Solubility Enhancement of PCDD/F in the Presence of Dissolved Humic Matter

Journal of Hazardous Materials. Apr, 2002  |  Pubmed ID: 11900909

From previous studies, we, the authors collected and arranged the octanol-water partition coefficients (K(ow)), water solubility (S0), and dissolved humic matter (DHM)-water partition coefficients (K(oc)) for 95 organic compounds, and presented the correlations between each physical property. The K(oc) and K(ow) of dioxins estimated were significantly increased while S0 was decreased on increasing the chlorine number. In the presence of DHM, solubility enhancement (Sw/S0, Sw is the actual solubility in the presence of DHM) in highly chlorinated PCDD/F such as HpCDDs and OCDD is higher than that in low chlorinated ones. It means that dioxins abundant wastes (fly ash) should not be codisposed with organic abundant wastes (sewage sludge, food waste or bottom ash, etc.) to minimize the leachability of dioxins.

Removal of Hydrophobic Organic Pollutants by Coagulation-precipitation Process with Dissolved Humic Matter

Waste Management & Research : the Journal of the International Solid Wastes and Public Cleansing Association, ISWA. Aug, 2002  |  Pubmed ID: 12363094

The removal of hydrophobic organic pollutants (HOPs) from water with precipitating dissolved humic matter (DHM) was found to depend on the physical and chemical properties of the HOPs themselves, and could be estimated theoretically. The removal efficiency of HOPs was decreased at high pH and with increasing ionic strength; in particular, when ionic strength increased, the decrease was small. In deionised water, the removal efficiencies of pyrene, fluoranthene, anthracene and phenanthrene were about 75%, 57%, 40% and 30% respectively in the DHM range used, and increased clearly with increasing concentration of DHM. The difference of removal efficiency resulted from the physical and chemical characteristics of the HOPs such as partition coefficient to DHM (K(OC)), whose order is pyrene > fluoranthene > anthracene > phenanthrene. Because of the large partition coefficients of dioxins to DHM, removal efficiencies of 90 to 99.9% could be obtained with only a few mg l(-1) of organic carbon (OC) in DHM and 99 to 99.99% with over ten mg-OC l(-1) in DHM.

Human SirT1 Interacts with Histone H1 and Promotes Formation of Facultative Heterochromatin

Molecular Cell. Oct, 2004  |  Pubmed ID: 15469825

We characterized human SirT1, one of the human homologs of the budding yeast Sir2p, an NAD+-dependent histone deacetylase involved in establishing repressive chromatin and increased life span. SirT1 deacetylates histone polypeptides with a preference for histone H4 lysine 16 (H4-K16Ac) and H3 lysine 9 (H3-K9Ac) in vitro. RNAi-mediated decreased expression of SirT1 in human cells causes hyperacetylation of H4-K16 and H3-K9 in vivo. SirT1 interacts with and deacetylates histone H1 at lysine 26. Using an inducible system directing expression of SirT1 fused to the Gal4-DNA binding domain and a Gal4-reporter integrated in euchromatin, Gal4-SirT1 expression resulted in the deacetylation of H4-K16 and H3-K9, recruitment of H1 within the promoter vicinity, drastically reduced reporter expression, and loss of H3-K79 methylation, a mark restricting silenced chromatin. We propose a model for SirT1-mediated heterochromatin formation that includes deacetylation of histone tails, recruitment and deacetylation of histone H1, and spreading of hypomethylated H3-K79 with resultant silencing.

Gradient-enhanced FAWSETS Perfusion Measurements

Journal of Magnetic Resonance (San Diego, Calif. : 1997). Aug, 2005  |  Pubmed ID: 15886031

This work describes the use of custom-built gradients to enhance skeletal muscle perfusion measurements acquired with a previously described arterial spin labeling technique known as FAWSETS (flow-driven arterial water stimulation with elimination of tissue signal). Custom-built gradients provide active control of the static magnetic field gradient on which FAWSETS relies for labeling. This allows selective, 180 degrees modulations of the phase of the perfusion component of the signal. Phase cycling can then be implemented to eliminate all extraneous components leaving a signal that exclusively reflects capillary-level perfusion. Gradient-enhancement substantially reduces acquisition time and eliminates the need to acquire an ischemic signal to quantify perfusion. This removes critical obstacles to application of FAWSETS in organs other than skeletal muscle and makes the measurements more desirable for clinical environments. The basic physical principles of gradient-enhancement are demonstrated in flow phantom experiments and in vivo utility is demonstrated in rat hind limb during stimulated exercise.

Optical and MRI Multifunctional Nanoprobe for Targeting Gliomas

Nano Letters. Jun, 2005  |  Pubmed ID: 15943433

A multifunctional nanoprobe capable of targeting glioma cells, detectable by both magnetic resonance imaging and fluorescence microscopy, was developed. The nanoprobe was synthesized by coating iron oxide nanoparticles with covalently bound bifunctional poly(ethylene glycol) (PEG) polymer, which were subsequently functionalized with chlorotoxin and the near-infrared fluorescing molecule Cy5.5. Both MR imaging and fluorescence microscopy showed significant preferential uptake of the nanoparticle conjugates by glioma cells. Such a nanoprobe could potentially be used to image resections of glioma brain tumors in real time and to correlate preoperative diagnostic images with intraoperative pathology at cellular-level resolution.

Reduced Mitochondrial Coupling in Vivo Alters Cellular Energetics in Aged Mouse Skeletal Muscle

The Journal of Physiology. Dec, 2005  |  Pubmed ID: 16254011

The mitochondrial theory of ageing proposes that the accumulation of oxidative damage to mitochondria leads to mitochondrial dysfunction and tissue degeneration with age. However, no consensus has emerged regarding the effects of ageing on mitochondrial function, particularly for mitochondrial coupling (P/O). One of the main barriers to a better understanding of the effects of ageing on coupling has been the lack of in vivo approaches to measure P/O. We use optical and magnetic resonance spectroscopy to independently quantify mitochondrial ATP synthesis and O2 uptake to determine in vivo P/O. Resting ATP demand (equal to ATP synthesis) was lower in the skeletal muscle of 30-month-old C57Bl/6 mice compared to 7-month-old controls (21.9 +/- 1.5 versus 13.6 +/- 1.7 nmol ATP (g tissue)(-1) s(-1), P = 0.01). In contrast, there was no difference in the resting rates of O2 uptake between the groups (5.4 +/- 0.6 versus 8.4 +/- 1.6 nmol O2 (g tissue)(-1) s(-1)). These results indicate a nearly 50% reduction in the mitochondrial P/O in the aged animals (2.05 +/- 0.07 versus 1.05 +/- 0.36, P = 0.02). The higher resting ADP (30.8 +/- 6.8 versus 58.0 +/- 9.5 micromol g(-1), P = 0.05) and decreased energy charge (ATP/ADP) (274 +/- 70 versus 84 +/- 16, P = 0.03) in the aged mice is consistent with an impairment of oxidative ATP synthesis. Despite the reduced P/O, uncoupling protein 3 protein levels were not different in the muscles of the two groups. These results demonstrate reduced mitochondrial coupling in aged skeletal muscle that alters cellular metabolism and energetics.

Quantitative Analysis of Methyl Parathion Pesticides in a Polydimethylsiloxane Microfluidic Channel Using Confocal Surface-enhanced Raman Spectroscopy

Applied Spectroscopy. Apr, 2006  |  Pubmed ID: 16613632

A fast and ultra-sensitive trace analysis of methyl parathion pesticides in a polydimethylsiloxane (PDMS) microfluidic channel was investigated using confocal surface-enhanced Raman spectroscopy (SERS). A three-dimensional PDMS-based passive micromixer was fabricated for this purpose. This PDMS micromixer showed a high mixing efficiency because a strong chaotic advection was developed by the simultaneous vertical and transverse dispersion of the confluent streams. The confocal SERS signal was measured after methyl parathion pesticides were effectively adsorbed onto silver nanoparticles while flowing along the upper and lower alligator-teeth-shaped PDMS channel. A quantitative analysis of the methyl parathion pesticides was performed based on the measured peak height at 1246 cm-1. Our method has a detection limit of 0.1 ppm. This value satisfies the requirement recommended by the Collaborative International Pesticides Analytical Council (CIPAC) for the determination of methyl parathion in pesticide formulations. This study demonstrates the feasibility of using confocal SERS for the highly sensitive detection of methyl parathion pesticides in a PDMS microfluidic channel.

Nonlinear Magnetic Field Gradients Can Reduce SAR in Flow-driven Arterial Spin Labeling Measurements

Journal of Magnetic Resonance (San Diego, Calif. : 1997). Mar, 2007  |  Pubmed ID: 17175188

This work describes how custom-built gradient coils, designed to generate magnetic fields with amplitudes that vary nonlinearly with position, can be used to reduce the potential for unsafe tissue heating during flow-driven arterial spin labeling processes. A model was developed to allow detailed analysis of the adiabatic excitation process used for flow-driven arterial water stimulation with elimination of tissue signal (FAWSETS) an arterial spin labeling method developed specifically for use in skeletal muscle. The model predicted that, by adjusting the amplitude of the gradient field, the specific absorption rate could be reduced by more than a factor of 6 while still achieving effective labeling. Flow phantom measurements and in vivo measurements from exercising rat hind limb confirmed the accuracy of the model's predictions. The modeling tools were also applied to the more widely used continuous arterial spin labeling (CASL) method and predicted that specially shaped gradients could allow similar reductions in SAR.

Brain Activation During Sentence Comprehension Among Good and Poor Readers

Cerebral Cortex (New York, N.Y. : 1991). Dec, 2007  |  Pubmed ID: 17317678

This study sought to increase current understanding of the neuropsychological basis of poor reading ability by using fMRI to examine brain activation during a visual sentence comprehension task among good and poor readers in the third (n = 32) and fifth (n = 35) grades. Reading ability, age, and the combination of both factors made unique contributions to cortical activation. The main finding was of parietotemporal underactivation (less activation than controls) among poor readers at the 2 grade levels. A positive linear relationship (spanning both the poor and good readers) was found between reading ability and activation in the left posterior middle temporal and postcentral gyri and in the right inferior parietal lobule such that activation increased with reading ability. Different developmental trajectories characterized good and poor readers in the left angular gyrus: activation increased with age among good readers, a change that failed to occur among poor readers. The parietotemporal cortex is discussed in terms of its role in reading acquisition, with the left angular gyrus playing a key role. It is proposed that the functioning of the cortical network underlying reading is dependent on a combination of interacting factors, including physiological maturation, neural integrity, skill level, and the nature of the task.

L3MBTL1, a Histone-methylation-dependent Chromatin Lock

Cell. Jun, 2007  |  Pubmed ID: 17540172

Distinct histone lysine methylation marks are involved in transcriptional repression linked to the formation and maintenance of facultative heterochromatin, although the underlying mechanisms remain unclear. We demonstrate that the malignant-brain-tumor (MBT) protein L3MBTL1 is in a complex with core histones, histone H1b, HP1gamma, and Rb. The MBT domain is structurally related to protein domains that directly bind methylated histone residues. Consistent with this, we found that the L3MBTL1 MBT domains compact nucleosomal arrays dependent on mono- and dimethylation of histone H4 lysine 20 and of histone H1b lysine 26. The MBT domains bind at least two nucleosomes simultaneously, linking repression of transcription to recognition of different histone marks by L3MBTL1. Consistently, L3MBTL1 was found to negatively regulate the expression of a subset of genes regulated by E2F, a factor that interacts with Rb.

The Timecourse of Activation Within the Cortical Network Associated with Visual Imagery

The Open Neuroimaging Journal. 2007  |  Pubmed ID: 19018309

The current study examined the hemodynamic timecourse of activation within a network of regions that is thought to be associated with visual imagery. Two experimental conditions were examined that were designed to place differential demands on specific nodes within the visual imagery network. The two tasks were an object inspection task and a mental rotation task. The two conditions recruited overlapping cortical regions; however several regions revealed a differential response to object inspection and mental rotation. The mental rotation condition elicited greater activation in parietal cortex, lateral occipital/temporal regions, and bilateral prefrontal cortex. Conversely, the object inspection condition elicited greater activation in inferior extrastriate cortex, the inferior frontal gyrus, and the right cerebellum. When examining the timecourse of activation three different timecourse patterns were observed across cortical regions and conditions. The shape of the hemodynamic timecourse appears to correspond strongly with the cognitive processing taking place within the region, not the stimulus paradigm. The paper discusses the significance of those varying timecourse shapes and has implications for the appropriateness of using the canonical hrf during fMRI data analysis.

In Vivo MRI Detection of Gliomas by Chlorotoxin-conjugated Superparamagnetic Nanoprobes

Small (Weinheim an Der Bergstrasse, Germany). Mar, 2008  |  Pubmed ID: 18232053

Converging advances in the development of nanoparticle-based imaging probes and improved understanding of the molecular biology of brain tumors offer the potential to provide physicians with new tools for the diagnosis and treatment of these deadly diseases. However, the effectiveness of promising nanoparticle technologies is currently limited by insufficient accumulation of these contrast agents within tumors. Here a biocompatible nanoprobe composed of a poly(ethylene glycol) (PEG) coated iron oxide nanoparticle that is capable of specifically targeting glioma tumors via the surface-bound targeting peptide, chlorotoxin (CTX), is presented. The preferential accumulation of the nanoprobe within gliomas and subsequent magnetic resonance imaging (MRI) contrast enhancement are demonstrated in vitro in 9L cells and in vivo in tumors of a xenograft mouse model. TEM imaging reveals that the nanoprobes are internalized into the cytoplasm of 9L cells and histological analysis of selected tissues indicates that there are no acute toxic effects of these nanoprobes. High targeting specificity and benign biological response establish this nanoprobe as a potential platform to aid in the diagnosis and treatment of gliomas and other tumors of neuroectodermal origin.

The Smo/Smo Model: Hedgehog-induced Medulloblastoma with 90% Incidence and Leptomeningeal Spread

Cancer Research. Mar, 2008  |  Pubmed ID: 18339857

Toward the goal of generating a mouse medulloblastoma model with increased tumor incidence, we developed a homozygous version of our ND2:SmoA1 model. Medulloblastomas form in 94% of homozygous Smo/Smo mice by 2 months of age. Tumor formation is, thus, predictable by age, before the symptomatic appearance of larger lesions. This high incidence and early onset of tumors is ideal for preclinical studies because mice can be enrolled before symptom onset and with a greater latency period before late-stage disease. Smo/Smo tumors also display leptomeningeal dissemination of neoplastic cells to the brain and spine, which occurs in many human cases. Despite an extended proliferation of granule neuron precursors (GNP) in the postnatal external granular layer (EGL), the internal granular layer formed normally in Smo/Smo mice and tumor formation occurred only in localized foci on the superficial surface of the molecular layer. Thus, tumor formation is not simply the result of over proliferation of GNPs within the EGL. Moreover, Smo/Smo medulloblastomas were transplantable and serially passaged in vivo, demonstrating the aggressiveness of tumor cells and their transformation beyond a hyperplastic state. The Smo/Smo model is the first mouse medulloblastoma model to show leptomeningeal spread. The adherence to human pathology, high incidence, and early onset of tumors thus make Smo/Smo mice an efficient model for preclinical studies.

Synthetic Signal Injection Using Inductive Coupling

Journal of Magnetic Resonance (San Diego, Calif. : 1997). Sep, 2008  |  Pubmed ID: 18595750

Conversion of MR signals into units of metabolite concentration requires a very high level of diligence to account for the numerous parameters and transformations that affect the proportionality between the quantity of excited nuclei in the acquisition volume and the integrated area of the corresponding peak in the spectrum. We describe a method that eases this burden with respect to the transformations that occur during and following data acquisition. The conceptual approach is similar to the ERETIC method, which uses a pre-calibrated, artificial reference signal as a calibration factor to accomplish the conversion. The distinguishing feature of our method is that the artificial signal is introduced strictly via induction, rather than radiation. We tested a prototype probe that includes a second RF coil rigidly positioned close to the receive coil so that there was constant mutual inductance between them. The artificial signal was transmitted through the second RF coil and acquired by the receive coil in parallel with the real signal. Our results demonstrate that the calibration factor is immune to changes in sample resistance. This is a key advantage because it removes the cumbersome requirement that coil loading conditions be the same for the calibration sample as for experimental samples. The method should be adaptable to human studies and could allow more practical and accurate quantification of metabolite content.

Tumor-targeted Drug Delivery and MRI Contrast Enhancement by Chlorotoxin-conjugated Iron Oxide Nanoparticles

Nanomedicine (London, England). Aug, 2008  |  Pubmed ID: 18694312

This study examines the capabilities of an actively targeting superparamagnetic nanoparticle to specifically deliver therapeutic and MRI contrast agents to cancer cells.

Off-line Sentence Processing: What is Involved in Answering a Comprehension Probe?

Human Brain Mapping. Aug, 2009  |  Pubmed ID: 19184993

The aim of this study was to better characterize the influence of the comprehension probe on syntax-related activation patterns observed in fMRI studies of sentence comprehension. In this study, sentence comprehension was assessed by presenting a true/false statement after each sentence. To disassociate the sentence reading from the comprehension probe activation, a 6-s delay was placed between these processing phases. Two factors were manipulated, one affected the sentence and the other affected the probe. The sentences were manipulated by varying their syntactic complexity; conjoined-active and object-relative sentences were examined. The comprehension probes asked whether one of the first two mentioned nouns in the preceding sentence performed the action of one of the two verbs. The probes were manipulated by varying the distance (number of intervening words) between the noun and verb within the sentence; there were three probe types: short distance, long distance, and false statements. The results, which focused on the processing taking place during the probe, showed that the distance manipulation resulted in significant differences in both behavioral and brain activation measures. This was particularly true of BA 44, which revealed an interaction between complexity and distance such that the complexity effect was all but eliminated for the long-distance condition. Additionally, we replicated our previous finding of syntactic complexity effects during the probe phase. Finally, post hoc analysis revealed that participants used two distinct strategies during sentence reading; significant effects of strategy use on both behavioral and brain activation data were observed.

Magnetic Resonance Imaging of Boiling Induced by High Intensity Focused Ultrasound

The Journal of the Acoustical Society of America. Apr, 2009  |  Pubmed ID: 19354416

Both mechanically induced acoustic cavitation and thermally induced boiling can occur during high intensity focused ultrasound (HIFU) medical therapy. The goal was to monitor the temperature as boiling was approached using magnetic resonance imaging (MRI). Tissue phantoms were heated for 20 s in a 4.7-T magnet using a 2-MHz HIFU source with an aperture and radius of curvature of 44 mm. The peak focal pressure was 27.5 MPa with corresponding beam width of 0.5 mm. The temperature measured in a single MRI voxel by water proton resonance frequency shift attained a maximum value of only 73 degrees C after 7 s of continuous HIFU exposure when boiling started. Boiling was detected by visual observation, by appearance on the MR images, and by a marked change in the HIFU source power. Nonlinear modeling of the acoustic field combined with a heat transfer equation predicted 100 degrees C after 7 s of exposure. Averaging of the calculated temperature field over the volume of the MRI voxel (0.3 x 0.5 x 2 mm(3)) yielded a maximum of 73 degrees C that agreed with the MR thermometry measurement. These results have implications for the use of MRI-determined temperature values to guide treatments with clinical HIFU systems.

An FMRI Study of the Tower of London: a Look at Problem Structure Differences

Brain Research. Aug, 2009  |  Pubmed ID: 19540214

The aim of the current study was to explore the effects of problem structure, namely goal hierarchy and number of optimal solution paths, on the neural architecture that supports problem-solving and planning. Here, six-move problems with both an unambiguous and ambiguous goal hierarchy and single and multiple optimal solution paths were examined. In the task used, participants were encouraged to generate a solution plan before execution. The behavioral results revealed that problem-solving time and accuracy were both affected by both problem parameters. The fMRI activation results revealed three major findings. First, the right prefrontal cortex revealed a significantly different activation pattern than the other regions examined. This was the only region that revealed a larger response during the execution phase than the planning phase. Second, the effect of goal hierarchy was strongest during the execution phase. Finally, while there was no main effect of number of optimal solution paths, this parameter interacted with goal hierarchy in a number of regions across the brain. The present study also suggests that the minimum number of moves may not be the best measure of problem difficulty and that greater care be taken in the selection of TOL problems for both experimental studies as well as clinical assessment.

Specific Targeting of Brain Tumors with an Optical/magnetic Resonance Imaging Nanoprobe Across the Blood-brain Barrier

Cancer Research. Aug, 2009  |  Pubmed ID: 19638572

Nanoparticle-based platforms have drawn considerable attention for their potential effect on oncology and other biomedical fields. However, their in vivo application is challenged by insufficient accumulation and retention within tumors due to limited specificity to the target, and an inability to traverse biological barriers. Here, we present a nanoprobe that shows an ability to cross the blood-brain barrier and specifically target brain tumors in a genetically engineered mouse model, as established through in vivo magnetic resonance and biophotonic imaging, and histologic and biodistribution analyses. The nanoprobe is comprised of an iron oxide nanoparticle coated with biocompatible polyethylene glycol-grafted chitosan copolymer, to which a tumor-targeting agent, chlorotoxin, and a near-IR fluorophore are conjugated. The nanoprobe shows an innocuous toxicity profile and sustained retention in tumors. With the versatile affinity of the targeting ligand and the flexible conjugation chemistry for alternative diagnostic and therapeutic agents, this nanoparticle platform can be potentially used for the diagnosis and treatment of a variety of tumor types.

A Case of Rectus Sheath Hematoma Caused by Yoga Exercise

The American Journal of Emergency Medicine. Sep, 2009  |  Pubmed ID: 19683130

Rectus sheath hematoma is a relatively rare condition but a significant cause of acute abdominal pain. The acute abdominal pain associated with rectus sheath hematoma can mimic several conditions, such as appendicitis, intestinal problems (obstruction, perforation, hernia, malignancy), and gynecologic disease (ovarian cyst, torsion, tubo-ovarian abscess, ectopic pregnancy). Correct diagnosis and subsequent treatment depends on careful history taking and appropriate use of diagnostic tools to avoid unnecessary laparotomy. We report a case of rectus sheath hematoma due to noncontact strenuous exercise, yoga, that mimicked gynecologic diseases.

The Relationship Between Alcohol Consumption and Injury in ED Trauma Patients

The American Journal of Emergency Medicine. Oct, 2009  |  Pubmed ID: 19857414

Alcohol-related injuries are significantly more serious than non-alcohol-related injuries. However, there have been few data on the relationship between alcohol consumption and injury in the Korea. This study was designed to determine the absence or presence of alcohol consumption at the time of injury and the relationship between the quantity of alcohol and the extent of injury.

PEI-PEG-Chitosan Copolymer Coated Iron Oxide Nanoparticles for Safe Gene Delivery: Synthesis, Complexation, and Transfection

Advanced Functional Materials. Jul, 2009  |  Pubmed ID: 20160995

Gene therapy offers the potential of mediating disease through modification of specific cellular functions of target cells. However, effective transport of nucleic acids to target cells with minimal side effects remains a challenge despite the use of unique viral and non-viral delivery approaches. Here we present a non-viral nanoparticle gene carrier that demonstrates effective gene delivery and transfection both in vitro and in vivo. The nanoparticle system (NP-CP-PEI) is made of a superparamagnetic iron oxide nanoparticle (NP), which enables magnetic resonance imaging, coated with a novel copolymer (CP-PEI) comprised of short chain polyethylenimine (PEI) and poly(ethylene glycol) (PEG) grafted to the natural polysaccharide, chitosan (CP), which allows efficient loading and protection of the nucleic acids. The function of each component material in this nanoparticle system is illustrated by comparative studies of three nanoparticle systems of different surface chemistries, through material property characterization, DNA loading and transfection analyses, and toxicity assessment. Significantly, NP-CP-PEI demonstrates an innocuous toxic profile and a high level of expression of the delivered plasmid DNA in a C6 xenograft mouse model, making it a potential candidate for safe in vivo delivery of DNA for gene therapy.

Quantitative 19F Imaging Using Inductively Coupled Reference Signal Injection

Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. Mar, 2010  |  Pubmed ID: 20187163

This report describes recent efforts on our continuous development of a synthetic signal injection method for quantification of metabolite content in MR spectroscopy and MRI. Previous work showed that conversion of spectral peaks to quantitative units of metabolite content could be achieved with a calibrated synthetic free induction decay generated by an inductively coupled injection coil. This work demonstrates that calibrated synthetic voxels, injected in the same manner, can be used to quantify metabolite content in real (19)F image voxels. Images of vials containing different concentrations of sodium fluoride (NaF) were converted to units of moles by reference to precalibrated synthetically injected voxels. Additional images of vials containing variable sodium chloride (NaCl) demonstrate that the quantification process is robust and immune to changes in coil loading conditions.

Rapid Pharmacokinetic and Biodistribution Studies Using Cholorotoxin-conjugated Iron Oxide Nanoparticles: a Novel Non-radioactive Method

PloS One. 2010  |  Pubmed ID: 20209054

Recent advances in nanotechnology have led to the development of biocompatible nanoparticles for in vivo molecular imaging and targeted therapy. Many nanoparticles have undesirable tissue distribution or unacceptably low serum half-lives. Pharmacokinetic (PK) and biodistribution studies can help inform decisions determining particle size, coatings, or other features early in nanoparticle development. Unfortunately, these studies are rarely done in a timely fashion because many nanotechnology labs lack the resources and expertise to synthesize radioactive nanoparticles and evaluate them in mice.

PEG-mediated Synthesis of Highly Dispersive Multifunctional Superparamagnetic Nanoparticles: Their Physicochemical Properties and Function in Vivo

ACS Nano. Apr, 2010  |  Pubmed ID: 20232826

Multifunctional superparamagnetic nanoparticles have been developed for a wide range of applications in nanomedicine, such as serving as tumor-targeted drug carriers and molecular imaging agents. To function in vivo, the development of these novel materials must overcome several challenging requirements including biocompatibility, stability in physiological solutions, nontoxicity, and the ability to traverse biological barriers. Here we report a PEG-mediated synthesis process to produce well-dispersed, ultrafine, and highly stable iron oxide nanoparticles for in vivo applications. Utilizing a biocompatible PEG coating bearing amine functional groups, the produced nanoparticles serve as an effective platform with the ability to incorporate a variety of targeting, therapeutic, or imaging ligands. In this study, we demonstrated tumor-specific accumulation of these nanoparticles through both magnetic resonance and optical imaging after conjugation with chlorotoxin, a peptide with high affinity toward tumors of the neuroectodermal origin, and Cy5.5, a near-infrared fluorescent dye. Furthermore, we performed preliminary biodistribution and toxicity assessments of these nanoparticles in wild-type mice through histological analysis of clearance organs and hematology assay, and the results demonstrated the relative biocompatibility of these nanoparticles.

A Modifier Screen for Bazooka/PAR-3 Interacting Genes in the Drosophila Embryo Epithelium

PloS One. 2010  |  Pubmed ID: 20368978

The development and homeostasis of multicellular organisms depends on sheets of epithelial cells. Bazooka (Baz; PAR-3) localizes to the apical circumference of epithelial cells and is a key hub in the protein interaction network regulating epithelial structure. We sought to identify additional proteins that function with Baz to regulate epithelial structure in the Drosophila embryo.

Chlorotoxin Labeled Magnetic Nanovectors for Targeted Gene Delivery to Glioma

ACS Nano. Aug, 2010  |  Pubmed ID: 20731441

Glioma accounts for 80% of brain tumors and currently remains one of the most lethal forms of cancers. Gene therapy could potentially improve the dismal prognosis of patients with glioma, but this treatment modality has not yet reached the bedside from the laboratory due to the lack of safe and effective gene delivery vehicles. In this study we investigate targeted gene delivery to C6 glioma cells in a xenograft mouse model using chlorotoxin (CTX) labeled nanoparticles. The developed nanovector consists of an iron oxide nanoparticle core, coated with a copolymer of chitosan, polyethylene glycol (PEG), and polyethylenimine (PEI). Green fluorescent protein (GFP) encoding DNA was bound to these nanoparticles, and CTX was then attached using a short PEG linker. Nanoparticles without CTX were also prepared as a control. Mice bearing C6 xenograft tumors were injected intravenously with the DNA-bound nanoparticles. Nanoparticle accumulation in the tumor site was monitored using magnetic resonance imaging and analyzed by histology, and GFP gene expression was monitored through Xenogen IVIS fluorescence imaging and confocal fluorescence microscopy. Interestingly, the CTX did not affect the accumulation of nanoparticles at the tumor site but specifically enhanced their uptake into cancer cells as evidenced by higher gene expression. These results indicate that this targeted gene delivery system may potentially improve treatment outcome of gene therapy for glioma and other deadly cancers.

JunB Transcription Factor Maintains Skeletal Muscle Mass and Promotes Hypertrophy

The Journal of Cell Biology. Oct, 2010  |  Pubmed ID: 20921137

The size of skeletal muscle cells is precisely regulated by intracellular signaling networks that determine the balance between overall rates of protein synthesis and degradation. Myofiber growth and protein synthesis are stimulated by the IGF-1/Akt/mammalian target of rapamycin (mTOR) pathway. In this study, we show that the transcription factor JunB is also a major determinant of whether adult muscles grow or atrophy. We found that in atrophying myotubes, JunB is excluded from the nucleus and that decreasing JunB expression by RNA interference in adult muscles causes atrophy. Furthermore, JunB overexpression induces hypertrophy without affecting satellite cell proliferation and stimulated protein synthesis independently of the Akt/mTOR pathway. When JunB is transfected into denervated muscles, fiber atrophy is prevented. JunB blocks FoxO3 binding to atrogin-1 and MuRF-1 promoters and thus reduces protein breakdown. Therefore, JunB is important not only in dividing populations but also in adult muscle, where it is required for the maintenance of muscle size and can induce rapid hypertrophy and block atrophy.

Functionalization of Iron Oxide Magnetic Nanoparticles with Targeting Ligands: Their Physicochemical Properties and in Vivo Behavior

Nanomedicine (London, England). Nov, 2010  |  Pubmed ID: 21128719

To develop and evaluate two tumor-specific nanoprobes by functionalization of a polyethylene glycol-immobilized nanoparticle with arginine-glycine-aspartic acid (RGD) or chlorotoxin ligand that targets α(v)β(3) integrin and matrix metalloproteinase-2 receptors, respectively.

Quantitative in Vivo Magnetic Resonance Spectroscopy Using Synthetic Signal Injection

PloS One. 2010  |  Pubmed ID: 21203385

Accurate conversion of magnetic resonance spectra to quantitative units of concentration generally requires compensation for differences in coil loading conditions, the gains of the various receiver amplifiers, and rescaling that occurs during post-processing manipulations. This can be efficiently achieved by injecting a precalibrated, artificial reference signal, or pseudo-signal into the data. We have previously demonstrated, using in vitro measurements, that robust pseudo-signal injection can be accomplished using a second coil, called the injector coil, properly designed and oriented so that it couples inductively with the receive coil used to acquire the data. In this work, we acquired nonlocalized phosphorous magnetic resonance spectroscopy measurements from resting human tibialis anterior muscles and used pseudo-signal injection to calculate the Pi, PCr, and ATP concentrations. We compared these results to parallel estimates of concentrations obtained using the more established phantom replacement method. Our results demonstrate that pseudo-signal injection using inductive coupling provides a robust calibration factor that is immune to coil loading conditions and suitable for use in human measurements. Having benefits in terms of ease of use and quantitative accuracy, this method is feasible for clinical use. The protocol we describe could be readily translated for use in patients with mitochondrial disease, where sensitive assessment of metabolite content could improve diagnosis and treatment.

Immune Responses to AAV in Canine Muscle Monitored by Cellular Assays and Noninvasive Imaging

Molecular Therapy : the Journal of the American Society of Gene Therapy. Mar, 2010  |  Pubmed ID: 20040912

We previously demonstrated that direct intramuscular injection of rAAV2 or rAAV6 in wild-type dogs resulted in robust T-cell responses to viral capsid proteins, and others have shown that cellular immunity to adeno-associated virus (AAV) capsid proteins coincided with liver toxicity and elimination of transgene expression in a human trial of hemophilia B. Here, we show that the heparin-binding ability of a given AAV serotype does not determine the induction of T-cell responses following intramuscular injection in dogs, and identify multiple epitopes in the AAV capsid protein that are recognized by T cells elicited by AAV injection. We also demonstrate that noninvasive magnetic resonance imaging (MRI) can accurately detect local inflammatory responses following intramuscular rAAV injection in dogs. These studies suggest that pseudotyping rAAV vectors to remove heparin-binding activity will not be sufficient to abrogate immunogenicity, and validate the utility of enzyme-linked immunosorbent spot (ELISpot) assay and MRI for monitoring immune and inflammatory responses following intramuscular injection of rAAV vectors in preclinical studies in dogs. These assays should be incorporated into future human clinical trials of AAV gene therapy to monitor immune responses.

The Effect of Presentation Paradigm on Syntactic Processing: An Event-related FMRI Study

Human Brain Mapping. Jan, 2010  |  Pubmed ID: 19554559

An event-related fMRI study was conducted to investigate the effect of two different sentence presentation paradigms-rapid serial visual presentation (RSVP) and whole sentence presentation-on syntactic processing. During scanning, sentences were presented using one of the two presentation paradigms and were followed by a short delay and a probe to verify sentence comprehension. The delay was included in an attempt to separate sentence-related activity from probe-related activity. The behavioral data showed a main effect of syntactic complexity for reaction time and accuracy, and accuracy revealed an interaction between complexity and the presentation paradigm employed-RSVP produced many more errors for syntactically complex sentences than did whole sentence presentation. The imaging data revealed a syntactic complexity effect during the sentence phase in left BA 44 and during the probe phase in left BA 44 and the left posterior MTG. In addition, timecourse analysis revealed that these two regions also showed an interaction between complexity and presentation paradigm such that there was no complexity effect during RSVP but a significant effect during whole sentence presentation. In addition to finding that these two presentation paradigms differentially affected syntactic processing, there were main effects within the visual pathway (V1/V2 vs. V5) and the hippocampus that revealed significant differences in activation between the paradigms.

CP47,497-C8 and JWH073, Commonly Found in 'Spice' Herbal Blends, Are Potent and Efficacious CB(1) Cannabinoid Receptor Agonists

European Journal of Pharmacology. Jun, 2011  |  Pubmed ID: 21333643

'Spice' is an herbal blend that has been reported to produce cannabis-like effects when smoked and is marketed as an alternative to marijuana. Synthetic additives have been identified in numerous 'Spice' preparations from different sources. Common among many of the preparations were the compounds JWH018 and a dimethyloctyl variant of CP47,497 (CP47,497-C8) and, more recently JWH073. The synaptic effects of each of these compounds were uncharacterized. We previously reported that JWH018 is a potent and efficacious CB(1) cannabinoid receptor agonist. In this study we have examined the abilities of CP47,497-C8 and JWH073 to inhibit neurotransmission in cultured autaptic hippocampal neurons. Each inhibited EPSCs with an efficacy and potency similar to JWH018. We also analyzed these compounds' effects on promoting internalization of CB(1) receptors in HEK293 cells stably expressing CB(1) receptors. Similar to our neurotransmission data, CP47,497-C8 internalized CB(1) in a fashion indistinguishable from JWH018. However, JWH073 was less potent and produced slower internalization than JWH018 and CP47,497-C8. It appears that 'Spice' contains a number of cannabinoid receptor agonists that activate CB(1) receptors to inhibit synaptic transmission with similar potencies and efficacies. It is highly probable that the cannabis-like effects of 'Spice' are due to the presence of these and analogous synthetic additives acting on CB(1) receptors.

Atrogin1/MAFbx: What Atrophy, Hypertrophy, and Cardiac Failure Have in Common

Circulation Research. Jul, 2011  |  Pubmed ID: 21737813

Synthetic Signal Injection Using a Single Radiofrequency Channel

Journal of Magnetic Resonance Imaging : JMRI. Dec, 2011  |  Pubmed ID: 22113992

To demonstrate that, when injecting an artificial reference signal for quantitation purposes, the real and artificial signals can be acquired separately, using a single radiofrequency (RF) channel, with no loss of fidelity. Conversion of MR signals to units of concentration can be simplified by injection of a precalibrated, artificial reference signal, or pseudo-signal. In previous implementations, the pseudo-signal was acquired simultaneously with the real signals arising from the sample and this requires a second, integrated RF channel.