LO contributes importantly to the atherogenic process and they provide strong presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis in CON6 mice.
Tomato nuclear proteome reveals the involvement of specific E2 ubiquitin-conjugating enzymes in fruit ripening
Authors: Yuying Wang, Weihao Wang, Jianghua Cai, Yanrui Zhang, Guozheng Qin, Shiping Tian
Journal: Genome biology (2014)

Abstract Background Fruits are unique to flowering plants and play a central role in seed maturation and dispersal. Molecular dissection of fruit ripening has received considerable interest because of the biological and dietary significance of fruit. To better understand the regulatory mechanisms underlying fruit ripening, we report here the first comprehensive analysis of the nuclear proteome in tomato fruits. Results Nuclear proteins were isolated from tomatoes in different stages of ripening, and subjected to iTRAQ (isobaric tags for relative and absolute quantification) analysis. We show that the proteins whose abundances change during ripening stages are involved in various cellular processes. We additionally evaluate changes in the nuclear proteome in the ripening-deficient mutant, ripening-inhibitor ( rin ), carrying a mutation in the transcription factor RIN. A set of proteins were identified and particular attention was paid to SlUBC32 and PSMD2, the components of ubiquitin-proteasome pathway. Through chromatin immunoprecipitation and gel mobility shift assays, we provide evidence that RIN directly binds to the promoters of SlUBC32 and PSMD2 . Moreover, loss of RIN function affects protein ubiquitination in nuclei. SlUBC32 encodes an E2 ubiquitin-conjugating enzyme and a genome-wide survey of the E2 gene family in tomatoes identified five more E2s as direct targets of RIN. Virus-induced gene silencing assays show that two E2s are involved in the regulation of fruit ripening. Conclusions Our results uncover a novel function of protein ubiquitination, identifying specific E2s as regulators of fruit ripening. These findings contribute to the unraveling of the gene regulatory networks that control fruit ripening.
Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet
Authors: Gary D. Foster
Journal: Annals of Internal Medicine (2010)

This article has been corrected. The original version (PDF) is appended to this article as a supplement. Background: Previous studies comparing low-carbohydrate and low-fat diets have not included a comprehensive behavioral treatment, resulting in suboptimal weight loss. Objective: To evaluate the effects of 2-year treatment with a low-carbohydrate or low-fat diet, each of which was combined with a comprehensive lifestyle modification program. Design: Randomized parallel-group trial. (ClinicalTrials.gov registration number: NCT00143936) Setting: 3 academic medical centers. Patients: 307 participants with a mean age of 45.5 years (SD, 9.7 years) and mean body mass index of 36.1 kg/m2 (SD, 3.5 kg/m2). Intervention: A low-carbohydrate diet, which consisted of limited carbohydrate intake (20 g/d for 3 months) in the form of low–glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants in the low-carbohydrate diet group increased their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. A low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d; ≤30% calories from fat). Both diets were combined with comprehensive behavioral treatment. Measurements: Weight at 2 years was the primary outcome. Secondary measures included weight at 3, 6, and 12 months and serum lipid concentrations, blood pressure, urinary ketones, symptoms, bone mineral density, and body composition throughout the study. Results: Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. There were no differences in weight, body composition, or bone mineral density between the groups at any time point. During the first 6 months, the low-carbohydrate diet group had greater reductions in diastolic blood pressure, triglyceride levels, and very-low-density lipoprotein cholesterol levels, lesser reductions in low-density lipoprotein cholesterol levels, and more adverse symptoms than did the low-fat diet group. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol levels at all time points, approximating a 23% increase at 2 years. Limitation: Intensive behavioral treatment was provided, patients with dyslipidemia and diabetes were excluded, and attrition at 2 years was high. Conclusion: Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years. Primary Funding Source: National Institutes of Health.
Limitation of Myocardial Function by Reduced Coronary Blood Flow during Isoproterenol Action
Authors: HERMAN B. DANIELL, ERVIN E. BAGWELL, ROBERT P. WALTON
Journal: Circulation Research (1967)

The interpolated decrease in heart force or isometric systolic tension that occurs during isoproterenol stimulation has been examined in terms of changes in coronary flow and myocardial metabolism. In 67 open-chest dogs under pentobarbital anesthesia, determinations were made of lactate, pyruvate, Po 2 and Pco 2 in arterial and coronary sinus blood; coronary flow was measured with an electromagnetic flow transducer and ventricular force with a strain gauge arch. Although the characteristic, uncomplicated effect of isoproterenol is a marked increase in coronary flow and contractile force, this is briefly interrupted by a sharp decrease in these functions, and the decrease is associated with evidence of anaerobic metabolism. This decrease is concomitant with decreased coronary perfusion pressure and is intensified by sustained infusion of isoproterenol or by lowered oxygen concentrations in the inspired air. The stage of depressed function is counteracted by mechanical maintenance of high aortic pressure or by slow, controlled heart rate. When uncontrolled, tachycardia due to isoproterenol continues without phasic interruption. The intermediate period of depressed function is interpreted in terms of sharply decreased oxygen delivery when both cardiac rate and force are increased. The hemodynamic and metabolic values for these acutely occurring, reversible extremes have been specified.
Absence of Canonical Smad Signaling in Ureteral and Bladder Mesenchyme Causes Ureteropelvic Junction Obstruction
Authors: Piyush Tripathi, Yinqiu Wang, Adam M. Casey, Feng Chen
Journal: Journal of the American Society of Nephrology (2012)

Obstruction of the ureteropelvic junction (UPJ) is a common congenital anomaly frequently associated with ureteral defects. To study the molecular mechanisms that modulate ureteral development, we inactivated Smad4, the common Smad critical for transcriptional responses to TGF-β and Bmp signaling, in the ureteral and bladder mesenchyme during embryogenesis. Loss of canonical Smad signaling in these tissues caused bilateral UPJ obstruction and severe hydronephrosis beginning at embryonic day 17.5. Despite a reduction in quantity of ureteral smooth muscle, differentiation proceeded without Smad4, producing a less severe phenotype than Bmp4 mutants; this finding suggests that at least some Bmp4 functions in ureteral smooth muscle may be Smad-independent. The absence of canonical Smad signaling in the ureteral mesenchyme, but not in the urothelium itself, led to urothelial disorganization, highlighting the importance of mesenchymal support for epithelial development. Transcript profiling revealed altered expression in known Bmp targets, smooth muscle-specific genes, and extracellular matrix-related genes in mutant ureters before the onset of hydronephrosis. Expression of the Bmp target Id2 was significantly lower in Smad4 mutants, consistent with the observation that Id2 mutants develop UPJ obstruction. In summary, Smad4 deficiency reduces the number and contractility of ureteral smooth muscle cells, leading to abnormal pyeloureteral peristalsis and functional obstruction. The subsequent bending and luminal constriction of the ureter at the UPJ marks the transition from a functional obstruction to a more intractable physical obstruction, suggesting that early intervention for this disease may prevent more irreversible damage to the urinary tract.
Validation of Prediction of Diabetes by the Archimedes Model and Comparison With Other Predicting Models
Authors: Michael Stern, Ken Williams, David Eddy, Richard Kahn
Journal: Diabetes Care (2008)

To validate the ability of the Archimedes model to accurately predict the risk of developing diabetes in individuals.Subjects were randomly selected from the San Antonio Heart Study population. The area under the receiver operating characteristic (aROC) curve derived from the Archimedes model was calculated and also compared with the aROCs from two published multiple logistic regression models designed to estimate diabetes risk.The aROC for the Archimedes model was 0.818 (95% CI 0.739-0.899) compared with aROCs of 0.869 (0.801-0.936) and 0.870 (0.802-0.937) for the two logistic regression models, respectively. Risk estimates from the logistic models were highly correlated with the estimates derived from the Archimedes model.The Archimedes model predicts individual diabetes risk with a high level of sensitivity and specificity, comparable with that of models designed specifically for that purpose. Unlike the latter models, Archimedes also predicts the risk of numerous other health outcomes.
Arthritogenicity of annexin VII revealed by phosphoproteomics of rheumatoid synoviocytes
Authors: K. Matsuo, M. Arito, K. Noyori, H. Nakamura, M. S. Kurokawa, K. Masuko, K. Okamoto, K. Nagai, N. Suematsu, K. Yudoh, M. Beppu, T. Saito, T. Kato
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To identify novel proteins involved in the pathogenesis of rheumatoid arthritis (RA) and to characterise the identified proteins based on pathogenic and therapeutic aspects. <h3>Methods</h3> The authors applied differential phosphoproteomic analysis to articular synoviocytes between RA and osteoarthritis (OA) to identify proteins differently phosphorylated between RA and OA. Focusing on annexin VII (Anx7), one of the highly phosphorylated proteins in RA, the authors prepared <i>Anx7</i>-transgenic C57BL/6 (<i>Anx7</i>-Tg-B6) mice to evaluate their susceptibility to collagen-induced arthritis (CIA). In addition, the authors examined the effect of anti-Anx7 antibodies (Abs) on CIA and serum levels of cytokines in wild-type DBA/1J mice, which are known to be susceptible to CIA, and in <i>Anx7</i>-Tg-B6 mice. In vitro, the authors examined the effect of the Anx7 knockdown by small interfering RNA on the secretion of cytokines in rheumatoid synoviocytes and the human synovial sarcoma cell line SW982. <h3>Results</h3> The <i>Anx7</i> transgene altered the CIA-resistant B6 mice to CIA-susceptible ones. The Abs treatment suppressed CIA even in the wild-type DBA/1J mice. The serum levels of cytokines including interleukin 6 (IL-6) and TNFα were not altered by the Abs treatment in vivo. On the other hand, the knockdown of Anx7 by small interfering RNA caused downregulation of IL-8 secretion in vitro. <h3>Conclusions</h3> These results indicate that Anx7 participates in the pathogenesis of RA partly through the secretion of IL-8. The study data have demonstrated the pathogenic roles and therapeutic significance of Anx7 in RA for the first time.