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1.  The Accumulation of Versican in the Nodules of Benign Prostatic Hyperplasia 
The Prostate  2009;69(2):149-158.
Background
Proteoglycans, a complex group of extracellular matrix (ECM) molecules, are elevated in benign prostatic hyperplasia (BPH). Versican is a stromal proteoglycan present in prostate tissue. Versican expression is elevated in tissues with increased proliferation. Based on these observations, we determined the extent and distribution of versican expression in prostates with BPH.
Methods
The involvement of versican in BPH nodules was compared with levels in non-nodular transition (TZ) and peripheral zone (PZ) tissues from 18 human prostate glands using immunohistochemistry, Northern blots and/or QRTPCR to localize versican and quantify versican mRNA transcript levels, and Western blots to assess gene product levels.
Results
Increased versican immunoreactivity was observed in the stroma of BPH nodules. Higher steady state levels of versican variants V0, V1, and V3 mRNA transcript and gene product were detected in the nodular tissues than in the non-nodular TZ or PZ parenchyma.
Conclusions
These results suggest that versican may play a role in nodule formation in BPH.
doi:10.1002/pros.20861
PMCID: PMC4092210  PMID: 18819099
Prostate hyperplasia; proteoglycans; extracellular matrix; versican
2.  Cell Adhesion on Polyelectrolyte Multilayer Coated Polydimethylsiloxane Surfaces with Varying Topographies 
Tissue engineering  2007;13(8):2105-2117.
This article demonstrates that the micro-topography of the surface with respect to the pattern size and pitch influences cell adhesion and proliferation. Extensive research has shown the dependence of cell proliferation on substrate chemistry, but the influence of substrate topography on cell attachment has only recently been appreciated. To evaluate the effect of substrate physical properties (i.e., periodic microstructures) on cell attachment and morphology, we compared the response of several cell types (fibroblasts, HeLa, and primary hepatocytes) cultured on various polydimethylsiloxane (PDMS) patterns. PDMS has been used as an artificial construct to mimic biological structures. Although PDMS is widely used in biomedical applications, membrane technology, and microlithography, it is difficult to maintain cells on PDMS for long periods, and the polymer has proved to be a relatively inefficient substrate for cell adhesion. To improve adhesion, we built polyelectrolyte multilayers (PEMs) on PDMS surfaces to increase surface wettability, thereby improving attachment and spreading of the cells. Micrographs demonstrate the cellular response to physical parameters, such as pattern size and pitch, and suggest that surface topography, in part, regulates cell adhesion and proliferation. Therefore, varying the surface topography may provide a method to influence cell attachment and proliferation for tissue-engineering applications.
doi:10.1089/ten.2006.0151
PMCID: PMC4059019  PMID: 17518734
3.  Application of Metabolic Flux Analysis to Identify the Mechanisms of Free Fatty Acid Toxicity to Human Hepatoma Cell Line 
Biotechnology and bioengineering  2008;99(2):399-410.
Chronic exposure to elevated levels of free fatty acids (FFAs) has been shown to cause cell death (lipotoxicity), but the underlying mechanisms of lipotoxicity in hepatocytes remain unclear. We have previously shown that the saturated FFAs cause much greater toxicity to human hepatoma cells (HepG2) than the unsaturated ones (Srivastava and Chan, 2007). In this study, metabolic flux analysis (MFA) was applied to identify the metabolic changes associated with the cytotoxicity of saturated FFA. Measurements of the fluxes revealed that the saturated FFA, palmitate, was oxidized to a greater extent than the non-toxic oleate and had comparatively less triglyceride synthesis and reduced cystine uptake. Although fatty acid oxidation had a high positive correlation to the cytotoxicity, inhibitor experiments indicated that the cytotoxicity was not due to the higher fatty acid oxidation. Application of MFA revealed that cells exposed to palmitate also had a consistently reduced flux of glutathione (GSH) synthesis but greater de novo ceramide synthesis. These predictions were experimentally confirmed. In silico sensitivity analyses identified that the GSH synthesis was limited by the uptake of cysteine. Western blot analyses revealed that the levels of the cystine transporter xCT, but not that of the GSH-synthesis enzyme glutamylcysteine synthase (GCS), were reduced in the palmitate cultures, suggesting the limitation of cysteine import as the cause of the reduced GSH synthesis. Finally, supplementing with N-acetyl L-cysteine (NAC), a cysteine-provider whose uptake does not depend on xCT levels, reduced the FFA-toxicity significantly. Thus, the metabolic alterations that contributed to the toxicity and suggested treatments to reduce the toxicity were identified, which were experimentally validated.
doi:10.1002/bit.21568
PMCID: PMC4059351  PMID: 17615559
metabolism; free fatty acid; toxicity; ceramide; glutathione; cystine transporter
4.  Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neurons 
The European journal of neuroscience  2007;26(8):2131-2141.
A high-fat diet has been shown to significantly increase the risk of the development of Alzheimer’s disease (AD), a neurodegenerative disease histochemically characterized by the accumulation of amyloid beta (Aβ) protein in senile plaques and hyperphosphorylated tau in neurofibrillary tangles. Previously, we have shown that saturated free fatty acids (FFAs), palmitic and stearic acids, caused increased amyloidogenesis and tau hyperphosphorylaion in primary rat cortical neurons. These FFA-induced effects observed in neurons were found to be mediated by astroglial FFA metabolism. Therefore, in the present study we investigated the basic mechanism relating astroglial FFA metabolism and AD-like changes observed in neurons. We found that palmitic acid significantly increased de-novo synthesis of ceramide in astroglia, which in turn was involved in inducing both increased production of the Aβ protein and hyperphosphorylation of the tau protein. Increased amyloidogenesis and hyperphoshorylation of tau lead to formation of the two most important pathophysiological characteristics associated with AD, Aβ or senile plaques and neurofibrillary tangles, respectively. In addition to these pathophysiological changes, AD is also characterized by certain metabolic changes; abnormal cerebral glucose metabolism is one of the distinct characteristics of AD. In this context, we found that palmitic acid significantly decreased the levels of astroglial glucose transporter (GLUT1) and down-regulated glucose uptake and lactate release by astroglia. Our present data establish an underlying mechanism by which saturated fatty acids induce AD-associated pathophysiological as well as metabolic changes, placing ‘astroglial fatty acid metabolism’ at the center of the pathogenic cascade in AD.
doi:10.1111/j.1460-9568.2007.05797.x
PMCID: PMC4059364  PMID: 17908174
Alzheimer’s disease; astroglia; ceramide; fat; rat
5.  Using Dynamic Gene Module Map Analysis To Identify Targets That Modulate Free Fatty Acid Induced Cytotoxicity 
Biotechnology progress  2007;24(1):29-37.
The objective of this study was to identify pathways that regulate the cytotoxicity induced by free fatty acids (FFAs) in human hepatoblastoma cells (HepG2/C3A). Gene expression profiles of HepG2/C3A cells were obtained at three time points, after 24, 48, and 72 h of exposure to different types of FFA. Saturated fatty acid (palmitate) was found to be cytotoxic. The pathways activated by the different FFAs at the different time points were identified using global gene module map analysis. Unsaturated FFAs exerted transcriptional regulation mainly within the first 24 h, whereas saturated FFA, palmitate, regulated energy production pathways, such as the electron transport chain (ETC) and tricarboxylic acid cycle, within the first 24 h. In the next 24 h, palmitate up-regulated 36 cell death relevant pathways and down-regulated several protective pathways, such as the pentose phosphate pathway and glutathione-related pathways. In the final 24 h, the FFAs did not induce significant transcriptional regulation. We hypothesized that palmitate induced cytotoxicity by first perturbing metabolic pathways in the initial 24 h, resulting in changes to factors, such as metabolites or signaling molecules, which subsequently triggered cell death relevant pathways in the next 24 h. The uptake and release of 27 metabolites were measured to further elucidate the metabolic changes in the first 24 h. It was determined that ketone bodies such as β-hydroxybutyrate and acetoacetate were important in separating the toxic from the nontoxic phenotypes. A regression model was used to identify the genes relevant to these metabolites. Some of the genes identified to be important were experimentally validated. It was found that ETC genes such as NADH dehydrogenase and succinate dehydrogenase were involved in palmitate induced cytotoxicity.
doi:10.1021/bp070120b
PMCID: PMC4059368  PMID: 18052188
6.  A multi-layer inference approach to reconstruct condition-specific genes and their regulation 
Bioinformatics  2013;29(12):1541-1552.
An important topic in systems biology is the reverse engineering of regulatory mechanisms through reconstruction of context-dependent gene networks. A major challenge is to identify the genes and the regulations specific to a condition or phenotype, given that regulatory processes are highly connected such that a specific response is typically accompanied by numerous collateral effects. In this study, we design a multi-layer approach that is able to reconstruct condition-specific genes and their regulation through an integrative analysis of large-scale information of gene expression, protein interaction and transcriptional regulation (transcription factor-target gene relationships). We establish the accuracy of our methodology against synthetic datasets, as well as a yeast dataset. We then extend the framework to the application of higher eukaryotic systems, including human breast cancer and Arabidopsis thaliana cold acclimation. Our study identified TACSTD2 (TROP2) as a target gene for human breast cancer and discovered its regulation by transcription factors CREB, as well as NFkB. We also predict KIF2C is a target gene for ER−/HER2− breast cancer and is positively regulated by E2F1. The predictions were further confirmed through experimental studies.
Availability: The implementation and detailed protocol of the layer approach is available at http://www.egr.msu.edu/changroup/Protocols/Three-layer%20approach%20to%20reconstruct%20condition.html.
Contact: krischan@egr.msu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt186
PMCID: PMC3673221  PMID: 23610368
7.  Tunable Resistive m-dPEG Acid Patterns on Polyelectrolyte Multilayers at Physiological Conditions: Template for Directed Deposition of Biomacromolecules 
This paper describes a new class of salt-responsive poly(ethylene glycol) (PEG) self-assembled monolayers (SAMs) on top of polyelectrolyte multilayer (PEMs) films. PEM surfaces with poly(diallyldimethylammonium chloride) as the topmost layer are chemically patterned by microcontact printing (μCP) oligomeric PEG molecules with an activated carboxylic acid terminal group (m-dPEG acid). The resistive m-d-poly(ethylene glycol) (m-dPEG) acid molecules on the PEMs films were subsequently removed from the PEM surface with salt treatment, thus converting the nonadhesive surfaces into adhesive surfaces. The resistive PEG patterns facilitate the directed deposition of various macromolecules such as polymers, dyes, colloidal particles, proteins, liposomes, and nucleic acids. Further, these PEG patterns act as a universal resist for different types of cells (e.g., primary cells, cell lines), thus permitting more flexibility in attaching a wide variety of cells to material surfaces. The patterned films were characterized by optical microscopy and atomic force microscopy (AFM). The PEG patterns were removed from the PEM surface at certain salt conditions without affecting the PEM films underneath the SAMs. Removal of the PEG SAMs and the stability of the PEM films underneath it were characterized with ellipsometry and optical microscopy. Such salt- and pH-responsive surfaces could lead to significant advances in the fields of tissue engineering, targeted drug delivery, materials science, and biology.
doi:10.1021/la702925r
PMCID: PMC4040536  PMID: 18052083
8.  Global Protein Phosphorylation Dynamics during Deoxynivalenol-Induced Ribotoxic Stress Response in the Macrophage 
Toxicology and applied pharmacology  2013;268(2):201-211.
Deoxynivalenol (DON), a trichothecenemycotoxin produced by Fusarium that commonly contaminates food, is capable of activating mononuclear phagocytes of the innate immune system via a process termed the ribotoxic stress response (RSR). To encapture global signaling events mediating RSR, we quantified the early temporal (≤30 min) phosphoproteome changes that occurred in RAW 264.7 murine macrophage during exposure to a toxicologically relevant concentration of DON (250 ng/mL). Large-scale phosphoproteomic analysis employing stable isotope labeling of amino acids in cell culture (SILAC) in conjunction with titanium dioxide chromatography revealed that DON significantly upregulated or downregulated phosphorylation of 188 proteins at both known and yet-to-be functionally characterized phosphosites. DON-induced RSR is extremely complex and goes far beyond its prior known capacity to inhibit translation and activate MAPKs. Transcriptional regulation was the main target during early DON-induced RSR, covering over 20 percent of the altered phosphoproteins as indicated by Gene Ontology annotation and including transcription factors/cofactors and epigenetic modulators. Other biological processes impacted included cell cycle, RNA processing, translation, ribosome biogenesis, monocyte differentiation and cytoskeleton organization. Some of these processes could be mediated by signaling networks involving MAPK-, NFκB-, AKT- and AMPK-linked pathways. Fuzzy c-means clustering revealed that DON-regulated phosphosites could be discretely classified with regard to the kinetics of phosphorylation/dephosphorylation. The cellular response networks identified provide a template for further exploration of the mechanisms of trichothecenemycotoxins and other ribotoxins, and ultimately, could contribute to improved mechanism-based human health risk assessment.
doi:10.1016/j.taap.2013.01.007
PMCID: PMC4041276  PMID: 23352502
Ribotoxic stress response; phosphorylation; quantitative proteomics; trichothecenemycotoxin; deoxynivalenol
9.  Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults 
Mechanisms of development  2013;130(0):272-289.
Global inactivation of the metalloproteinase ADAM17 during mouse development results in perinatal lethality and abnormalities of the heart, including late embryonic cardiomegaly and thickened semilunar and atrioventricular valves. These defects have been attributed in part to a lack of ADAM17-mediated processing of HB-EGF, as absence of soluble HB-EGF results in similar phenotypes. Because valvular mesenchymal cells are largely derived from cardiac endothelial cells, we generated mice with a floxed Adam17 allele and crossed these animals with Tie2-Cre transgenics to focus on the role of endothelial ADAM17 in valvulogenesis. We find that although hearts from late-stage embryos with ablation of endothelial ADAM17 appear normal, an increase in valve size and cell number is evident, but only in the semilunar cusps. Unlike Hbegf−/− valves, ADAM17-null semilunar valves do not differ from controls in acute cell proliferation at embryonic day 14.5 (E14.5), suggesting compensatory processing of HB-EGF. However, levels of the proteoglycan versican are significantly reduced in mutant hearts early in valve remodeling (E12.5). After birth, aortic valve cusps from mutants are not only hyperplastic but also show expansion of the glycosaminoglycan-rich component, with the majority of adults exhibiting aberrant compartmentalization of versican and increased deposition of collagen. The inability of mutant outflow valve precursors to transition into fully mature cusps is associated with decreased postnatal viability, progressive cardiomegaly, and systolic dysfunction. Together, our data indicate that ADAM17 is required in valvular endothelial cells for regulating cell content as well as extracellular matrix composition and organization in semilunar valve remodeling and homeostasis.
doi:10.1016/j.mod.2013.01.001
PMCID: PMC3622831  PMID: 23354118
Valve; metalloproteinase; proteoglycan; echocardiography; endothelial; extracellular matrix
10.  Quantitative, solution-phase profiling of multiple transcription factors in parallel 
Analytical and bioanalytical chemistry  2013;405(8):2461-2468.
Transcription factors are regulatory proteins that bind to specific sites of chromosomal DNA to enact responses to intracellular and extracellular stimuli. Transcription factor signalling networks are branched and interconnected so that any single transcription factor can activate many different genes and one gene can be activated by a combination of different transcription factors. Thus, trying to characterize a cellular response to a stimulus by measuring the level of only one transcription factor potentially ignores important simultaneous events that contribute to the response. Hence, parallel measurements of transcription factors are necessary to capture the breadth of valuable information about cellular responses that would not be obtained by measuring only a single transcription factor. We have sought to develop a new, scalable, flexible, and sensitive approach to analysis of transcription factor levels that complements existing parallel approaches. Here, we describe proof-of-principle analyses of purified human transcription factors and breast cancer nuclear extracts. Our assay can successfully quantify transcription factors in parallel with ~10-fold better sensitivity than current techniques. Sensitivity of the assay can be further increased by 200-fold through the use of PCR for signal amplification.
doi:10.1007/s00216-013-6712-9
PMCID: PMC3582790  PMID: 23361227
Transcription Factors; Parallel; DNA binding activity; Magnetic Beads separation; Breast Cancer
11.  Palmitate-activated astrocytes via SPT increase BACE1 in primary neurons by SMases 
Neurobiology of aging  2012;34(2):540-550.
Astrocytes play a critical role in neurodegenerative diseases, including Alzheimer’s disease (AD). Previously, we showed that saturated free-fatty acid, palmitate (PA), upregulates BACE1 level and amyloidogenesis in primary rat neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned media from PA-treated astrocytes upregulates BACE1 level in neurons are unknown. This study demonstrates that serine palmitoyltransferase (SPT) in the astrocytes increases ceramide levels, which enhances the release of cytokines that mediate the activation of neural and acidic sphingomyelinase (N-SMase and A-SMase) in the neurons, to propagate the deleterious effects of palmitate, i.e. BACE1 upregulation. In support of the relevance of SPT in AD, our lab recently measure and found SPT levels to be significantly upregulated in AD brains as compared to controls (Geekiyanage and Chan, 2011). Cytokines, namely TNFα and IL-1β, released into the conditioned media of PA-treated astrocytes activate N-SMase and A-SMase in the neurons. Neutralizing the cytokines in the PA-treated astrocyte conditioned media reduced BACE1 upregulation. However, inhibiting SPT in the astrocytes decreased the levels of both TNFα and IL-1β in the conditioned media, which in turn reduced the SMase activities and BACE1 level in primary neurons. Thus, our results suggest that the activation of the astrocytes by PA is mediated by SPT, and the activated astrocytes increases BACE1 level in the neurons, the latter is mediate by the SMases.
doi:10.1016/j.neurobiolaging.2012.05.017
PMCID: PMC3459302  PMID: 22727944
Alzheimer’s disease; Fatty acid; Sphingomyelinase; Serine palmitoyltransferase; Ceramide; TNFα; IL-1β
12.  Cleavage of Hyaluronan is Impaired in Aged Dermal Wounds 
Changes in extracellular matrix (ECM) are one of many components that contribute to impaired wound healing in aging. This study examined the effect of age on the glycosaminoglycan hyaluronan (HA) in normal and wounded dermis from young (4–6 month-old) and aged (22–24 month-old) mice. HA content and size was similar in the normal dermis of young and aged mice. Dermal explants labeled with [3H]-glucosamine showed decreased generation of smaller forms of HA in aged explants relative to young explants. Aged mice exhibited delayed wound repair compared with young mice with the greatest differential at 5 days. Expression of hyaluronan synthase (HAS) 2,3 and hyaluronidase (HYAL) 1-3 mRNA in wounds of young and aged mice was similar. There was a trend toward decreased HYAL protein expression in aged wound dermis, which was accompanied by changes in detectable HYAL activity. Total HA content was similar in young and aged wound dermis. There was significantly less HA in the lower MW range (~250 kDa and smaller) in 5-day wound dermis, but not 9-day wound dermis, from aged mice relative to young mice. We propose that decreased cleavage of HA is an additional component of impaired dermal wound healing in aging.
doi:10.1016/j.matbio.2012.09.004
PMCID: PMC3570623  PMID: 23022999
Wound healing; Dermis; Age; Mice; Hyaluronan; Hyaluronan Synthase; Hyaluronidase
13.  A Classification Framework Applied to Cancer Gene Expression Profiles 
Journal of healthcare engineering  2013;4(2):10.1260/2040-2295.4.2.255.
Classification of cancer based on gene expression has provided insight into possible treatment strategies. Thus, developing machine learning methods that can successfully distinguish among cancer subtypes or normal versus cancer samples is important. This work discusses supervised learning techniques that have been employed to classify cancers. Furthermore, a two-step feature selection method based on an attribute estimation method (e.g., ReliefF) and a genetic algorithm was employed to find a set of genes that can best differentiate between cancer subtypes or normal versus cancer samples. The application of different classification methods (e.g., decision tree, k-nearest neighbor, support vector machine (SVM), bagging, and random forest) on 5 cancer datasets shows that no classification method universally outperforms all the others. However, k-nearest neighbor and linear SVM generally improve the classification performance over other classifiers. Finally, incorporating diverse types of genomic data (e.g., protein-protein interaction data and gene expression) increase the prediction accuracy as compared to using gene expression alone.
doi:10.1260/2040-2295.4.2.255
PMCID: PMC3873740  PMID: 23778014
classification; cancer; feature selection; gene expression; machine learning; supervised learning
14.  Time Controlled Release of Arabinofuranosylcytosine (Ara-C) from Agarose Hydrogels using Layer-by-Layer Assembly: An In Vitro Study 
Journal of biomaterials science. Polymer edition  2011;23(0):10.1163/092050610X552221.
Experimentally induced axonal regeneration is compromised by glial scar formation arising from leptomeningeal fibroblasts cells in and around the hydrogel scaffold implanted for nerve repair. Strategies are needed to prevent such fibroblastic reactive cell layer formation for enhanced axonal regeneration. Here, we implement the technique of layer-by-layer assembled degradable, hydrogen bonded multilayers on agarose hydrogels to incorporate an anti-mitotic drug (1-β-D-arabinofuranosylcytosine (Ara-C)) within the agarose hydrogels. We show controlled release of Ara-C under physiological conditions over a period of days. The concentrations of Ara-C released from agarose at the different time points were sufficient to inhibit fibroblast growth in vitro, while not adversely affecting the viability of the neuronal cells.
doi:10.1163/092050610X552221
PMCID: PMC3873741  PMID: 21294967
Time controlled release; agarose; Ara-C; layer-by-layer assembly; reactive cell layer; nerve repair
15.  Oligomerization of the transmembrane domain of IRE1α in SDS micelles 
IRE1α (Inositol-requiring enzyme 1 α), an endoplasmic reticulum (ER)-resident sensor for mammalian unfolded protein response, is a type I transmembrane protein which has a bifunctional enzyme containing kinase and RNase domains. Although the luminal domain and cytosolic domain of IRE1α are thought to play crucial roles in regulating the protein activity, no functional and structural studies of the transmembrane domain exist thus far. Herein, using CD spectroscopy, we report that the transmembrane domain of the IRE1α is alpha helical in a membrane-like environment. In addition, SDS-PAGE and FRET analyses support that the transmembrane domain forms oligomers in SDS micelles. Thus, the study would provide insights into how the transmembrane domain plays a role in regulating the IRE1α protein activity.
doi:10.1016/j.bbrc.2012.09.135
PMCID: PMC3489956  PMID: 23041190
endoplasmic reticulum; transmembrane domain; dimerization; IRE1α
16.  ENDOCYTOSIS PATHWAYS FOR NUCLEIC ACID THERAPEUTICS 
Nano LIFE  2012;2(3):1241005-.
The development of nanoscale delivery vehicles for siRNAs is a current topic of considerable importance. However, little is understood about the exact trafficking mechanisms for siRNA-vehicle complexes across the plasma membrane and into the cytoplasm. While some information can be gleaned from studies on delivery of plasmid DNA, the different delivery requirements for these two vehicles makes drawing specific conclusions a challenge. However, using chemical inhibitors of different endocytosis pathways, studies on which endocytotic pathways are advantageous and deleterious for the delivery of nucleic acid drugs are emerging. Using this information as a guide, it is expected that the future development of effective siRNA delivery vehicles and therapeutics will be greatly improved.
doi:10.1142/S179398441241005X
PMCID: PMC3743083  PMID: 23956796
RNA interference; siRNA; pDNA; nanoparticles; therapeutics; endocytosis
17.  Design of siRNA Therapeutics from the Molecular Scale 
While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics.
doi:10.3390/ph6040440
PMCID: PMC3749788  PMID: 23976875
siRNA therapeutic; RNAi; liver cancer; siRNA design; delivery vehicle design
18.  Historical Epidemiology of the Second Cholera Pandemic: Relevance to Present Day Disease Dynamics 
PLoS ONE  2013;8(8):e72498.
Despite nearly two centuries of study, the fundamental transmission dynamic properties of cholera remain incompletely characterized. We used historical time-series data on the spread of cholera in twelve European and North American cities during the second cholera pandemic, as reported in Amariah Brigham’s 1832 A Treatise on Epidemic Cholera, to parameterize simple mathematical models of cholera transmission. Richards growth models were used to derive estimates of the basic reproductive number (R0) (median: 16.0, range: 1.9 to 550.9) and the proportion of unrecognized cases (mean: 96.3%, SD: 0.04%). Heterogeneity in model-generated R0 estimates was consistent with variability in cholera dynamics described by contemporary investigators and may represent differences in the nature of cholera spread. While subject to limitations associated with measurement and the absence of microbiological diagnosis, historical epidemic data are a potentially rich source for understanding pathogen dynamics in the absence of control measures, particularly when used in conjunction with simple and readily interpretable mathematical models.
doi:10.1371/journal.pone.0072498
PMCID: PMC3749991  PMID: 23991117
19.  Latest developments in experimental and computational approaches to characterize protein–lipid interactions 
Proteomics  2012;12(22):3273-3285.
Understanding the functional roles of all the molecules in cells is an ultimate goal of modern biology. An important facet is to understand the functional contributions from intermolecular interactions, both within a class of molecules (e.g. protein–protein) or between classes (e.g. protein-DNA). While the technologies for analyzing protein–protein and protein–DNA interactions are well established, the field of protein–lipid interactions is still relatively nascent. Here, we review the current status of the experimental and computational approaches for detecting and analyzing protein–lipid interactions. Experimental technologies fall into two principal categories, namely solution-based and array-based methods. Computational methods include large–scale data-driven analyses and predictions/dynamic simulations based on prior knowledge of experimentally identified interactions. Advances in the experimental technologies have led to improved computational analyses and vice versa, thereby furthering our understanding of protein–lipid interactions and their importance in biological systems.
doi:10.1002/pmic.201200255
PMCID: PMC3740713  PMID: 22997137
Computational; Experimental; Protein–lipid interactions; Technology
20.  Acute Myocardial Infarction and Stress Cardiomyopathy following the Christchurch Earthquakes 
PLoS ONE  2013;8(7):e68504.
Background
Christchurch, New Zealand, was struck by 2 major earthquakes at 4:36am on 4 September 2010, magnitude 7.1 and at 12:51pm on 22 February 2011, magnitude 6.3. Both events caused widespread destruction. Christchurch Hospital was the region's only acute care hospital. It remained functional following both earthquakes. We were able to examine the effects of the 2 earthquakes on acute cardiac presentations.
Methods
Patients admitted under Cardiology in Christchurch Hospital 3 week prior to and 5 weeks following both earthquakes were analysed, with corresponding control periods in September 2009 and February 2010. Patients were categorised based on diagnosis: ST elevation myocardial infarction, Non ST elevation myocardial infarction, stress cardiomyopathy, unstable angina, stable angina, non cardiac chest pain, arrhythmia and others.
Results
There was a significant increase in overall admissions (p<0.003), ST elevation myocardial infarction (p<0.016), and non cardiac chest pain (p<0.022) in the first 2 weeks following the early morning September earthquake. This pattern was not seen after the early afternoon February earthquake. Instead, there was a very large number of stress cardiomyopathy admissions with 21 cases (95% CI 2.6–6.4) in 4 days. There had been 6 stress cardiomyopathy cases after the first earthquake (95% CI 0.44–2.62). Statistical analysis showed this to be a significant difference between the earthquakes (p<0.05).
Conclusion
The early morning September earthquake triggered a large increase in ST elevation myocardial infarction and a few stress cardiomyopathy cases. The early afternoon February earthquake caused significantly more stress cardiomyopathy. Two major earthquakes occurring at different times of day differed in their effect on acute cardiac events.
doi:10.1371/journal.pone.0068504
PMCID: PMC3699519  PMID: 23844213
21.  Blood serum miRNA: Non-invasive biomarkers for Alzheimer’s disease 
Experimental Neurology  2011;235(2):491-496.
There is an urgent need to identify non-invasive biomarkers for the detection of sporadic Alzheimer’s disease (AD). We previously studied microRNAs (miRNAs) in AD autopsy brain samples and reported a connection between miR-137, -181c, -9, -29a/b and AD, through the regulation of ceramides. In this study, the potential role of these miRNAs as diagnostic markers for AD was investigated. We identified that these miRNAs were down-regulated in the blood serum of probable AD patients. The levels of these miRNAs were also reduced in the serum of AD risk factor models. Although the ability of these miRNAs to conclusively diagnose for AD is currently unknown, our findings suggest a potential use for circulating miRNAs, along with other markers, as non-invasive and relatively inexpensive biomarkers for the early diagnosis of AD, however, with further research and validation.
doi:10.1016/j.expneurol.2011.11.026
PMCID: PMC3361462  PMID: 22155483
Alzheimer’s disease; microRNA; blood serum
22.  Chronic back problems and labor force participation in a national population survey: impact of comorbid arthritis 
BMC Public Health  2013;13:326.
Background
Back problems and arthritis are common chronic conditions, while having back problems is a frequent reason for lost work time. The objective of this study was to investigate employment status amongst individuals who report having both back problems and arthritis, compared to having either condition alone.
Methods
We analyzed data from the 2007/2008 Canadian Community Health Survey (ages 25–64, n = 79,719). Respondents who reported neither having worked in the past 12 months nor the past week were coded as not currently employed. Those reported being permanently unable to work were considered to be out of the labor force. Log-Poisson regressions, adjusting for socio-demographic and lifestyle factors, were used to estimate risks for being not currently employed or being out of the labor force for 5 mutually exclusive groups of chronic conditions: arthritis and back problems, back problems, arthritis, any other chronic conditions, and no chronic conditions.
Results
12.7% of respondents reported being not currently employed and 2.9% being out of the labor force. 5.8% of respondents reported both arthritis and back problems, while 16.1% reported back problems and 7.3% arthritis. The back problems and arthritis group had the highest risk of not being currently employed. The risk was higher for men (PR = 1.90; 95% CI = 1.58, 2.29) than for women (PR = 1.31; 95% CI = 1.18, 1.46). Risks of being permanently unable to work were also the greatest for those with comorbid back problems and arthritis.
Conclusions
There is a need for a reappraisal of back problems as a cause of work disability to account for the possibility of co-occurring arthritis.
doi:10.1186/1471-2458-13-326
PMCID: PMC3626871  PMID: 23575216
Arthritis; Back problems; Employment; Comorbidity
23.  Design of siRNA Therapeutics from the Molecular Scale 
Pharmaceuticals  2013;6(4):440-468.
While protein-based therapeutics is well-established in the market, development of nucleic acid therapeutics has lagged. Short interfering RNAs (siRNAs) represent an exciting new direction for the pharmaceutical industry. These small, chemically synthesized RNAs can knock down the expression of target genes through the use of a native eukaryotic pathway called RNA interference (RNAi). Though siRNAs are routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic has proven challenging. Early efforts to design an siRNA therapeutic have demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue. In this review article, we discuss design considerations for siRNA therapeutics, identifying criteria for choosing therapeutic targets, producing highly-active siRNA sequences, and designing an optimized delivery vehicle. Taken together, these design considerations provide logical guidelines for generating novel siRNA therapeutics.
doi:10.3390/ph6040440
PMCID: PMC3749788  PMID: 23976875
siRNA therapeutic; RNAi; liver cancer; siRNA design; delivery vehicle design
24.  Learning transcriptional regulation on a genome scale: a theoretical analysis based on gene expression data 
Briefings in Bioinformatics  2011;13(2):150-161.
The recent advent of high-throughput microarray data has enabled the global analysis of the transcriptome, driving the development and application of computational approaches to study transcriptional regulation on the genome scale, by reconstructing in silico the regulatory interactions of the gene network. Although there are many in-depth reviews of such ‘reverse-engineering’ methodologies, most have focused on the practical aspect of data mining, and few on the biological problem and the biological relevance of the methodology. Therefore, in this review, from a biological perspective, we used a set of yeast microarray data as a working example, to evaluate the fundamental assumptions implicit in associating transcription factor (TF)–target gene expression levels and estimating TFs’ activity, and further explore cooperative models. Finally we confirm that the detailed transcription mechanism is overly-complex for expression data alone to reveal, nevertheless, future network reconstruction studies could benefit from the incorporation of context-specific information, the modeling of multiple layers of regulation (e.g. micro-RNA), or the development of approaches for context-dependent analysis, to uncover the mechanisms of gene regulation.
doi:10.1093/bib/bbr029
PMCID: PMC3294238  PMID: 21622543
transcription factors; transcriptional regulation; network reconstruction; gene expression
25.  Effects of Aging and Tai Chi on a Finger-Pointing Task with a Choice Paradigm 
Background. This cross-sectional study examined the effect of aging on performing finger-pointing tasks involving choices and whether experienced older Tai Chi practitioners perform better than healthy older controls in such tasks. Methods. Thirty students and 30 healthy older controls were compared with 31 Tai Chi practitioners. All the subjects performed a rapid index finger-pointing task. The visual signal appeared randomly under 3 conditions: (1) to touch a black ball as quickly and as accurately as possible, (2) not to touch a white ball, (3) to touch only the white ball when a black and a white ball appeared simultaneously. Reaction time (RT) of anterior deltoid electromyogram, movement time (MT) from electromyogram onset to touching of the target, end-point accuracy from the center of the target, and the number of wrong movements were recorded. Results. Young students displayed significantly faster RT and MT, achieving significantly greater end-point accuracy and fewer wrong movements than older controls. Older Tai Chi practitioners had significantly faster MT than older controls. Conclusion. Finger-pointing tasks with a choice paradigm became slower and less accurate with age. Positive findings suggest that Tai Chi may slow down the aging effect on eye-hand coordination tasks involving choices that require more cognitive progressing.
doi:10.1155/2013/653437
PMCID: PMC3588207  PMID: 23476699

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