tbuckley/cabot-search huggingface dataset:
Passive Stiffness Changes Caused by Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts
Authors: I. Makarenko, C.A. Opitz, M.C. Leake, C. Neagoe, M. Kulke, J.K. Gwathmey, F. del Monte, R.J. Hajjar, W.A. Linke
Journal: Circulation Research (2004)

In the pathogenesis of dilated cardiomyopathy, cytoskeletal proteins play an important role. In this study, we analyzed titin expression in left ventricles of 19 control human donors and 9 severely diseased (nonischemic) dilated cardiomyopathy (DCM) transplant-patients, using gel-electrophoresis, immunoblotting, and quantitative RT-PCR. Both human-heart groups coexpressed smaller (approximately 3 MDa) N2B-isoform and longer (3.20 to 3.35 MDa) N2BA-isoforms, but the average N2BA:N2B-protein ratio was shifted from approximately 30:70 in controls to 42:58 in DCM hearts, due mainly to increased expression of N2BA-isoforms >3.30 MDa. Titin per unit tissue was decreased in some DCM hearts. The titin-binding protein obscurin also underwent isoform-shifting in DCM. Quantitative RT-PCR revealed a 47% reduction in total-titin mRNA levels in DCM compared with control hearts, but no differences in N2B, all-N2BA, and individual-N2BA transcripts. The reduction in total-titin transcripts followed from a decreased area occupied by myocytes and increased connective tissue in DCM hearts, as detected by histological analysis. Force measurements on isolated cardiomyofibrils showed that sarcomeric passive tension was reduced on average by 25% to 30% in DCM, a reduction readily predictable with a model of wormlike-chain titin elasticity. Passive-tension measurements on human-heart fiber bundles, before and after titin proteolysis, revealed a much-reduced relative contribution of titin to total passive stiffness in DCM. Results suggested that the titin-isoform shift in DCM depresses the proportion of titin-based stiffness by approximately 10%. We conclude that a lower-than-normal proportion of titin-based stiffness in end-stage failing hearts results partly from loss of titin and increased fibrosis, partly from titin-isoform shift. The titin-isoform shift may be beneficial for myocardial diastolic function, but could impair the contractile performance in systole.
Relationship Between Childhood Behavioral Disturbance and Later Schizophrenia in the New York High-Risk Project
Authors: G. Paul Amminger, Sky Pape, Donald Rock, Simone A. Roberts, Salome Looser Ott, Elizabeth Squires-Wheeler, Clarice Kestenbaum, L. Erlenmeyer-Kimling
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: An association between childhood behavioral disturbance and adulthood schizophrenia has been seen previously in retrospective or follow-back studies and in prospective studies. The authors examined the relationship between childhood behavioral problems and adulthood schizophrenia-related psychoses. Because a high rate of childhood behavioral problems is known to be associated with adult substance abuse, these analyses controlled for substance abuse. METHOD: The subjects of this investigation (N=185) were offspring of parents with schizophrenia or affective disorder and of normal parents from the New York High-Risk Project (sample A). Data on childhood behavioral problems were obtained in a parent interview at initial assessment in 1971–1972. Adulthood outcomes (schizophrenia-related psychoses, affective disorders, anxiety disorders, substance abuse) were based on lifetime axis I diagnoses according to the Research Diagnostic Criteria. RESULTS: Substance abuse had a significant interaction with the clinical outcome groups. In subjects without substance abuse, those with schizophrenia-related psychoses had exhibited significantly more behavioral problems as children than had adult offspring with affective or anxiety disorder or with substance abuse only or no disorder. CONCLUSIONS: These results support the view that schizophrenia-related psychoses can be followed back to early behavioral disturbances. The confounding effects of substance abuse should be statistically controlled in studies of longitudinal associations between childhood behavioral disturbance and axis I outcomes.
Bone scintigraphy for osteonecrosis of the knee in patients with non-traumatic osteonecrosis of the femoral head: comparison with magnetic resonance imaging
Authors: T Sakai
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> To determine whether technetium bone scintigraphy (BS) is useful for screening of non-traumatic osteonecrosis of the knee (ONK), which was a major affected site, secondary to the femoral head, among multiple osteonecrosis, in patients with non-traumatic osteonecrosis of the femoral head (ONFH). <h3>METHODS</h3> A total of 214 knee joints in 107 patients with ONFH were evaluated by BS and a comparison made with magnetic resonance imaging (MRI). ONK was classified into five sites, including the femoral condyles (ONFC), distal femoral metaphysis (ONFM), tibial plateau (ONTP), proximal tibial metaphysis (ONTM), and patella (ONP). <h3>RESULTS</h3> Based on the diagnosis by MRI, ONK was detected in 103 knees of 62 patients (48%). ONFC was most common (86 knees, 40%), ONFM (15%), followed by ONTM (10%), ONP (3%), and ONTP (0.9%). Sensitivity, specificity, and accuracy of BS for ONFC detection were 63%, 71%, and 68%, respectively. When the ONFC lesions on the coronal views of MRI were large or medium sized and occupied two thirds, or the entire anteroposterior joint surface on the sagittal views, the sensitivity of BS for ONFC detection increased to 89% (34/38 knees). The sensitivity of BS for ONFM, ONTM, and ONP detection was 3%, 0%, and 0%, respectively, but these lesions showed a low likelihood of collapse. <h3>CONCLUSION</h3> BS is useful for screening large ONK in patients with ONFH given that 89% of patients with ONFC who had a high risk of collapse of the knee were identified.
Regulation of eNOS Expression in Brain Endothelial Cells by Perinuclear EP <sub>3</sub> Receptors
Authors: Fernand Gobeil, Isabelle Dumont, Anne Marilise Marrache, Alejandro Vazquez-Tello, Sylvie G. Bernier, Daniel Abran, Xin Hou, Martin H. Beauchamp, Christiane Quiniou, Asmaa Bouayad, Sanaa Choufani, Mousumi Bhattacharya, Stephane Molotchnikoff, Alfredo Ribeiro-da-Silva, Daya R. Varma, Ghassan Bkaily, Sylvain Chemtob
Journal: Circulation Research (2002)

We reported upregulation of endothelial nitric oxide synthase (eNOS) by PGE(2) in tissues and presence of perinuclear PGE(2) receptors (EP). We presently studied mechanisms by which PGE(2) induces eNOS expression in cerebral microvessel endothelial cells (ECs). 16,16-Dimethyl PGE(2) and selective EP(3) receptor agonist M&B28767 increased eNOS expression in ECs and the NO-dependent vasorelaxant responses induced by substance P on cerebral microvessels. These effects could be prevented by prostaglandin transporter blocker bromcresol green and actinomycin D. EP(3) immunoreactivity was confirmed on plasma and perinuclear membrane of ECs. M&B28767 increased eNOS RNA expression in EC nuclei, and this effect was augmented by overexpression of EP(3) receptors. M&B28767 also induced increased phosphorylation of Erk-1/2 and Akt, as well as changes in membrane potential revealed by the potentiometric fluorescent dye RH421, which were prevented by iberiotoxin; perinuclear K(Ca) channels were detected, and their functionality corroborated by NS1619-induced Ca(2+) signals and nuclear membrane potential changes. Moreover, pertussis toxin, Ca(2+) chelator, and channel blockers EGTA, BAPTA, and SK&F96365, as well as K(Ca) channel blocker iberiotoxin, protein-kinase inhibitors wortmannin and PD 98059, and NF-kappaB inhibitor pyrrolidine dithiocarbamate prevented M&B28767-induced increase in Ca(2+) transients and/or eNOS expression in EC nuclei. We describe for the first time that PGE(2) through its access into cell by prostaglandin transporters induces eNOS expression by activating perinuclear EP(3) receptors coupled to pertussis toxin-sensitive G proteins, a process that depends on nuclear envelope K(Ca) channels, protein kinases, and NF-kappaB; the roles for nuclear EP(3) receptors seem different from those on plasma membrane.
WHAT WORKS, AND WHAT REMAINS TO BE DONE, IN HIV PREVENTION IN THE UNITED STATES
Authors: David R. Holtgrave, James W. Curran
Journal: Annual Review of Public Health (2005)

▪ Abstract Since the beginning of the HIV epidemic in the United States, HIV prevention programs have prevented hundreds of thousands of HIV infections, and the investment in these programs has actually been cost-saving to society in terms of medical costs averted. A substantial body of evidence exists (including randomized controlled trials and careful meta-analyses) which demonstrates that various HIV prevention services are effective; an increasingly large body of data also demonstrates the cost-effectiveness of these interventions. However, the efforts to utilize these interventions in a comprehensive HIV prevention program are hampered by insufficient funding, imperfect targeting strategies, and a problematic policy environment that creates barriers to the use of some of these life-saving interventions. Progress toward reducing new HIV infections will likely be as much a function of improvements in funding and policies as it will in the development of new tools for HIV prevention.
IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge
Authors: Shabaana A Khader, Guy K Bell, John E Pearl, Jeffrey J Fountain, Javier Rangel-Moreno, Garth E Cilley, Fang Shen, Sheri M Eaton, Sarah L Gaffen, Susan L Swain, Richard M Locksley, Laura Haynes, Troy D Randall, Andrea M Cooper
Journal: Nature Immunology (2007)
Differentiation Between Obesity and Insulin Resistance in the Association With C-Reactive Protein
Authors: Tracey McLaughlin, Fahim Abbasi, Cindy Lamendola, Lynn Liang, Gerald Reaven, Patricia Schaaf, Peter Reaven
Journal: Circulation (2002)

Background— Plasma C-reactive protein (CRP) concentrations are increased in obese and/or hyperinsulinemic individuals. The goal of this study was to determine if the relation between insulin resistance and CRP was independent of obesity. Methods and Results— Plasma CRP concentrations were measured before and after 3 months of calorie restriction in 38 healthy, obese women. Steady-state plasma glucose (SSPG) concentration during a 180-minute infusion of octreotide, glucose, and insulin was used to stratify participants into insulin-resistant (IR, n=20) or insulin-sensitive (n=18) groups, similar in terms of mean age (46±2 versus 44±2 years), body mass index (32.0±0.4 versus 31.4±0.3 kg/m 2 ), and waist circumference (96±2 versus 95±2 cm). Mean CRP (0.39±0.08 versus 0.12±0.03 mg/dL, P =0.003) concentrations were higher in the IR group, as were day-long plasma glucose and insulin responses ( P &lt;0.001). There was a significant correlation at baseline between CRP and day-long plasma integrated insulin response ( r =0.47, P =0.001) but not between CRP and body mass index ( r =0.14) or waist circumference ( r =0.10). Weight loss was similar in the two groups ( 8.7±0.9 versus 8.4±0.8 kg) but was associated with significant ( P &lt;0.001) decreases in SSPG and CRP concentrations in the IR group only. Regression analysis showed that SSPG and day-long plasma insulin response were the only significant predictors of CRP concentration. Conclusions— CRP concentrations are elevated predominantly in obese individuals who are also insulin resistant and fall in parallel with weight loss–associated improvements in insulin resistance. The relation between CRP concentrations and insulin resistance is independent of obesity.
Podocyte Biology and Response to Injury
Authors: Peter Mundel, Stuart J. Shankland
Journal: Journal of the American Society of Nephrology (2002)

The visceral glomerular epithelial cell, also called podocyte, is a terminally differentiated cell that lines the outer aspect of the glomerular basement membrane (GBM). It therefore forms the final barrier to protein loss, which explains why podocyte injury is typically associated with marked
Abstract A29: Genomic alteration of E2F/Rb activates EZH2 in small cell lung cancer
Authors: Kelsie L. Thu, Roland Hubaux, Sarit Aviel-Ronen, Calum E. MacAulay, Ming-Sound Tsao, Stephen Lam, Wan L. Lam, Bradley P. Coe
Journal: Clinical Cancer Research (2012)

Abstract Introduction: Small Cell Lung Cancer (SCLC) is a highly aggressive lung tumor with a 5 year survival rate of only 5% for extensive stage disease, which has only modestly improved over the last few decades. Identification of new molecular diagnostic and therapeutic targets is thus imperative. The purpose of this study was to employ genomic profiling of SCLC tumors to identify novel genomic alterations responsible for driving the aggressive biology of SCLC. Methods: DNA was extracted from a panel of 14 formalin fixed paraffin embedded SCLC tumors and used to perform high resolution array comparative genomic hybridization (aCGH) on a tiling array to identify recurrent copy number alterations. RNA was harvested from a series of SCLC cell lines and used to perform qRT-PCR on candidate genes. Publicly available SCLC tumor microarray data was also analyzed to interrogate the expression of candidate genes. Results: Through application of integrated genome and transcriptome microarray profiling, and comparison of SCLC to less aggressive non-small cell lung cancers (NSCLC) we have identified novel patterns of genomic alteration mediated pathway disruption specific to SCLC. This includes activation of the cell cycle through deregulation of downstream pathway components, as opposed to upstream deregulation of receptors such as EGFR which is characteristic of NSCLC. Strikingly we observed direct genomic activation of E2F transcription factors, in addition to the classically described loss of the Rb tumor suppressor. Analysis of targets of the E2F/Rb pathway identified EZH2, a polycomb repressive complex 2 (PRC2) member involved in epigenetic silencing of genes involved in differentiation. EZH2 has been characterized as a target of genomic amplification in prostate and breast cancers, however, no genomic amplifications were detected in our SCLC samples, thus any overexpression is likely regulated by upstream elements of the E2F/Rb pathway. qRT-PCR confirmed EZH2 as being specifically hyper-activated with a mean 42 fold over-expression (range 10 to 74 fold) in SCLC compared to 13 fold in NSCLC. This pattern was verified from an analysis of an independent array study of SCLC. Moreover, shRNA-mediated knockdown demonstrated a significant reduction in cell viability in SCLC cell lines. Conclusion: We conclude that EZH2 activation through genomic alteration of E2F/Rb contributes to the malignant phenotype of SCLC and may represent a potential therapeutic target.
Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21
Authors: G Monteleone, R Caruso, D Fina, I Peluso, V Gioia, C Stolfi, M C Fantini, F Caprioli, R Tersigni, L Alessandroni, T T MacDonald, F Pallone
Journal: Gut (2006)

<b>Background:</b> T cell-mediated immunity plays a central part in the pathogenesis of tissue damage in inflammatory bowel disease (IBD). The mechanism by which T cells mediate tissue damage during IBD remains unclear, but evidence indicates that T cell-derived cytokines stimulate fibroblasts to synthesise matrix metalloproteinases (MMPs), which then mediate mucosal degradation. We have previously shown that, in IBD, there is high production of interleukin (IL) 21, a T cell-derived cytokine, which enhances Th1 activity. <b>Aim:</b> To investigate whether IL21 controls MMP production by intestinal fibroblasts. <b>Methods:</b> IL21 receptor (IL21R) was evaluated in intestinal fibroblasts by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. Fibroblasts were stimulated with IL21 and MMPs were evaluated by RT-PCR and western blotting. The effect of a neutralising IL21R fusion protein (IL21R/Fc) on the induction of MMPs in fibroblasts stimulated with IBD lamina propria mononuclear cell (LPMC) supernatants was also evaluated. <b>Results:</b> Intestinal fibroblasts constitutively express both IL21R and the common γ chain receptor, which are necessary for IL21-driven signalling. IL21 enhances fibroblast production of MMP-1, MMP-2, MMP-3 and MMP-9, but not tissue inhibitors of MMP-1 and MMP-2. Moreover, IL21 synergises with tumour necrosis factor α to increase synthesis of MMP synthesis. IL21 enhances MMP secretion without affecting gene transcription and protein synthesis. IBD LPMC supernatants stimulate MMP secretion by intestinal fibroblasts, and this effect is partly inhibited by IL21R/Fc. <b>Conclusions:</b> These results suggest that fibroblasts are a potential target of IL21 in the gut and that IL21 controls MMP secretion by fibroblasts.
LRRC50, a Conserved Ciliary Protein Implicated in Polycystic Kidney Disease
Authors: Ellen van Rooijen, Rachel H. Giles, Emile E. Voest, Carina van Rooijen, Stefan Schulte-Merker, Freek J. van Eeden
Journal: Journal of the American Society of Nephrology (2008)

OBJECTIVE: To identify the optimal office cognitive screening exam by comparing patterns of performance on three commonly administered office mental status examinations in adults with Autism Spectrum Disorders (ASDs) BACKGROUND: Though there is extensive knowledge regarding neuropsychological performance in individuals with ASDs, to our knowledge there is no data evaluating performance of such individuals on routine office mental examinations. DESIGN/METHODS: In this cross sectional study 51 adults with ASDs, mean age 32 +/- 12 years (range 20-58 years), 71[percnt] men, with mean educational level of 13.5 +/- 2.3 years (range 10-20 years), and mean WAIS Full Scale IQ 94 +/- 21, underwent three office mental status examinations - the Folstein Mini-Mental State Exam (MMSE), the Kokmen Short Test of Mental Status (STMS), and the Montreal Cognitive Assessment (MoCA). RESULTS: Total scores (mean +/- SD) and percent correct (mean +/- SD of total possible points) for each of the mental status examinations were as follows: MMSE 27.1 +/- 3.7, 90 +/- 12[percnt]; STMS 34 +/- 4.4, 89 +/- 12[percnt]; MoCA 25.2 +/- 4.3, 84 +/- 14[percnt]. Recall was the domain most commonly missed on each of the mental status examinations: MMSE 79 +/- 28([percnt]); STMS 76 +/- 27([percnt]); MoCA 65 +/- 33([percnt]). CONCLUSIONS: The MoCA is a better office screening assessment for cognitive dysfunction in adults with ASDs as compared to the STMS or MMSE. The most prominent cognitive deficit evident on routine office mental status examination in this cohort of adults with ASDs was verbal recall, which may have diagnostic implications for individuals who do not have an established ASD diagnosis. An abnormal MoCA screening exam should be followed by confirmatory neuropsychological testing. Supported by: Mayo Clinic Intramural Career Development Award <b>Disclosure:</b> Dr. Woodruff has received research support from Genentech Inc. and Avid Pharmaceuticals. Dr. Locke has nothing to disclose. Dr. Hentz has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Geda has nothing to disclose.
Insulin-induced remission in new-onset NOD mice is maintained by the PD-1–PD-L1 pathway
Authors: Brian T. Fife, Indira Guleria, Melanie Gubbels Bupp, Todd N. Eagar, Qizhi Tang, Helene Bour-Jordan, Hideo Yagita, Miyuki Azuma, Mohamed H. Sayegh, Jeffrey A. Bluestone
Journal: The Journal of Experimental Medicine (2006)

The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)-programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte-associated antigen 4 pathway. Anti-PD-1 and anti-PD-L1, but not anti-PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1-PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1-PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1-PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues.
Renal Tubule Development in Drosophila
Authors: Alain C. Jung, Barry Denholm, Helen Skaer, Markus Affolter
Journal: Journal of the American Society of Nephrology (2005)

The function of excretion in insects is performed by the Malpighian tubules, a functional equivalent of the vertebrate kidney. Malpighian tubules are long, thin tubes connected to the hindgut. Upon the determination of the Malpighian tubule major cell type early in embryogenesis, the tubular architecture is achieved by extensive cell division and cell rearrangements. During the tube elongation process, cells exchange their neighbors, allowing the short and fat Malpighian tubule primordia to grow and become a thin tube. Cell rearrangement and intercalation underlie the morphogenesis of other epithelial tissues in Drosophila melanogaster, such as the embryonic epidermis. Recent work has provided insights in the cellular and molecular basis of cell intercalation. These advances are reviewed and discussed with regard to what is known about Malpighian tubule morphogenesis. Mature Malpighian tubules are composed of two cell types, each having a specific function in excretion: The principal cells and the stellate cells. Drosophila and mammalian kidney development show striking similarities, as the recruitment of the stellate cells to the Malpighian tubules, like the cells of the metanephric mesenchyme, requires that cells undergo a mesenchymal-to-epithelial transition. The molecular similarities between these two cases is reviewed here.