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1.  Correction: Continuous Regional Arterial Infusion with Fluorouracil and Octreotide Attenuates Severe Acute Pancreatitis in a Canine Model 
PLoS ONE  2013;8(10):10.1371/annotation/9e189146-9c58-44d0-8bff-347bde7018e9.
PMCID: PMC3794072
2.  Process optimization and evaluation of novel baicalin solid nanocrystals 
The objective of this study was to prepare baicalin solid nanocrystals (BCN-SNS) to enhance oral bioavailability of baicalin. A Box–Behnken design approach was used for process optimization. The physicochemical properties and pharmacokinetics of the optimal BCN-SNS were investigated. Multiple linear regression analysis for process optimization revealed that the fine BCN-SNS was obtained wherein the optimal values of homogenization pressure (bar), homogenization cycles (cycles), amount of TPGS to drug (w/w), and amount of MCCS to drug (w/w) were 850 bar, 25 cycles, 10%, and 10%, respectively. Transmission electron microscopy and scanning electron microscopy results indicated that no significant aggregation or crystal growth could be observed in the redispersed freeze-dried BCN-SNS. Differential scanning calorimetry and X-ray diffraction results showed that BCN remained in a crystalline state. Dissolution velocity of the freeze-dried BCN-SNS powder was distinctly superior compared to those of the crude powder and physical mixture. The bioavailability of BCN in rats was increased remarkably after oral administration of BCN-SNS (P < 0.05), compared with those of BCN or the physical mixture. The SNS might be a good choice for oral administration of poorly soluble BCN, due to an improvement of the bioavailability and dissolution velocity of BCN-SNS.
PMCID: PMC3746734  PMID: 23976849
baicalin; solid nanocrystals; optimization; in vivo/vitro evaluation
3.  miR-221/222 Targets Adiponectin Receptor 1 to Promote the Epithelial-to-Mesenchymal Transition in Breast Cancer 
PLoS ONE  2013;8(6):e66502.
The epithelial-to-mesenchymal transition (EMT) is a highly conserved physiological program involved in development and tissue repair; however, its aberrant activation has been implicated in accelerating the progression of a variety of cancers. In breast cancer, the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) are differentially expressed in the clinically more aggressive basal-like subtype compared to luminal subtype of breast cancer and upregulation of miR-221/222 induces the EMT by targeting the 3′ untranslated region (3′UTR) of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1). The complete mechanism through which miR-221/222 promotes the EMT, however, is not fully understood. We identified adiponectin receptor 1 (ADIPOR1), a receptor for the adipocytokine adiponectin, as a direct target of miR-221/222. ADIPOR1 is expressed at higher levels in the luminal compared to the basal-like subtype of breast cancer cell lines, which can be reduced by miR-221/222 targeting of its 3’UTR. In addition, miR-221/222 were negatively correlated with ADIPOR1 expression across breast cancer cell lines and tumors. ADIPOR1 depletion by siRNA in MCF10A cells induced the EMT and increased cell invasion. Depletion of ADIPOR1 by siRNA induced activation of the canonical nuclear factor-kappaB (NF-κB) and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an interleukin 6 (IL6)-dependent manner. Finally, overexpression of ADIPOR1 in the basal-like cell line, MDA-MB-231, attenuated cell invasion and promoted the mesenchymal-to-epithelial transition (MET). We conclude that ADIPOR1 negatively regulates EMT in breast cancer and provides an additional node by which miR-221/222 induces the EMT. These results suggest that ADIPOR1 may play an important role in breast cancer progression and metastasis, and could potentially offer an alternative therapeutic strategy for basal-like breast cancer patients.
PMCID: PMC3679042  PMID: 23776679
4.  WNT signaling underlies the pathogenesis of neuropathic pain in rodents 
The Journal of Clinical Investigation  2013;123(5):2268-2286.
Treating neuropathic pain is a major clinical challenge, and the underlying mechanisms of neuropathic pain remain elusive. We hypothesized that neuropathic pain–inducing nerve injury may elicit neuronal alterations that recapitulate events that occur during development. Here, we report that WNT signaling, which is important in developmental processes of the nervous system, plays a critical role in neuropathic pain after sciatic nerve injury and bone cancer in rodents. Nerve injury and bone cancer caused a rapid-onset and long-lasting expression of WNTs, as well as activation of WNT/frizzled/β-catenin signaling in the primary sensory neurons, the spinal dorsal horn neurons, and astrocytes. Spinal blockade of WNT signaling pathways inhibited the production and persistence of neuropathic pain and the accompanying neurochemical alterations without affecting normal pain sensitivity and locomotor activity. WNT signaling activation stimulated production of the proinflammatory cytokines IL-18 and TNF-α and regulated the NR2B glutamate receptor and Ca2+-dependent signals through the β-catenin pathway in the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the WNT signaling pathway may be an effective approach for treating neuropathic pain, including bone cancer pain.
PMCID: PMC3635721  PMID: 23585476
5.  Cyp2c44-epoxygenase is essential for preventing the renal sodium absorption during increasing dietary potassium (K)-intake 
Hypertension  2011;59(2):339-347.
The aim of this study is to test whether the Cyp2c44 epoxygenase dependent metabolism of arachidonic acid (AA) prevents the hypertensive effect of a high K intake (HK) by inhibiting the ENaC activity. A HK intake elevated Cyp2c44 mRNA expression and 11,12-epoxyeicosatrienoic acid (11,12-EET) levels in the cortical collecting duct (CCD) in Cyp2c44(+/+) mice(wt). However, a HK intake failed to increase 11,12-EET formation in the CCDs of Cyp2c44(-/-) mice. Moreover, increasing K intake enhanced AA-induced inhibition of ENaC in the wt but not in Cyp2c44(-/-) mice. In contrast, 11,12-EET, a Cyp2c44 metabolite, inhibited ENaC in the wt and Cyp2c44(-/-) mice. The notion that Cyp2c44 is the epoxygenase responsible for mediating the inhibitory effects of AA on ENaC is further suggested by the observation that inhibiting Cyp-epoxygenase increased the whole-cell Na currents in principal cells of wt but not in Cyp2c44(-/-) mice. Feeding mice with a HK diet raised the systemic blood pressures of Cyp2c44(-/-) mice but was without an effect on wt mice. Moreover, application of amiloride abolished the HK-induced hypertension in Cyp2c44(-/-) mice. The HK-induced hypertension of Cyp2c44(-/-) mice was accompanied by decreasing 24-hr urinary Na excretion and increasing the plasma Na concentration, the effects were absent in wt mice. In contrast, disruption of the Cyp2c44 gene did not alter K excretion. We conclude that Cyp2c44 epoxygenase mediates the inhibitory effect of AA on ENaC and that Cyp2c44 functions as a HK-inducible anti-hypertensive enzyme responsible for inhibiting ENaC activity and Na absorption in the aldosterone-sensitive distal nephron (ASDN).
PMCID: PMC3382086  PMID: 22184322
11,12-EET; Arachidonic acid; ENaC; hypertension; kidney
6.  K+ Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension 
Science (New York, N.Y.)  2011;331(6018):768-772.
Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K+) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na+) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca2+) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na+ conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K+ channel selectivity in constitutive cell proliferation and hormone production.
PMCID: PMC3371087  PMID: 21311022
7.  Continuous Regional Arterial Infusion with Fluorouracil and Octreotide Attenuates Severe Acute Pancreatitis in a Canine Model 
PLoS ONE  2012;7(5):e37347.
To investigate the therapeutic effects of fluorouracil (5-Fu) and octreotide (Oct) continuous regional arterial infusion (CRAI,) alone or in combination, was administered in a canine model of severe acute pancreatitis (SAP).
Materials and Methods
The animals were divided into five groups; group A (Sham), group B (SAP), group C (SAP and 5-Fu), group D (SAP and Oct), and group E (SAP and 5-Fu + Oct). Levels of amylase, α-tumor necrosis factor (TNF-α), blood urea nitrogen (BUN), creatinine, thromboxane B2 and 6-keto- prostaglandin F1α were measured both before and after the induction of SAP. Pathologic examination of the pancreas and kidneys was performed after termination of the study.
Pathologic changes noted in the pancreas in SAP significantly improved following CRAI with either single or combined administration of 5-Fu and Oct, where combination therapy demonstrated the lowest injury score. All treatment groups had significantly lower levels of serum TNF-α and amylase activity (P<0.05), though only groups D and E had a lower BUN level as compared to group B. The plasma thromboxane B2 level increased in SAP, but the ratio of thromboxane B2/6-keto- prostaglandin F1α decreased in the treatment groups, with the combination therapy (group E) demonstrating the lowest ratio as compared to the other 3 experimental groups (P<0.05).
The findings in the present study demonstrate an attenuation of SAP in a canine model following CRAI administration with 5-Fu or Oct, alone or in combination.
PMCID: PMC3360032  PMID: 22655040
8.  Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation 
Cancer cell  2009;16(6):463-474.
Members of the mammalian phosphoinositide-3-OH kinase (PI3K) family of proteins are critical regulators of various cellular process including cell survival, growth, proliferation and motility. Oncogenic activating mutations in the p110α catalytic subunit of the heterodimeric p110/p85 PI3K enzyme are frequent in human cancers. Here we show the presence of frequent mutations in p85α in colon cancer, a majority of which occurs in the inter-Src homology-2 (iSH2) domain. These mutations uncouple and retain p85α's p110-stabilizing activity, while abrogating its p110-inhibitory activity. The p85α mutants promote cell survival, Akt activation, anchorage independent cell growth, and oncogenesis in a p110-dependent manner.
Somatic mutations in the catalytic p110α subunit of PI3K are common in cancers. In this study, we show the occurrence of frequent mutations in the regulatory p85α subunit of PI3K in human cancers. Our data demonstrate an alternate mechanism for PI3K-pathway activation and oncogenesis resulting from the impaired regulation of p110 activity by mutant p85α. Further, p85α mutations are likely to be useful as diagnostic markers for identification of p110-dependent tumors that may not carry an activating p110α mutation, but are candidates for targeted treatment with PI3K pathway inhibitors that are in development.
PMCID: PMC2804903  PMID: 19962665
9.  Spinal Matrix Metalloproteinase-9 Contributes to Physical Dependence on Morphine in Mice 
The Journal of Neuroscience  2010;30(22):7613-7623.
Preventing and reversing opioid dependence continues to be a clinical challenge and underlying mechanisms of opioid actions remain elusive. We report that matrix metalloproteinase-9 (MMP-9) in the spinal cord contributes to development of physical dependence on morphine. Chronic morphine exposure and naloxone-precipitated withdrawal increase activity of spinal MMP-9. Spinal inhibition or targeted mutation of MMP-9 suppresses behavioral signs of morphine withdrawal and the associated neurochemical alterations. The increased MMP-9 activity is mainly distributed in the superficial dorsal horn and colocalized primarily with neurons and small numbers of astrocytes and microglia. Morphine exposure and withdrawal increase phosphorylation of NR1 and NR2B receptors, ERK1/2, calmodulin-dependent kinase II, and cAMP response element binding proteins; and such phosphorylation is suppressed by either spinal inhibition or targeted mutation of MMP-9. Further, spinal administration of exogenous MMP-9 induces morphine withdrawal-like behavioral signs and mechanical allodynia, activates NR1 and NR2 receptors, and downregulates integrin-β1, while a function-neutralizing antibody against integrin-β1 suppresses MMP-9-induced phosphorylation of NR1 and NR2B. Morphine withdrawal-induced MMP-9 activity is also reduced by an nNOS inhibitor. Thus, we hypothesize that spinal MMP-9 may contribute to the development of morphine dependence primarily through neuronal activation and interaction with NR1 and NR2B receptors via integrin-β1 and NO pathways. The other gelatinase, MMP-2, is not involved in morphine dependence. Inhibiting spinal MMP-9 or MMP-2 reduces chronic and/or acute morphine tolerance. This study suggests a novel therapeutic approach for preventing, minimizing, or reversing opioid dependence and tolerance.
PMCID: PMC3842477  PMID: 20519536
10.  Statistical techniques to construct assays for identifying likely responders to a treatment under evaluation from cell line genomic data 
BMC Cancer  2010;10:586.
Developing the right drugs for the right patients has become a mantra of drug development. In practice, it is very difficult to identify subsets of patients who will respond to a drug under evaluation. Most of the time, no single diagnostic will be available, and more complex decision rules will be required to define a sensitive population, using, for instance, mRNA expression, protein expression or DNA copy number. Moreover, diagnostic development will often begin with in-vitro cell-line data and a high-dimensional exploratory platform, only later to be transferred to a diagnostic assay for use with patient samples. In this manuscript, we present a novel approach to developing robust genomic predictors that are not only capable of generalizing from in-vitro to patient, but are also amenable to clinically validated assays such as qRT-PCR.
Using our approach, we constructed a predictor of sensitivity to dacetuzumab, an investigational drug for CD40-expressing malignancies such as lymphoma using genomic measurements of cell lines treated with dacetuzumab. Additionally, we evaluated several state-of-the-art prediction methods by independently pairing the feature selection and classification components of the predictor. In this way, we constructed several predictors that we validated on an independent DLBCL patient dataset. Similar analyses were performed on genomic measurements of breast cancer cell lines and patients to construct a predictor of estrogen receptor (ER) status.
The best dacetuzumab sensitivity predictors involved ten or fewer genes and accurately classified lymphoma patients by their survival and known prognostic subtypes. The best ER status classifiers involved one or two genes and led to accurate ER status predictions more than 85% of the time. The novel method we proposed performed as well or better than other methods evaluated.
We demonstrated the feasibility of combining feature selection techniques with classification methods to develop assays using cell line genomic measurements that performed well in patient data. In both case studies, we constructed parsimonious models that generalized well from cell lines to patients.
PMCID: PMC2984428  PMID: 20979617
11.  The Study on the Entrapment Efficiency and In Vitro Release of Puerarin Submicron Emulsion 
AAPS PharmSciTech  2009;10(2):376-383.
The entrapment efficiency (EE) and release in vitro are very important physicochemical characteristics of puerarin submicron emulsion (SME). In this paper, the performance of ultrafiltration (UF), ultracentrifugation (UC), and microdialysis (MD) for determining the EE of SME were evaluated, respectively. The release study in vitro of puerarin from SME was studied by using MD and pressure UF technology. The EE of SME was 86.5%, 72.8%, and 55.8% as determined by MD, UF, and UC, respectively. MD was not suitable for EE measurements of puerarin submicron oil droplet, which could only determine the total EE of submicron oil droplet and liposomes micelles, but it could be applied to determine the amount of free drug in SMEs. Although UC was the fastest and simplest to use, its results were the least reliable. UF was still the relatively accurate method for EE determination of puerarin SME. The release of puerarin SME could be evaluated by using MD and pressure UF, but MD seemed to be more suitable for the release study of puerarin emulsion. The drug release from puerarin SME at three drug concentrations was initially rapid, but reached a plateau value within 30 min. Drug release of puerarin from the SME occurred via burst release.
PMCID: PMC2690779  PMID: 19381837
drug release; entrapment efficiency; microdialysis; pressure ultrafiltration technology; submicron emulsion
12.  Web GIS in practice VIII: HTML5 and the canvas element for interactive online mapping 
HTML5 is being developed as the next major revision of HTML (Hypertext Markup Language), the core markup language of the World Wide Web. It aims at reducing the need for proprietary, plug-in-based rich Internet application (RIA) technologies such as Adobe Flash. The canvas element is part of HTML5 and is used to draw graphics using scripting (e.g., JavaScript). This paper introduces Cartagen, an open-source, vector-based, client-side framework for rendering plug-in-free, offline-capable, interactive maps in native HTML5 on a wide range of Web browsers and mobile phones. Cartagen was developed at MIT Media Lab's Design Ecology group. Potential applications of the technology as an enabler for participatory online mapping include mapping real-time air pollution, citizen reporting, and disaster response, among many other possibilities.
PMCID: PMC2838837  PMID: 20199681
13.  Poly[[tetra­aquadi-μ3-oxalato-μ2-oxalato-diprasedymium(III)] dihydrate] 
In the title compound, {[Pr2(C2O4)3(H2O)4]·2H2O}n, the three-dimensional network structure has the PrIII ion coordinated by nine O atoms in a distorted tricapped trigonal-prismatic geometry. The coordinated and uncoordinated water mol­ecules inter­act with the carboxyl­ate O atoms to consolidate the network via O—H⋯O hydrogen bonds.
PMCID: PMC2980182  PMID: 21579975
14.  The Role of the Exocyst in Matrix Metalloproteinase Secretion and Actin Dynamics during Tumor Cell Invadopodia Formation 
Molecular Biology of the Cell  2009;20(16):3763-3771.
Invadopodia are actin-rich membrane protrusions formed by tumor cells that degrade the extracellular matrix for invasion. Invadopodia formation involves membrane protrusions driven by Arp2/3-mediated actin polymerization and secretion of matrix metalloproteinases (MMPs) at the focal degrading sites. The exocyst mediates the tethering of post-Golgi secretory vesicles at the plasma membrane for exocytosis and has recently been implicated in regulating actin dynamics during cell migration. Here, we report that the exocyst plays a pivotal role in invadopodial activity. With RNAi knockdown of the exocyst component Exo70 or Sec8, MDA-MB-231 cells expressing constitutively active c-Src failed to form invadopodia. On the other hand, overexpression of Exo70 promoted invadopodia formation. Disrupting the exocyst function by siEXO70 or siSEC8 treatment or by expression of a dominant negative fragment of Exo70 inhibited the secretion of MMPs. We have also found that the exocyst interacts with the Arp2/3 complex in cells with high invasion potential; blocking the exocyst-Arp2/3 interaction inhibited Arp2/3-mediated actin polymerization and invadopodia formation. Together, our results suggest that the exocyst plays important roles in cell invasion by mediating the secretion of MMPs at focal degrading sites and regulating Arp2/3-mediated actin dynamics.
PMCID: PMC2777935  PMID: 19535457
15.  Analytical methods for inferring functional effects of single base pair substitutions in human cancers 
Human Genetics  2009;126(4):481-498.
Cancer is a genetic disease that results from a variety of genomic alterations. Identification of some of these causal genetic events has enabled the development of targeted therapeutics and spurred efforts to discover the key genes that drive cancer formation. Rapidly improving sequencing and genotyping technology continues to generate increasingly large datasets that require analytical methods to identify functional alterations that deserve additional investigation. This review examines statistical and computational approaches for the identification of functional changes among sets of single-nucleotide substitutions. Frequency-based methods identify the most highly mutated genes in large-scale cancer sequencing efforts while bioinformatics approaches are effective for independent evaluation of both non-synonymous mutations and polymorphisms. We also review current knowledge and tools that can be utilized for analysis of alterations in non-protein-coding genomic sequence.
PMCID: PMC2762536  PMID: 19434427
16.  Hydrogen Peroxide Stimulates the Ca2+-activated Big-Conductance K Channels (BK) Through cGMP Signaling Pathway in Cultured Human Endothelial Cells 
We used the whole cell patch-clamp technique to examine the effect of hydrogen peroxide (H2O2) on the Ca2+-activated BK channels in human endothelial cells. We confirmed the previous finding that a 200 pS BK channel activity was detected when the cell membrane potential was clamped at 50 mV. Application of H2O2 or adding glucose oxidase (GO) stimulated BK channels. The stimulatory effect of H2O2 and GO was absent in cells treated with ebselen, a scavenger of reactive oxygen species (ROS). To determine whether the stimulatory effect of H2O2 and GO on BK channels is the result of increasing NO production in the endothelial cells, we examined the effect of H2O2 and GO on BK channels in the presence of 0.1 mM L-NAME which inhibits NO synthase (NOS). Inhibition of NOS completely abolished the stimulatory effect of H2O2 on BK channels. In contrast, treatment of endothelial cells with D-NAME did not block the effect of H2O2 on BK channels. Moreover, inhibiting soluble guanylate cyclase (sGC) with ODQ mimicked the effect of L-NAME and abolished the effect of H2O2. Addition of 8-bromo-cGMP stimulated BK channels and further application of H2O2 did not increase BK channel activity in the presence of cGMP analog. The notion that the effect of H2O2 on BK channels was the result of stimulating NO-cGMP pathway is further indicated by the observation that inhibition of PKG with KT5823 also abolished the stimulatory effect of H2O2 on BK channels. We conclude that H2O2 stimulates the Ca2+ BK channels through NO/sGC/cGMP pathway in cultured human endothelial cells.
PMCID: PMC2730122  PMID: 18769038
Hydrogen peroxide; Nitric oxide; Endothelial cell; cGMP; K channel
17.  Role of gp91phox-Containing NADPH Oxidase in Mediating the Effect of K Restriction on ROMK Channels and Renal K Excretion 
Previous study has demonstrated that superoxide and the related products are involved in mediating the effect of low K intake on renal K secretion and ROMK channel activity in the cortical collecting duct (CCD). This study investigated the role of gp91phox-containing NADPH oxidase (NOXII) in mediating the effect of low K intake on renal K excretion and ROMK channel activity in gp91(-/-) mice. K depletion increased superoxide levels, phosphorylation of c-Jun, expression of c-Src, and tyrosine phosphorylation of ROMK in renal cortex and outer medulla in wild-type (WT) mice. In contrast, tempol treatment in WT mice abolished whereas deletion of gp91 significantly attenuated the effect of low K intake on superoxide production, c-Jun phosphorylation, c-Src expression, and tyrosine phosphorylation of ROMK. Patch-clamp experiments demonstrated that low K intake decreased mean product of channel number (N) and open probability (P) (NPo) of ROMK channels from 1.1 to 0.4 in the CCD. However, the effect of low K intake on ROMK channel activity was significantly attenuated in the CCD from gp91(-/-) mice and completely abolished by tempol treatment. Immunocytochemical staining also was used to examine the ROMK distribution in WT, gp91(-/-), and WT mice with tempol treatment in response to K restriction. K restriction decreased apical staining of ROMK in WT mice. In contrast, a sharp apical ROMK staining was observed in the tempol-treated WT or gp91(-/-) mice. Metabolic cage study further showed that urinary K loss is significantly higher in gp91(-/-) mice than in WT mice. It is concluded that superoxide anions play a key role in suppressing K secretion during K restriction and that NOXII is involved in mediating the effect of low K intake on renal K secretion and ROMK channel activity.
PMCID: PMC2702222  PMID: 17538186
18.  Process Optimization, Characterization and Pharmacokinetic Evaluation in Rats of Ursodeoxycholic Acid–Phospholipid Complex 
AAPS PharmSciTech  2008;9(1):322-329.
The purpose of this research was to study whether the bioavailability of ursodeoxycholic acid could be improved by administering ursodeoxycholic acid–phospholipid complex (UDCA–PLC) orally to rats. A central composite design approach was used for process optimization in order to obtain the acceptable UDCA–PLC. The physicochemical properties of the complex obtained by optimal parameters were investigated by means of scanning electron microscopy and X-ray diffraction. The pharmacokinetic parameters and bioavailability studies were conducted in rats of UDCA after oral administration of UDCA–PLC and UDCA tablet. Multiple linear regression analysis for process optimization revealed that the acceptable UDCA–PLC was obtained wherein the optimal values of X1, X2 and X3 were 3, 60°C and 3 h, respectively. The XRD studies of UDCA–PLC obtained by the optimal parameters demonstrated that UDCA and phospholipids in the UDCA–PLC were combined by non-covalent bonds, not form new compounds. But pharmacokinetic parameters of the complex in rats were Tmax 1.6 h, Cmax 0.1346 μg/ml, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{AUC}}_{0 - \infty } $$\end{document}11.437 μg·h/ml, respectively. The relative bioavailability of UDCA of UDCA–PLC was increased by 241%,compared with the reference ursodeoxycholic acid tablet.
PMCID: PMC2976878  PMID: 18446498
characterization; optimization; pharmacokinetics; phospholipid complex; ursodeoxycholic acid
19.  1-{2-[(2-hydroxybenzylidene)-amino]-ethyl}-3-methyl-3H-imidazolium hexafluorophosphate 
The title Schiff base compound, C13H16N3O+·PF6 −, was derived from the condensation of 2-hydroxy­benaldehyde with the ionic liquid 1-(2-amino­ethyl)-3-methyl­imidazolium hexa­fluoro­phosphate in an ethanol solution. The asymmetric unit comprises one cation and two PF6 − anions. The dihedral angle between the aromatic and imidazole rings is 15.2 (2)°. An intra­molecular O—H⋯N hydrogen bond is found which generates an S(6) ring motif.
PMCID: PMC2959942  PMID: 21581337
20.  3,3′-Dibromo-5,5′-bis­[(S)-l-menth­yloxy]-4,4′-(hexane-1,6-diyldiimino)difuran-2(5H)-one 
The title compound, C34H54Br2N2O6, was obtained by the Michael addition–elimination reaction of (5S)-5-(l-menthyl­oxy)-3,4-dibromo­furan-2(5H)-one with 1,6-hexa­nediamine in the presence of triethyl­amine. The crystal structure contains two chiral five-membered furan­one rings, in twist and envelope conformations, and two six-membered cyclo­hexane rings in chair conformations.
PMCID: PMC2962195  PMID: 21203330
21.  8-(Carboxy­methoxy)­quinolinium nitrate monohydrate 
In the title compound, C11H10NO3 +·NO3 −·H2O, the planar 8-carboxy­methoxy­quinolinium cation, the nitrate anion and the water mol­ecule are dimerized by hydrogen bonds into square building-block units, and then further assembled into two-dimensional gently undulating supra­molecular layers.
PMCID: PMC2962242  PMID: 21203329
22.  Bis[methyl 2-(2-pyridylmethyl­idene)hydrazinecarbodithio­ato]zinc(II) 
In the title compound, [Zn(C8H8N3S2)2], the Zn atom is coordinated by the two ligands in a tridentate manner, via the pyridyl N, the azomethine N and the thiol­ate S atom; the coordination geometry is distorted octa­hedral, with the two ligands in the mer configuration (two S atoms and two pyridyl N atoms are cis with respect to each other and the azomethine N atoms is trans). The mol­ecules are linked by C—H⋯S hydrogen bonds, forming a three-dimensional network structure.
PMCID: PMC2960303  PMID: 21201296
23.  Phosphatidylinositol 4,5-Bisphosphate Mediates the Targeting of the Exocyst to the Plasma Membrane for Exocytosis in Mammalian Cells 
Molecular Biology of the Cell  2007;18(11):4483-4492.
The exocyst is an evolutionarily conserved octameric protein complex that tethers post-Golgi secretory vesicles at the plasma membrane for exocytosis. To elucidate the mechanism of vesicle tethering, it is important to understand how the exocyst physically associates with the plasma membrane (PM). In this study, we report that the mammalian exocyst subunit Exo70 associates with the PM through its direct interaction with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Furthermore, we have identified key conserved residues at the C-terminus of Exo70 that are crucial for the interaction of Exo70 with PI(4,5)P2. Disrupting Exo70-PI(4,5)P2 interaction abolished the membrane association of Exo70. We have also found that wild-type Exo70 but not the PI(4,5)P2-binding–deficient Exo70 mutant is capable of recruiting other exocyst components to the PM. Using the ts045 vesicular stomatitis virus glycoprotein trafficking assay, we demonstrate that Exo70-PI(4,5)P2 interaction is critical for the docking and fusion of post-Golgi secretory vesicles, but not for their transport to the PM.
PMCID: PMC2043555  PMID: 17761530
24.  Genomic distribution and functional analyses of potential G-quadruplex-forming sequences in Saccharomyces cerevisiae 
Nucleic Acids Research  2007;36(1):144-156.
Although well studied in vitro, the in vivo functions of G-quadruplexes (G4-DNA and G4-RNA) are only beginning to be defined. Recent studies have demonstrated enrichment for sequences with intramolecular G-quadruplex forming potential (QFP) in transcriptional promoters of humans, chickens and bacteria. Here we survey the yeast genome for QFP sequences and similarly find strong enrichment for these sequences in upstream promoter regions, as well as weaker but significant enrichment in open reading frames (ORFs). Further, four findings are consistent with roles for QFP sequences in transcriptional regulation. First, QFP is correlated with upstream promoter regions with low histone occupancy. Second, treatment of cells with N-methyl mesoporphyrin IX (NMM), which binds G-quadruplexes selectively in vitro, causes significant upregulation of loci with QFP-possessing promoters or ORFs. NMM also causes downregulation of loci connected with the function of the ribosomal DNA (rDNA), which itself has high QFP. Third, ORFs with QFP are selectively downregulated in sgs1 mutants that lack the G4-DNA-unwinding helicase Sgs1p. Fourth, a screen for yeast mutants that enhance or suppress growth inhibition by NMM revealed enrichment for chromatin and transcriptional regulators, as well as telomere maintenance factors. These findings raise the possibility that QFP sequences form bona fide G-quadruplexes in vivo and thus regulate transcription.
PMCID: PMC2248735  PMID: 17999996
25.  SNPs3D: Candidate gene and SNP selection for association studies 
BMC Bioinformatics  2006;7:166.
The relationship between disease susceptibility and genetic variation is complex, and many different types of data are relevant. We describe a web resource and database that provides and integrates as much information as possible on disease/gene relationships at the molecular level.
The resource has three primary modules. One module identifies which genes are candidates for involvement in a specified disease. A second module provides information about the relationships between sets of candidate genes. The third module analyzes the likely impact of non-synonymous SNPs on protein function. Disease/candidate gene relationships and gene-gene relationships are derived from the literature using simple but effective text profiling. SNP/protein function relationships are derived by two methods, one using principles of protein structure and stability, the other based on sequence conservation. Entries for each gene include a number of links to other data, such as expression profiles, pathway context, mouse knockout information and papers. Gene-gene interactions are presented in an interactive graphical interface, providing rapid access to the underlying information, as well as convenient navigation through the network. Use of the resource is illustrated with aspects of the inflammatory response and hypertension.
The combination of SNP impact analysis, a knowledge based network of gene relationships and candidate genes, and access to a wide range of data and literature allow a user to quickly assimilate available information, and so develop models of gene-pathway-disease interaction.
PMCID: PMC1435944  PMID: 16551372

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