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51.
Yoonha Choi Tiffany Ting Liu Daniel G. Pankratz Thomas V. Colby Neil M. Barth David A. Lynch P. Sean Walsh Ganesh Raghu Giulia C. Kennedy Jing Huang 《BMC genomics》2018,19(2):101
Background
We developed a classifier using RNA sequencing data that identifies the usual interstitial pneumonia (UIP) pattern for the diagnosis of idiopathic pulmonary fibrosis. We addressed significant challenges, including limited sample size, biological and technical sample heterogeneity, and reagent and assay batch effects.Results
We identified inter- and intra-patient heterogeneity, particularly within the non-UIP group. The models classified UIP on transbronchial biopsy samples with a receiver-operating characteristic area under the curve of ~?0.9 in cross-validation. Using in silico mixed samples in training, we prospectively defined a decision boundary to optimize specificity at ≥85%. The penalized logistic regression model showed greater reproducibility across technical replicates and was chosen as the final model. The final model showed sensitivity of 70% and specificity of 88% in the test set.Conclusions
We demonstrated that the suggested methodologies appropriately addressed challenges of the sample size, disease heterogeneity and technical batch effects and developed a highly accurate and robust classifier leveraging RNA sequencing for the classification of UIP.52.
53.
Rieks D. van Klinken Louise Morin Andy Sheppard S. Raghu 《Biological invasions》2016,18(10):2853-2870
Prioritising investments in classical weed biological control (biocontrol) is a common decision-making challenge: biocontrol programmes can yield substantial benefits but are typically long-term and costly, and the outcome uncertain. Experts are often relied upon to help, but their role is generally restricted to providing facts and judgements to populate an existing prioritisation model, which in turn receives little scrutiny. We developed and applied a new prioritisation framework to guide biocontrol investment decisions by livestock industries that required eliciting experts’ functional understanding (including their in-depth knowledge of the theoretical and practical drivers of weed biocontrol programmes). This consultative and transparent framework drew on expertise from most biocontrol practitioners in Australia through a structured workshop, and the literature. Each of the 75 weed taxa considered was placed in a matrix according to their impact (current or potential) and the prospects of biocontrol achieving pre-defined management goals. There was considerable knowledge uncertainty regarding potential impacts, which is of concern when making pre-emptive investments. Feasibility (likelihood of finding host-specific agents) and likelihood of success (management goals being met, assuming that host-specific agents are available) of biocontrol were both assessed as low for 51 % of taxa. Predicted barriers to successful biocontrol were diverse and idiosyncratic, suggesting that application of more quantitative prioritisation approaches would be challenging. A short-list of 13 weed taxa was identified for further consideration as biocontrol targets, based on the trade-off between potential impact and prospects for biocontrol. Research priorities emerged from the prioritisation process that would maximise investment outcomes for each taxon. Only two short-listed taxa are new targets, reflecting the maturity of the biocontrol discipline targeting weeds of livestock industries in Australia. Accessing the in-depth functional understanding of experts resulted in explicit characterisation of the barriers to successful biocontrol and if/how they might be overcome, improved characterisation of uncertainty, and provided directed guidance for investment. Such an approach would be readily applicable to analogous decision-making challenges in other sectors and countries. 相似文献
54.
Marfan's syndrome is a genetic disorder affecting connective tissues, and it can lead to death due to aortic defects if left untreated. beta-blocker therapy has been used to slow the progression of this disease. Brooke et al. (2008) now report that combining angiotensin II receptor blockade by losartan with beta-blocker treatment is an effective treatment combination therapy for this disorder. 相似文献
55.
Yi-Ping Yan Bradley T. Lang Raghu Vemuganti†‡ Robert J. Dempsey† 《Journal of neurochemistry》2009,109(6):1624-1635
We investigated intracerebral hemorrhage (ICH)-induced lateral migration of neuroblasts and the mechanism underlying this migration. ICH model was induced by collagenase injection into the striatum of adult wild-type and osteopontin (OPN) knockout mice. In the wild-type mice, the lateral migration of neuroblasts from the ipsislateral subventricular zone (SVZ) towards the hematoma started at day 3 and continued up to day 28 after ICH. In addition to migrating towards the hematoma, neuroblasts also migrated to the area of ipsilateral striatum remote to the hematoma. The migrating neuroblasts were closely associated with activated astrocytes and blood vessels in the injured striatum. Following ICH, the expression of OPN was up-regulated in the ipsilateral striatum from day 1 to day 28. In vitro , OPN treatment did not affect the proliferation of neural progenitors, but enhanced the trans-well and radial migration of neural progenitors. In vivo , OPN deficiency did not affect the proliferation of neural progenitors in the SVZ. However, following ICH a significant decrease in lateral neuroblast migration was observed in the OPN knockout mice compared with the wild-type mice. These results suggest that increased OPN expression in the injured striatum plays a significant role in the lateral migration of neuroblasts following ICH. 相似文献
56.
Raghu Pullakhandam 《Archives of biochemistry and biophysics》2009,485(2):115-895
Biophysical evidences suggest that transthyretin (TTR) tetramer dissociation to the monomeric intermediate and subsequent polymerization leads to amyloid fibril formation, which is implicated in the pathogenesis of familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA). Hence, inhibition of fibril formation is considered a potential therapeutic strategy. Here in we demonstrate that curcumin, a phenolic constituent of curry spice turmeric, binds to the active site of TTR through fluorescence quenching and ANS displacement studies. Binding of curcumin appears to inhibit the denaturant induced tertiary and quaternary structural changes in TTR as monitored by intrinsic emission fluorescence and glutaraldehyde cross-linking studies. However, curcumin did not bind to TTR at acidic pH. Protonation/ isomerization of the side chain oxygen atoms of curcumin at low pH might hamper the binding. These results suggest that curcumin binds to and stabilizes TTR thereby highlight the importance of the side chain conformations of the ligand in binding to TTR. 相似文献
57.
Sharma-Walia N Raghu H Sadagopan S Sivakumar R Veettil MV Naranatt PP Smith MM Chandran B 《Journal of virology》2006,80(13):6534-6552
58.
59.
Gogada R Prabhu V Amadori M Scott R Hashmi S Chandra D 《The Journal of biological chemistry》2011,286(33):28749-28760
Resveratrol, a naturally occurring phytoalexin, is known to induce apoptosis in multiple cancer cell types, but the underlying molecular mechanisms remain unclear. Here, we show that resveratrol induced p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated translocation of Bax to mitochondria where it underwent oligomerization to initiate apoptosis. Resveratrol treatment promoted interaction between Bax and XIAP in the cytosol and on mitochondria, suggesting that XIAP plays a critical role in the activation and translocation of Bax to mitochondria. This process did not involve p53 but required accumulation of Bim and t-Bid on mitochondria. Bax primarily underwent homo-oligomerization on mitochondria and played a major role in release of cytochrome c to the cytosol. Bak, another key protein that regulates the mitochondrial membrane permeabilization, did not interact with p53 but continued to associate with Bcl-xL. Thus, the proapoptotic function of Bak remained suppressed during resveratrol-induced apoptosis. Caspase-9 silencing inhibited resveratrol-induced caspase activation, whereas caspase-8 knockdown did not affect caspase activity, suggesting that resveratrol induces caspase-9-dependent apoptosis. Together, our findings characterize the molecular mechanisms of resveratrol-induced caspase activation and subsequent apoptosis in cancer cells. 相似文献
60.
Mitochondrial dysfunction plays a critical role in the development of cardiac hypertrophy and heart failure. So mitochondria are emerging as one of the important druggable targets in the management of cardiac hypertrophy and other associated complications. In the present study, effects of ethanolic extract of Boerhaavia diffusa (BDE), a green leafy vegetable against mitochondrial dysfunction in angiotensin II (Ang II) induced hypertrophy in H9c2 cardiomyoblasts was evaluated. H9c2 cells challenged with Ang II exhibited pathological hypertrophic responses and mitochondrial dysfunction which was evident from increment in cell volume (49.09±1.13%), protein content (55.17±1.19%), LDH leakage (58.74±1.87%), increased intracellular ROS production (26.25±0.91%), mitochondrial superoxide generation (65.06±2.27%), alteration in mitochondrial transmembrane potential (ΔΨm), opening of mitochondrial permeability transition pore (mPTP) and mitochondrial swelling. In addition, activities of mitochondrial respiratory chain complexes (I-IV), aconitase, NADPH oxidase, thioredoxin reductase, oxygen consumption rate and calcium homeostasis were evaluated. Treatment with BDE significantly prevented the generation of intracellular ROS and mitochondrial superoxide radicals and protected the mitochondria by preventing dissipation of ΔΨm, opening of mPTP, mitochondrial swelling and enhanced the activities of respiratory chain complexes and oxygen consumption rate in H9c2 cells. Activities of aconitase and thioredoxin reductase which was lowered (33.77±0.68% & 45.81±0.71% respectively) due to hypertrophy, were increased in BDE treated cells (P≤0.05). Moreover, BDE also reduced the intracellular calcium overload in Ang II treated cells. Overall results revealed the protective effects of B. diffusa against mitochondrial dysfunction in hypertrophy in H9c2 cells and the present findings may shed new light on the therapeutic potential of B. diffusa in addition to its nutraceutical potentials. 相似文献