tbuckley/cabot-search huggingface dataset:
α6 Integrins Are Required for Langerhans Cell Migration from the Epidermis
Authors: Abigail A. Price, Marie Cumberbatch, Ian Kimber, Ann Ager
Journal: The Journal of Experimental Medicine (1997)

Topical exposure of mice to chemical allergens results in the migration of epidermal Langerhans cells (LCs) from the skin and their accumulation as immunostimulatory dendritic cells (DCs) in draining lymph nodes. Epidermal cell–derived cytokines have been implicated in the maturation and migration of LCs, but the adhesion molecules that regulate LC migration have not been studied. We hypothesized that integrin-mediated interactions with extracellular matrix components of the skin and lymph node may regulate LC/DC migration. We found that α6 integrins and α4 integrins were differentially expressed by epidermal LCs and lymph node DCs. A majority of LCs (70%) expressed the α6 integrin subunit, whereas DCs did not express α6 integrins. In contrast, the α4 integrin subunit was expressed at high levels on DCs but at much lower levels on LCs. The anti-α6 integrin antibody, GoH3, which blocks binding to laminin, completely prevented the spontaneous migration of LCs from skin explants in vitro and the rapid migration of LCs from mouse ear skin induced after intradermal administration of TNF-α in vivo. GoH3 also reduced the accumulation of DCs in draining lymph nodes by a maximum of 70% after topical administration of the chemical allergen oxazolone. LCs remaining in the epidermis in the presence of GoH3 adopted a rounded morphology, rather than the interdigitating appearance typical of LCs in naive skin, suggesting that the cells had detached from neighboring keratinocytes and withdrawn cellular processes in preparation for migration, but were unable to leave the epidermis. The anti-α4 integrin antibody PS/2, which blocks binding to fibronectin, had no effect on LC migration from the epidermis either in vitro or in vivo, or on the accumulation of DCs in draining lymph nodes after oxazolone application. RGD-containing peptides were also without effect on LC migration from skin explants. These results identify an important role for α6 integrins in the migration of LC from the epidermis to the draining lymph node by regulating access across the epidermal basement membrane. In contrast, α4 integrins, or other integrin-dependent interactions with fibronectin that are mediated by the RGD recognition sequence, did not influence LC migration from the epidermis. In addition, α4 integrins did not affect the accumulation of LCs as DCs in draining lymph nodes.
Expression, Localization, and Function of the Thioredoxin System in Diabetic Nephropathy
Authors: Andrew Advani, Richard E. Gilbert, Kerri Thai, Renae M. Gow, Robyn G. Langham, Alison J. Cox, Kim A. Connelly, Yuan Zhang, Andrew M. Herzenberg, Per Knud Christensen, Carol A. Pollock, Weier Qi, Sih Min Tan, Hans-Henrik Parving, Darren J. Kelly
Journal: Journal of the American Society of Nephrology (2009)

Excessive reactive oxygen species play a key role in the pathogenesis of diabetic nephropathy, but to what extent these result from increased generation, impaired antioxidant systems, or both is incompletely understood. Here, we report the expression, localization, and activity of the antioxidant thioredoxin and its endogenous inhibitor thioredoxin interacting protein (TxnIP) in vivo and in vitro. In normal human and rat kidneys, expression of TxnIP mRNA and protein was most abundant in the glomeruli and distal nephron (distal convoluted tubule and collecting ducts). In contrast, thioredoxin mRNA and protein localized to the renal cortex, particularly within the proximal tubules and to a lesser extent in the distal nephron. Induction of diabetes in rats increased expression of TxnIP but not thioredoxin mRNA. Kidneys from patients with diabetic nephropathy had significantly higher levels of TxnIP than control kidneys, but thioredoxin expression did not differ. In vitro, high glucose increased TxnIP expression in mesangial, NRK (proximal tubule), and MDCK (distal tubule/collecting duct) cells, and decreased the expression of thioredoxin in mesangial and MDCK cells. Knockdown of TxnIP with small interference RNA suggested that TxnIP mediates the glucose-induced impairment of thioredoxin activity. Knockdown of TxnIP also abrogated both glucose-induced 3H-proline incorporation (a marker of collagen production) and oxidative stress. Taken together, these findings suggest that impaired thiol reductive capacity contributes to the generation of reactive oxygen species in diabetes in a site- and cell-specific manner.
Genotype-phenotype correlation in combined deficiency of factor V and factor VIII
Authors: Bin Zhang, Marta Spreafico, Chunlei Zheng, Angela Yang, Petra Platzer, Michael U. Callaghan, Zekai Avci, Namik Ozbek, Johnny Mahlangu, Tabitha Haw, Randal J. Kaufman, Kandice Marchant, Edward G. D. Tuddenham, Uri Seligsohn, Flora Peyvandi, David Ginsburg
Journal: Blood (2008)
Divide to survive: myocardial regeneration and functional recovery after cell cycle activation in injured hearts
Authors: A. D.T. Costa
Journal: Cardiovascular Research (2008)

Necrotic and apoptotic cell deaths are the two main causes of the heart's loss of cardiac tissue and haemodynamic function after myocardial infarction (MI). The loss of functional cardiac myocytes through necrotic/apoptotic processes during ischaemia in the absence of de novo cell proliferation has been postulated to be a fundamental cause of ventricular remodelling, increased tissue fibrosis, and diminished ventricular pump function.

In the past decade, several approaches have been tested hoping to increase the number of myocytes after MI, including transplantation of progenitor or adult cells,1 mobilization of endogenous stem cells,2 and cell cycle activation.3 Each of these approaches demonstrated some degree of myocardial functional improvement, with cell cycle activation being the most promising one.3

Although there is evidence for adult cardiomyocyte proliferation,4 it is clear that this process is not capable of fully recovering the … 

*Corresponding author. Tel: +55 41 3316 3230/3237; fax: +55 41 3316 3267. E-mail address : adcosta{at}tecpar.br; adtcosta{at}gmail.com
Optic nerve crush induces spatial and temporal gene expression patterns in retina and optic nerve of BALB/cJ mice
Authors: Tasneem P Sharma, Colleen M McDowell, Yang Liu, Alex H Wagner, David Thole, Benjamin P Faga, Robert J Wordinger, Terry A Braun, Abbot F Clark
Journal: Molecular Neurodegeneration (2014)

Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets.Only 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (≥1.5, ≤-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR.A number of detrimental gene expression changes occur that contribute to trauma-induced neurodegeneration after injury to ON axons. Nrn1 (synaptic plasticity gene), Synpr and Syt1 (synaptic vesicle fusion genes), and Vsnl1 (neuron differentiation associated gene) were a few of the potentially unique genes identified that were down-regulated spatially and temporally in our rodent ONC model. Bioinformatic meta-analysis identified significant tissue-specific and time-dependent gene clusters associated with regenerative changes, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure.
Strict Sex-Specific mtDNA Segregation in the Germ line of the DUI Species Venerupis philippinarum (Bivalvia: Veneridae)
Authors: F. Ghiselli, L. Milani, M. Passamonti
Journal: Molecular Biology and Evolution (2010)

Doubly Uniparental Inheritance (DUI) is one of the most striking exceptions to the common rule of standard maternal inheritance of metazoan mitochondria. In DUI, two mitochondrial genomes are present, showing different transmission routes, one through eggs (F-type) and the other through sperm (M-type). In this paper, we report results from a multiplex real-time quantitative polymerase chain reaction analysis on the Manila clam Venerupis philippinarum (formerly Tapes philippinarum). We quantified M- and F-types in somatic tissues, gonads, and gametes. Nuclear and external reference sequences were used, and the whole experimental process was designed to avoid any possible cross-contamination. In most male somatic tissues, the M-type is largely predominant: This suggests that the processes separating sex-linked mitochondrial DNAs (mtDNAs) in somatic tissues are less precise than in other DUI species. In the germ line, we evidenced a strict sex-specific mtDNA segregation because both sperm and eggs do carry exclusively M- and F-types, respectively, an observation that is in contrast with a previous analysis on Mytilus galloprovincialis. More precisely, whereas two mtDNAs are present in the whole gonad, only the sex-specific one is detected in gametes. Because of this, we propose that the mtDNA transmission is achieved through a three-checkpoint process in V. philippinarum. The cytological mechanisms of male mitochondria segregation in males and degradation in females during the embryo development (here named Checkpoint #1 and Checkpoint #2) are already well known for DUI species; a Checkpoint #3 would act when primordial germ cells (PGCs) are first formed and would work in both males and females. We believe that Checkpoint #3 is a mere variation of the "mitochondrial bottleneck" in species with standard maternal inheritance, established when their PGCs separate during embryo cleavage.
Vitamin K-dependent Calcium Binding Proteins in Aortic Valve Calcification
Authors: Robert J. Levy, John A. Zenker, Jane B. Lian
Journal: Journal of Clinical Investigation (1980)

The pathogenesis of valvar calcification, which complicates the course of cardiac valve disease and also affects tissue valve prostheses, is incompletely understood. The present work explores the possible role of the vitamin K-dependent, calcium-binding amino acid, γ-carboxyglutamic acid (Gla) in valve mineralization. Gla is normally found in the vitamin K-dependent clotting factor proteins, and is also present in unique calcium binding proteins in bone, kidney, and lung. Unique Gla-containing proteins have also been isolated from pathologic calcifications including calcium containing renal stones and calcified atherosclerotic plaque. Calcified valves including specimens with calcific aortic stenosis, calcified porcine xenograft valves, and a calcified aortic homograft valve were analyzed for Gla content, complete amino acid analysis, and tissue calcium and phosphorus levels. Normal porcine valves contained protein-bound Gla (2.0-10.6 Gla/104 amino acids): no Gla was present in normal valve leaflets. Furthermore, Gla levels paralleled tissue calcium content in the calcified valves. In addition, complete amino acid analysis indicated a decline in valvar collagen content plus increased acidic proteins in conjunction with valvar calcification and the presence of Gla-containing proteins. These results suggest that calcific valvar disease may result in part from vitamin K-dependent processes.
Contractile Properties of Cardiac Muscle in Hyperthyroidism
Authors: Roger R. Taylor, Peter Burrows
Journal: Circulation Research (1970)

Right ventricular papillary muscles from hyperthyroid and normal cats were studied in vitro at 30°C, at contraction frequencies of 12, 30 and 60/min. At 12/min the contractility of hyperthyroid muscles was significantly greater than normal, as indicated by greater velocity of isotonic shortening, isometric tension development, and rate of tension development. Isotonically contracted muscle lengths were smaller and time to peak isometric tension less. At 60/min, velocity of shortening was still greater and time to peak tension less in hyperthyroid muscles, but isometric developed tension, rate of tension development, and isotonically contracted muscle lengths and shortening were not different. Increasing frequency from 12/min to 60/min resulted in immediate positive inotropic responses in both groups, but a smaller response in hyperthyroid than normal muscles. Over subsequent minutes, a slight decrease in contractility occurred in normal muscles but the decrease was significantly greater in hyperthyroid muscles. The difference in response to increasing frequency is attributed to more profound hypoxia in hyperthyroid muscles at high contraction frequencies. Predisposition of the muscle to hypoxia induced by hyperthyroidism then becomes an important determinant of the net effect of hyperthyroidism on myocardial contractility. The experimental situation is analogous to the coexistence, in vivo, of thyrotoxicosis and other conditions predisposing to coronary insufficiency, such as coronary artery disease or ventricular hypertrophy; that hyperthyroidism does not then augment contractile state in respect to tension development or muscle shortening helps explain the occurrence of thyrotoxic heart failure in response to the body's increased requirements for blood flow.
Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis.
Authors: A A Quyyumi, N Dakak, N P Andrews, S Husain, S Arora, D M Gilligan, J A Panza, R O Cannon
Journal: Journal of Clinical Investigation (1995)

The bioavailability of nitric oxide (NO) in the human coronary circulation at rest and after acetylcholine (ACH)-induced vasodilation was investigated in 32 patients with angiographically normal coronary arteries. The effects of intracoronary L-NG monomethyl arginine (L-NMMA) were investigated at rest and after ACH, sodium nitroprusside, and adenosine. L-NMMA (64 mumol/min) increased resting coronary vascular resistance by 22% (P < 0.001), reduced distal epicardial coronary artery diameter by 12.6% (P < 0.001), and inhibited ACH-induced coronary epicardial and microvascular vasodilation. These effects were reversed with intracoronary L-arginine. L-NMMA did not inhibit dilation in response to sodium nitroprusside and adenosine. 23 patients were exposed to one or more coronary risk factors. The vasoconstrictor effect of L-NMMA on the epicardial and microvessels was greater in patients free of risk factors: Coronary vascular resistance was 36% higher in patients without risks, compared to 17% higher in patients with risks (P < 0.05). Both epicardial and microvascular dilator effects of ACH were greater in patients without risk factors, and the inhibition of these effects by L-NMMA was also greater in patients without risk factors. Thus: (a) NO contributes importantly to resting epicardial and coronary microvascular tone, (b) coronary vascular dilation in response to ACH is predominantly due to increased production of NO, and (c) despite the absence of angiographic evidence of atherosclerosis, exposure to coronary risk factors is associated with reduced resting and stimulated bioavailability of NO from the human coronary circulation.
A Bill of "Rights" for patients with COPD: the "right" therapy for the "right" patient at the "right" time
Authors: L. Nici
Journal: Thorax (2009)

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and poses significant burdens on patients, their families and the healthcare system. It is currently the fourth leading cause of death in the USA and is projected to rank fifth in burden of disease globally by 2020.1 Pulmonary rehabilitation (PR) for COPD is an effective therapeutic intervention that reduces breathlessness, increases exercise capacity and improves health-related quality of life.2 3 Emerging evidence also supports its effectiveness in reducing healthcare utilisation, decreasing frequency and severity of acute exacerbations and improving survival.4 5 6 7

Despite the robust evidence on the effectiveness of this intervention, the availability of PR remains dismal worldwide, with various estimates suggesting 1–14% of patients with COPD are actually referred for the service.8 9 10 This partly has to do with the fact that PR is most often delivered as an outpatient and hospital-based programme. If PR could be delivered effectively in the home setting, this could vastly increase the number of patients receiving this important therapy. Simply put, the right therapy for the right patient at the right time.

Few studies have looked at the efficacy of home-based rehabilitation, but the programmes vary widely, making comparisons difficult. One study from the Netherlands looked at a 12-week programme using community-based healthcare personnel and visits to local physiotherapists.11 While the study did demonstrate feasibility of the programme, high exercise compliance as assessed by patient diaries and some improvement of exercise tolerance, patients attended supervised exercise training …
Endothelin Receptor B Inhibition Triggers Apoptosis and Enhances Angiogenesis in Melanomas
Authors: Ronit Lahav, Mario-Luca Suvà, Donata Rimoldi, Paul H. Patterson, Ivan Stamenkovic
Journal: Cancer Research (2004)

Abstract Endothelin receptor B (ETRB or EDNRB) is overexpressed in most human melanomas and is proposed to provide a marker of melanoma progression. We have shown previously that inhibition of ETRB leads to increased human melanoma cell death in vitro and in vivo, resulting in shrinkage of tumors grown in immunocompromised mice. In the present work, we analyzed the effects of ETRB inhibition on 10 human melanoma cell lines derived from tumors at distinct stages of progression. Our observations suggest that the ETRB antagonist BQ788 induces apoptosis most effectively in metastatic melanoma cells. Microarray analysis shows that BQ788 treatment leads to a reduction in the expression of the survival factor BCL-2A1 and the DNA repair factor poly(ADP-ribose) polymerase 3 that is more pronounced in cells derived from metastatic than primary melanoma. Decreased cell viability was observed to correlate with reduction in ETRB expression, and reduction in ETRB protein levels by small interfering RNA led to an increase in cell death. Interestingly, reduction of ETRB expression by BQ788 was accompanied by a strong induction of VEGF expression and repression of the angiogenic suppressor gravin. These changes in gene expression correlated with increased angiogenesis in tumors injected with ETRB antagonist in vivo. Taken together, our observations suggest that ETRB may provide a potential therapeutic target in high-grade melanomas and identify candidate pathways that may be implicated in the regulation of cell survival and tumor progression associated with ETRB signaling.
Microalbuminuria and Lower Glomerular Filtration Rate at Young Adult Age in Subjects Born Very Premature and after Intrauterine Growth Retardation
Authors: Mandy G. Keijzer-Veen, Marlies Schrevel, Martijn J.J. Finken, Friedo W. Dekker, Jeroen Nauta, Elyse[Combining Acute Accent]e T.M. Hille, Marijke Fro[Combining Diaeresis]lich, Bert J. van der Heijden
Journal: Journal of the American Society of Nephrology (2005)

This prospective follow-up study of 422 19-yr-old subjects born very preterm in The Netherlands was performed to determine whether intrauterine growth retardation (IUGR) predisposes to abnormal GFR and microalbuminuria in adolescents. GFR (ml/min per 1.73 m2) was estimated using the Cockcroft-Gault equation, and albumin-creatinine ratio (mg/mmol) was calculated in a cohort of 19-yr-old subjects born very preterm (gestational age <32 wk) in 1983. Birth weights were adjusted for gestational age and expressed as standard deviation scores (sds) as a measure of IUGR. All subjects had normal renal function. Birth weight (sds) was associated negatively with serum creatinine concentration (μmol/L) (β = −1.0 μmol/L, 95% confidence interval [CI]: −1.9 to −0.2), positively with GFR (β = 3.0, 95% CI: 1.7 to 4.2), and negatively with the logarithm of albumin-creatinine ratio (β = −0.05, 95% CI: −0.09 to −0.01) in young adults born very preterm. IUGR is associated with unfavorable renal functions at young adult age in subjects born very premature. These data suggest that intrauterine growth–retarded subjects born very premature have an increased risk to develop progressive renal failure in later life.
Language is shaped by the body
Authors: Mark Aronoff, Irit Meir, Carol Padden, Wendy Sandler
Journal: Behavioral and Brain Sciences (2008)

Abstract Sign languages provide direct evidence for the relation between human languages and the body that engenders them. We discuss the use of the hands to create symbols and the role of the body in sign language verb systems, especially in two quite recently developed sign languages, Israeli Sign Language and Al-Sayyid Bedouin Sign Language.
The rise and fall of endothelin receptor antagonists in congestive heart failure
Authors: M.L. Handoko, F.S. de Man, A. Vonk-Noordegraaf
Journal: European Respiratory Journal (2011)

Since its discovery in 1988 1, the role of endothelin in cardiovascular disease has been intensively studied. Activation of the endothelin system is considered part of the neurohormonal response in congestive heart failure. Endothelin is produced by vascular endothelial cells and has potent vasoconstrictor effects 2. Elevated endothelin levels induce adverse cardiac remodelling and cause progressive aggravation of congestive heart failure by influencing loading conditions of the heart and by reducing coronary flow; endothelin also has direct (toxic) myocardial effects 2. Several clinical studies have demonstrated that higher plasma levels of endothelin-1 correlates with the degree of haemodynamic and functional impairment, and worse …