tbuckley/cabot-search huggingface dataset:
T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer
Authors: Bradley S. Cobb, Tatyana B. Nesterova, Elizabeth Thompson, Arnulf Hertweck, Eric O'Connor, Jonathan Godwin, Christopher B. Wilson, Neil Brockdorff, Amanda G. Fisher, Stephen T. Smale, Matthias Merkenschlager
Journal: The Journal of Experimental Medicine (2005)

The ribonuclease III enzyme Dicer is essential for the processing of micro-RNAs (miRNAs) and small interfering RNAs (siRNAs) from double-stranded RNA precursors. miRNAs and siRNAs regulate chromatin structure, gene transcription, mRNA stability, and translation in a wide range of organisms. To provide a model system to explore the role of Dicer-generated RNAs in the differentiation of mammalian cells in vivo, we have generated a conditional Dicer allele. Deletion of Dicer at an early stage of T cell development compromised the survival of αβ lineage cells, whereas the numbers of γδ-expressing thymocytes were not affected. In developing thymocytes, Dicer was not required for the maintenance of transcriptional silencing at pericentromeric satellite sequences (constitutive heterochromatin), the maintenance of DNA methylation and X chromosome inactivation in female cells (facultative heterochromatin), and the stable shutdown of a developmentally regulated gene (developmentally regulated gene silencing). Most remarkably, given that one third of mammalian mRNAs are putative miRNA targets, Dicer seems to be dispensable for CD4/8 lineage commitment, a process in which epigenetic regulation of lineage choice has been well documented. Thus, although Dicer seems to be critical for the development of the early embryo, it may have limited impact on the implementation of some lineage-specific gene expression programs.
T<scp>ROPHIC AND</scp> C<scp>YTOPROTECTIVE</scp> N<scp>UTRITION FOR</scp> I<scp>NTESTINAL</scp> A<scp>DAPTATION</scp>, M<scp>UCOSAL</scp> R<scp>EPAIR, AND</scp> B<scp>ARRIER</scp> F<scp>UNCTION</scp>
Authors: Thomas R. Ziegler, Mary E. Evans, Concepción Fernández-Estívariz, Dean P. Jones
Journal: Annual Review of Nutrition (2003)

▪ Abstract Intestinal epithelial cell turnover (proliferation, migration, differentiation, and apoptosis) and gut barrier functions are dynamic processes that are markedly affected by nutritional status, the route of feeding, and the adequacy of specific nutrients in the diet. Emerging studies are defining potential therapeutic roles for specific nutrients and diet-derived compounds (including arginine, glutamate, glutamine, glutathione, glycine, vitamin A, zinc, and specific lipids) in gut mucosal turnover, repair, adaptation after massive bowel resection, and barrier function. The role and regulation of endogenous bowel flora in generating short-chain fatty acids from diet-derived fiber and other diet-derived compounds and the effects of these agents on gut function are increasingly being elucidated. Results of these investigations should define new nutritional methods for trophic and cytoprotective effects on the intestine in conditions such as inflammatory bowel disease, malnutrition, and short bowel syndrome.
Human Liver Aldehyde Oxidase: Differential Inhibition of Oxidation of Charged and Uncharged Substrates*
Authors: David G. Johns
Journal: Journal of Clinical Investigation (1967)

HUMAN LIVER ALDEHYDE OXIDASE (ALDEHYDE: O(2) oxidoreductase, EC 1.2.3.1) has been purified 60-fold and some of its properties studied. Like aldehyde oxidase from other mammalian species, human liver aldehyde oxidase is an enzyme with dual substrate specificity, possessing the ability to catalyze not only the oxidation of aldehydes to the corresponding carboxylic acids, but also the hydroxylation of a number of nonaldehydic heterocyclic compounds; its relative activity towards the latter group of substrates is low, however, when compared with that of liver aldehyde oxidase from rabbit and guinea pig. When the aromatic aldehyde benzaldehyde is used as substrate, human liver aldehyde oxidase, like the rabbit enzyme, is strongly inhibited by menadione, estradiol-17beta, antimycin A, Triton X-100, and N-alkylphenothiazines; the human enzyme differs from the rabbit enzyme, however, in being relatively insensitive to oligomycin and Amytal. Like the rabbit enzyme, the human enzyme can catalyze the 3-hydroxylation of phenazine methosulfate (PMS) and the 6-hydroxylation of N-methylnicotinamide (NMN). With the rabbit enzyme, however, the aerobic hydroxylation of these substrates proceeds by a conventional mechanism, while with the human enzyme, the aerobic hydroxylation of PMS and NMN is anomalous in that the reaction is inhibited only by agents with affinity for the substrate-binding site, such as cyanide and N-alkylphenothiazines, and not by agents which inhibit the "internal electron transport chain" of the enzyme, such as menadione and diethylstilbestrol. This mode of oxidation appears to be unique to substrates with a positively charged quaternary nitrogen; the hydroxylation of other nonaldehydic heterocyclic substrates for the human enzyme is sensitive to conventional aldehyde oxidase inhibitors.
Chromogranin B Regulates Calcium Signaling, Nuclear Factor κB Activity, and Brain Natriuretic Peptide Production in Cardiomyocytes
Authors: Felix M. Heidrich, Kun Zhang, Manuel Estrada, Yan Huang, Frank J. Giordano, Barbara E. Ehrlich
Journal: Circulation Research (2008)

Altered regulation of signaling pathways can lead to pathologies including cardiac hypertrophy and heart failure. We report that neonatal and adult cardiomyocytes express chromogranin B (CGB), a Ca(2+) binding protein that modulates Ca(2+) release by the inositol 1,4,5-trisphosphate receptor (InsP(3)R). Using fluorescent Ca(2+) indicator dyes, we found that CGB regulates InsP(3)-dependent Ca(2+) release in response to angiotensin II, an octapeptide hormone that promotes cardiac hypertrophy. ELISA experiments and luciferase reporter assays identified angiotensin II as a potent inducer of brain natriuretic peptide (BNP), a hormone that recently emerged as an important biomarker in cardiovascular disease. CGB was found to regulate angiotensin II-stimulated and basal secretion, expression and promoter activity of BNP that depend on the InsP(3)R. Moreover, we provide evidence that CGB acts via the transcription activity of nuclear factor kappaB in an InsP(3)/Ca(2+)-dependent manner but independent of nuclear factor of activated T cells. In vivo experiments further showed that cardiac hypertrophy induced by angiotensin II, a condition characterized by increased ventricular BNP production, is associated with upregulation of ventricular CGB expression. Overexpression of CGB in cardiomyocytes, in turn, induced the BNP promoter. The evidence presented in this study identifies CGB as a novel regulator of cardiomyocyte InsP(3)/Ca(2+)-dependent signaling, nuclear factor kappaB activity, and BNP production.
Neutrophil-mediated vasoconstriction and endothelial dysfunction in low-flow perfusion-reperfused cat coronary artery.
Authors: X L Ma, P S Tsao, G E Viehman, A M Lefer
Journal: Circulation Research (1991)

We investigated the interaction between activated cat polymorphonuclear neutrophils (PMNs) and coronary vascular endothelial cells in vitro. It was shown that 1) 90 minutes of low-flow perfusion without reperfusion had no deleterious effects on endothelium-dependent vasodilation, whereas 90 minutes of low-flow perfusion and 20 minutes of reperfusion with a blood cell-free solution induced a 20-25% endothelial dysfunction; 2) activated PMNs produced endothelium-dependent vasoconstriction in coronary artery rings isolated from cat hearts undergoing 90 minutes of low-flow perfusion and 20 minutes of reperfusion with a blood cell-free Krebs-Henseleit solution; 3) addition of the superoxide free radical scavenger, superoxide dismutase (150 micrograms/ml), or an antibody directed against CD18 of PMN adherence glycoprotein complex (MAbR15.7, 20 micrograms/ml) attenuated PMN-induced vasoconstriction significantly, but addition of a hydroxyl radical scavenger [N-(2-mercaptopropionyl)-glycine, 150 micrograms/ml], a cyclooxygenase inhibitor, or a lipoxygenase inhibitor had no protective effect; 4) exposure of rings to a superoxide radical-generating system (i.e., xanthine and xanthine oxidase) produced significant vasoconstriction that was similar to that observed with activated PMNs and was inhibited by superoxide dismutase; and 5) activated PMNs produced a marked coronary endothelial dysfunction characterized by a decreased response to the endothelium-dependent vasodilators acetylcholine and A23187. Addition of either superoxide dismutase or MAbR15.7 protected against endothelial dysfunction. These results indicate that activated PMNs produce significant vasoconstriction and endothelial dysfunction in coronary arteries isolated from low-flow perfusion-reperfused hearts. These effects appear to be mediated primarily by superoxide radicals generated by activated PMNs that either inactivate or inhibit the synthesis and release of endothelium-derived relaxing factor. We conclude that activated PMNs are able to induce endothelial dysfunction by releasing free radicals and possibly other substances.
miR-192 Mediates TGF-β/Smad3-Driven Renal Fibrosis
Authors: Arthur C.K. Chung, Xiao R. Huang, Xiaoming Meng, Hui Y. Lan
Journal: Journal of the American Society of Nephrology (2010)

Seed-chain-extend with k-mer seeds is a powerful heuristic technique for sequence alignment employed by modern sequence aligners. While effective in practice for both runtime and accuracy, theoretical guarantees on the resulting alignment do not exist for seed-chain-extend. In this work, we give the first rigorous bounds for the efficacy of seed-chain-extend with k-mers in expectation. Assume we are given a random nucleotide sequence of length ≈ n that is indexed (or seeded) and a mutated substring of length ≈ m ≤ n with mutation rate θ &lt; 0.206. We prove that we can find a k = Θ(log n) for the k-mer size such that the expected runtime of seed-chain-extend under optimal linear gap cost chaining and quadratic time gap extension is O(mn<sup>f(θ)</sup> log n) where f(θ) &lt; 2.43·θ holds as a loose bound. In fact, for reasonable θ = 0.05, f(θ) &lt; 0.08, indicating nearly quasilinear running time in practice. The alignment also turns out to be good; we prove that more than 1 − O(1/√m) fraction of the homologous bases are recoverable under an optimal chain. We also show that our bounds work when k-mers are sketched, i.e. only a subset of all k-mers is selected. Under the open syncmer sketching method, one can sketch with decreasing density as a function of n and achieve asymptotically smaller chaining time, yet the same bounds for extension time and recoverability hold. In other words, sketching reduces chaining time without increasing alignment time or decreasing accuracy too much, justifying the effectiveness of sketching as a practical speedup in sequence alignment. We verify our results in simulation and conjecture that f(θ) can be further reduced.
Lymphatic Microvessels in the Rat Remnant Kidney Model of Renal Fibrosis
Authors: Katsuyuki Matsui, Katalyn Nagy-Bojarsky, Pirjo Laakkonen, Sigurd Krieger, Karl Mechtler, Shunya Uchida, Silvana Geleff, Due-Hee Kang, Richard J. Johnson, Dontscho Kerjaschki
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Rat remnant kidney is an established model of renal tubulointerstitial fibrosis and progression to end-stage renal failure. The morphologic lesions comprise nephron loss and regeneratory tubular hypertrophy, interstitial infiltration, predominately by macrophages, and progressive fibrosis. A critical role in this complex pathology was assigned to tubulointerstitial blood microvessels that regulate the supply of oxygen and nutrients of tubuli. Whereas some investigations reported a rarefaction of the vascular network in association with the degenerative cortical changes, others observed an increase in vascularization. Here these discrepant findings are addressed by reinvestigation of the vascularization of rat remnant kidneys by the use of two novel endothelial lineage specific, discriminatory markers, i.e., the membrane mucoprotein podoplanin with specificity for lymphatic endothelia, and the glycosyl-phosphatidylinositol (GPI)–anchored membrane enzyme aminopeptidase P that is recognized by a monoclonal antibody designated JG12 and that is specifically expressed by endothelial cells of blood vessels only. The results obtained confirm a regional rarefaction of aminopeptidase P–positive blood microvessels; they also establish major changes in the renal lymphatic vasculature. Massive proliferation of lymphatic vessels was observed in fibrotic tubulointerstitial regions, whereas in kidneys of sham-operated rats, only a few lymphatic vessels were found adjoined with arteries. The lymphatic vessels frequently contained mononuclear cells that were also encountered in the interstitial spaces and expressed relative large amounts of vascular endothelial growth factor-C mRNA by in situ hybridization. Collectively, these results indicate that a large proportion of the microvessels encountered in the cortex of remnant kidneys are of lymphatic origin and cannot be discriminated by common endothelial markers, such as CD34, that are expressed by both lymphatic and blood endothelia cells. As lymphatic endothelial cells secrete chemokines that attract dendritic cells, it is possible that the increase in lymphatic vascularization could enhance the immunologic surveillance of remnant kidneys. E-mail: [email protected]
The Effect of Age and Duration of Disease on Airway Structure in Fatal Asthma
Authors: TONY R. BAI, JAMIE COOPER, TIM KOELMEYER, PETER D. PARÉ, TRACEY D. WEIR
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We hypothesized that if airway remodeling is related to duration of asthma, that when matched for severity, the airways of older adults should show greater alterations than the airways of younger adults. Using standard morphometric techniques, we compared airways with basement membrane perimeters (Pbm) between 2 and 10 mm from young individuals who died of asthma (n = 14, range 17–23 yr), and older individuals with fatal asthma (n = 13, range 40–49 yr). Comparisons were also made with normal airways from age-matched adults. Wall area was increased in old individuals with fatal asthma compared with young individuals with fatal asthma, primarily due to greater adventitial area, whereas wall area in young individuals with fatal asthma was not different from control subjects. Within muscle bundles the connective tissue matrix was increased around individual cells in individuals with asthma, unrelated to age. After adjustment for this change, smooth muscle area in both asthma groups was still greater than in age-matched control subjects, in old individuals with fatal asthma 4-fold greater (p = 0.04), and in young individuals with fatal asthma 2-fold greater (p = 0.03). Airway narrowing was increased in old versus young individuals with fatal asthma, with both groups more narrowed than control subjects. Intralumenal obstruction and subepithelial collagen in the two asthma groups were significantly greater than in control subjects, but there was no age effect. These data provide support for the hypothesis that there is an increase in airway wall area, including smooth muscle, and airway narrowing with increasing duration of severe asthma or with older age. The observation that total wall thickness was not greater in young individuals with young fatal asthma than in control subjects suggests that factors other than airway wall geometry contribute to the pathogenesis of fatal attacks in this age group.
Endothelial Chromosome 13 Deletion in Congenital Heart Disease–associated Pulmonary Arterial Hypertension Dysregulates <i>SMAD9</i> Signaling
Authors: Kylie M. Drake, Suzy A. Comhair, Serpil C. Erzurum, Rubin M. Tuder, Micheala A. Aldred
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Supported in part by the National Heart, Lung and Blood Institute of the National Institutes of Health under award numbers R01HL098199, R03HL110831, and RC37HL60917.



Author Contributions: K.M.D. and M.A.A. designed the study; acquired, analyzed, and interpreted data; and wrote the manuscript. S.A.C. and S.C.E. acquired samples, established cells, and reviewed the clinical information. R.M.T. reviewed and interpreted the pathology. All authors contributed to writing the manuscript.



This letter has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org



Author disclosures are available with the text of this letter at www.atsjournals.org.
Influence of wakefulness on pharyngeal airway muscle activity
Authors: Y.-L. Lo, A. S Jordan, A. Malhotra, A. Wellman, R. A Heinzer, M. Eikermann, K. Schory, L. Dover, D. P White
Journal: Thorax (2007)

Whether loss of wakefulness itself can influence pharyngeal dilator muscle activity and responsiveness is currently unknown. A study was therefore undertaken to assess the isolated impact of sleep on upper airway muscle activity after minimising respiratory/mechanical inputs.Ten healthy subjects were studied. Genioglossus (GG), tensor palatini (TP) and diaphragm (DIA) electromyography (EMG), ventilation and sleep-wake status were recorded. Non-invasive positive pressure ventilation was applied. Expiratory pressure was adjusted to yield the lowest GGEMG, thereby minimising airway negative pressure (mechanoreceptor) effects. Inspiratory pressure, respiratory rate and inspiratory time were adjusted until the subjects ceased spontaneous ventilation, thereby minimising central respiratory input. Muscle activity during wakefulness, wake-sleep transitions, stable non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep were evaluated in the supine position.In transitions from wakefulness to sleep, significant decrements were observed in both mean GGEMG and TPEMG (1.6 (0.5)% to 1.3 (0.4)% of maximal GGEMG; 4.3 (2.3)% to 3.7 (2.1)% of maximal TPEMG). Compared with sleep onset, the activity of TP during stable NREM sleep and REM sleep was further decreased (3.7 (2.1)% vs 3.0 (2.0)% vs 3.0 (2.0)% of maximal EMG). However, GGEMG was only further reduced during REM sleep (1.3 (0.4)% vs 1.0 (0.3)% vs 1.1 (0.4)% of maximal EMG).This study suggests that wakefulness per se, independent of respiratory/mechanical stimuli, can influence pharyngeal dilator muscle activity.
Is Age at Symptom Onset Associated With Severity of Memory Impairment in Adults With Obsessive-Compulsive Disorder?
Authors: Aude Henin, Cary R. Savage, Scott L. Rauch, Thilo Deckersbach, Sabine Wilhelm, Lee Baer, Michael W. Otto, Michael A. Jenike
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Age at onset is a potentially important marker for neurobiological features of obsessive-compulsive disorder (OCD). This study examined the relationship between age at symptom onset and memory impairment in adults with OCD. METHOD: The authors used the Rey-Osterrieth Complex Figure Test and the California Verbal Learning Test to compare memory functioning of 37 adult OCD patients with self-reported childhood onset of symptoms (onset at less than 18 years of age) with that of 31 patients with adult-onset symptoms. RESULTS: No differences were found between the two groups on any of the verbal and nonverbal memory measures. CONCLUSIONS: Self-reported age at symptom onset is not associated with memory performance in adult patients with OCD according to tests previously found to be sensitive to frontal-striatal system dysfunction and impairment in OCD. Such dysfunction appears to be a consistent feature of OCD in adults, regardless of age at initial symptom onset.
TIMP-3 Deficiency Leads to Dilated Cardiomyopathy
Authors: Paul W.M. Fedak, David S. Smookler, Zamaneh Kassiri, Nobuhisa Ohno, Kevin J. Leco, Subodh Verma, Donald A.G. Mickle, Katrina L. Watson, Carlo V. Hojilla, William Cruz, Richard D. Weisel, Ren-Ke Li, Rama Khokha
Journal: Circulation (2004)

Background— Despite the mounting clinical burden of heart failure, the biomolecules that control myocardial tissue remodeling are poorly understood. TIMP-3 is an endogenous inhibitor of matrix metalloproteinases (MMPs) that has been found to be deficient in failing human myocardium. We hypothesized that TIMP-3 expression prevents maladaptive tissue remodeling in the heart, and accordingly, its deficiency in mice would alone be sufficient to trigger progressive cardiac remodeling and dysfunction similar to human heart failure. Methods and Results— Mice with a targeted timp-3 deficiency were evaluated with aging and compared with age-matched wild-type littermates. Loss of timp-3 function triggered spontaneous LV dilatation, cardiomyocyte hypertrophy, and contractile dysfunction at 21 months of age consistent with human dilated cardiomyopathy. Its absence also resulted in interstitial matrix disruption with elevated MMP-9 activity, and activation of the proinflammatory tumor necrosis factor-α cytokine system, molecular hallmarks of human myocardial remodeling. Conclusions— TIMP-3 deficiency disrupts matrix homeostasis and the balance of inflammatory mediators, eliciting the transition to cardiac dilation and dysfunction. Therapeutic restoration of myocardial TIMP-3 may provide a novel approach to limit cardiac remodeling and the progression to failure in patients with dilated cardiomyopathy.
Postnatal expansion of the natural killer and keller cell population in humans identified by the monoclonal HNK-1 antibody.
Authors: T Abo, M D Cooper, C M Balch
Journal: The Journal of Experimental Medicine (1982)

Human natural killer (NK) and killer (K) cells were directly enumerated using a monoclonal antibody (HNK-1) and an immunofluorescence assay. The frequency of cells bearing surface HNK-1 antigen was very low in the newborn (less than 1.0%) and increased progressively through childhood and into adult life. This was correlated with an age-related increase in functional NK and K cell activities. Males had a slightly higher proportion of HNK-1+ cells than females. In addition to HNK-1 expression on the surface membrane, a prominent cytoplasmic expression of HNK-1 antigen was found in some but not all surface HNK-1+ cells. The cytoplasmic accumulation of HNK-1 molecules appeared to occur in more mature cells of this lineage.