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51.
Cardiac responses to graded treadmill exercise were compared in conscious dogs before and after excision of the sinoatrial node (SAN) and adjacent tissue along the sulcus terminalis. The chronotropic and dromotropic responses to dynamic exercise were compared with and without selective muscarinic (atropine) and/or beta-adrenergic (timolol) blockade. With the SAN intact, cardiac acceleration was prompt during onset of exercise and in proportion to work intensity. Immediately after SAN excision (1-7 days), pacemaker activity exhibited marked instability in rate and pacemaker location, with rapid shifts between atrial and junctional foci. Soon thereafter (1-2 wk), subsidiary atrial pacemakers (SAPs) assumed the primary pacemaker function. Although the SAP foci demonstrated stable heart rates and atrioventricular (AV) intervals at rest and during exercise, heart rates at rest and during steady-state exercise were reduced 34% from corresponding levels in the SAN-intact state, both with and without selective autonomic blockade. For control of dromotropic function, animals with SAP foci showed pronounced shortening in AV interval in conjunction with exercise that was further exacerbated by pretreatment with atropine. Eight weeks after excision of the primary SAN pacemakers, direct electrophysiological mapping localized the SAP foci to either the inferior right atrium along the sulcus terminalis or the dorsal cranial right atrium (in or near Bachmann's bundle). Animals with SAPs localized to the inferior right atrium had a more marked suppression in heart rate with a corresponding greater decrease in AV interval during exercise than dogs with SAP foci identified within the dorsal cranial right atrium. 相似文献
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Aamir Ahmad Shadan Ali Alia Ahmed Azfur S. Ali Avraham Raz Wael A. Sakr KM Wahidur Rahman 《PloS one》2013,8(1)
Herceptin failure is a major clinical problem in breast cancer. A subset of breast cancer patients with high HER-2/neu levels eventually experience metastatic disease progression when treated with Herceptin as a single agent. Mechanistic details of development of this aggressive disease are not clear. Therefore, there is a dire need to better understand the mechanisms by which drug resistance develops and to design new combined treatments that benefit patients with aggressive breast cancer and have minimal toxicity. We hypothesized that 3, 3′-diindolylmethane (DIM), a non-toxic agent can be combined with Herceptin to treat breast cancers with high levels of HER-2/neu. Here, we evaluated the effects of Herceptin alone and in combination with DIM on cell viability, apoptosis and clonogenic assays in SKBR3 (HER-2/neu-expressing) and MDA-MB-468 (HER-2/neu negative) breast cancer cells. We found that DIM could enhance the effectiveness of Herceptin by significantly reducing cell viability, which was associated with apoptosis-induction and significant inhibition of colony formation, compared with single agent treatment. These results were consistent with the down-regulation of Akt and NF-kB p65. Mechanistic investigations revealed a significant upregulation of miR-200 and reduction of FoxM1 expression in DIM and Herceptin-treated breast cancer cells. We, therefore, transfected cells with pre-miR-200 or silenced FoxM1 in these cells for understanding the molecular mechanism involved. These results provide experimental evidence, for the first time, that DIM plus Herceptin therapy could be translated to the clinic as a therapeutic modality to improve treatment outcome of patients with breast cancer, particularly for the patients whose tumors express high levels of HER-2/neu. 相似文献
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The Auxin-Binding Protein 1 (ABP1) was identified over 30 years ago thanks to it''s high affinity for active auxins. ABP1 plays an essential role in plant life yet to this day, its function remains ‘enigmatic.’ A recent study by our laboratory shows that ABP1 is critical for regulation of the cell cycle, acting both in G1 and at the G2/M transition. We showed that ABP1 is likely to mediate the permissive auxin signal for entry into the cell cycle. These data were obtained by studying a conditional functional knock-out of ABP1 generated by cellular immunization in the model tobacco cell line, Bright Yellow 2.Key Words: auxin responses, auxin-binding protein 1, immunomodulation, cellular immunisation 相似文献
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There has been extensive recent interest in the concepts of behavioral types, behavioral syndromes, and personalities in nonhuman animal species. Evidence for behavioral types now exists from a wide range of taxa, from mollusks to mammals. However, marine mammals are poorly represented in this literature. Here, we describe an in‐field experimental test of behavioral types in breeding gray seals, using a remotely controlled vehicle to deliver a standardized test stimulus to target individuals. We report on the design and implementation of this test and on the behavioral responses of individuals. Analysis of behavioral responses from both males and females revealed consistent individual differences across tests, suggesting that this is a practical and viable technique for determining individual variation in behavioral type in the field. Despite extensive literature on behavioral types, studies of behavioral types in wild populations remain rare. It is, therefore, important to develop ways to identify and quantify the existence of behavioral types in natural populations, because only by doing this, can we hope to ascertain the ecological and evolutionary relevance of behavioral types. 相似文献
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Jagani Z Mora-Blanco EL Sansam CG McKenna ES Wilson B Chen D Klekota J Tamayo P Nguyen PT Tolstorukov M Park PJ Cho YJ Hsiao K Buonamici S Pomeroy SL Mesirov JP Ruffner H Bouwmeester T Luchansky SJ Murtie J Kelleher JF Warmuth M Sellers WR Roberts CW Dorsch M 《Nature medicine》2010,16(12):1429-1433
Aberrant activation of the Hedgehog (Hh) pathway can drive tumorigenesis. To investigate the mechanism by which glioma-associated oncogene family zinc finger-1 (GLI1), a crucial effector of Hh signaling, regulates Hh pathway activation, we searched for GLI1-interacting proteins. We report that the chromatin remodeling protein SNF5 (encoded by SMARCB1, hereafter called SNF5), which is inactivated in human malignant rhabdoid tumors (MRTs), interacts with GLI1. We show that Snf5 localizes to Gli1-regulated promoters and that loss of Snf5 leads to activation of the Hh-Gli pathway. Conversely, re-expression of SNF5 in MRT cells represses GLI1. Consistent with this, we show the presence of a Hh-Gli-activated gene expression profile in primary MRTs and show that GLI1 drives the growth of SNF5-deficient MRT cells in vitro and in vivo. Therefore, our studies reveal that SNF5 is a key mediator of Hh signaling and that aberrant activation of GLI1 is a previously undescribed targetable mechanism contributing to the growth of MRT cells. 相似文献
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