Kern MJ
University of California Irvine, Orange, California.
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Cardiac Catheterization on the Road Less Traveled Navigating the Radial Versus Femoral Debate.
JACC Cardiovasc Interv. 2009 Nov;2(11):1055-1056
PMID: 19926043
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Rothholtz VS,Djalilian HR
Department of Otolaryngology-Head and Neck Surgery, University of California Irvine Medical Center, Orange, CA, USA.
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Complete obstruction of the stapes footplate by a dehiscent facial nerve in stapedectomy.
Ear Nose Throat J. 2009 Nov;88(11):1192-1193
PMID: 19924658
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Crampton SP,Wu B,Park EJ,Kim JH,Solomon C,Waterman ML,Hughes CC
Department of Molecular Biology and Biochemistry, UCI Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
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Integration of the beta-Catenin-Dependent Wnt Pathway with Integrin Signaling through the Adaptor Molecule Grb2.
PLoS One. 2009;4(11):e7841
BACKGROUND: THE COMPLEXITY OF WNT SIGNALING LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and c-jun have recently been implicated in wnt signaling, however their upstream activators have not been identified. METHODOLOGY/PRINCIPAL FINDINGS: Here we identify the adapter protein Grb2, which is itself an integrator of multiple signaling pathways, as a modifier of beta-catenin-dependent wnt signaling. Grb2 synergizes with wnt3A, constitutively active (CA) LRP6, Dvl2 or CA-beta-catenin to drive a LEF/TCF-responsive reporter, and dominant negative (DN) Grb2 or siRNA to Grb2 block wnt3A-mediated reporter activity. MMP9 is a target of beta-catenin-dependent wnt signaling, and an MMP9 promoter reporter is also responsive to signals downstream of Grb2. Both a jnk inhibitor and DN-c-jun block transcriptional activation downstream of Dvl2 and Grb2, as does DN-rac1. Integrin ligation by collagen also synergizes with wnt signaling as does overexpression of Focal Adhesion Kinase (FAK), and this is blocked by DN-Grb2. CONCLUSIONS/SIGNIFICANCE: These data suggest that integrin ligation and FAK activation synergize with wnt signaling through a Grb2-rac-jnk-c-jun pathway, providing a context-dependent mechanism for modulation of wnt signaling.
PMID: 19924227
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Kirby AE,Middlebrooks JC
University of California-Irvine.
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Auditory Temporal Acuity Probed with Cochlear Implant Stimulation and Cortical Recording.
J Neurophysiol. 2009 Nov 18;:
Cochlear implants stimulate the auditory nerve with amplitude-modulated electric pulse trains. Pulse rates >2000 pulses per second (pps) have been hypothesized to enhance transmission of temporal information. Recent studies, however, have shown that higher pulse rates impair phase locking to sinusoidal amplitude modulation in the auditory cortex and impair perceptual modulation detection. Here, we investigated the effects of high pulse rates on the temporal acuity of transmission of pulse trains to the auditory cortex. In anesthetized guinea pigs, signal-detection analysis was used to measure the thresholds for detection of gaps in pulse trains at rates of 254, 1017, and 4069 pps and in acoustic noise. Gap detection thresholds decreased by an order of magnitude with increases in pulse rate from 254 to 4069 pps. Such a pulse-rate dependence likely would impact speech reception through clinical speech processors. To elucidate the neural mechanisms of gap detection, we measured recovery from forward masking after a 196.6 ms pulse train. Recovery from masking was faster at higher carrier pulse rates, and masking increased linearly with current level. We fit the data with a dual-exponential recovery function, consistent with a peripheral and a more central process. High-rate pulse trains evoked less central masking, possibly due to adaptation of the response in the auditory nerve. Neither gap detection nor forward masking varied with cortical depth, indicating that these processes likely are sub-cortical. These results indicate that gap detection and modulation detection are mediated by two separate neural mechanisms.
PMID: 19923242
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Suchard JR
(jsuchard@uci.edu) University of California Irvine Medical Center Orange, CA.
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Toxicology Recall.
Acad Emerg Med. 2009 Nov 16;:
PMID: 19919559
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Rugg MD
Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California Irvine, 116 Bonney Research Lab, Irvine, CA92697-3800, United States.
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Editorial.
Neuropsychologia. 2009 Nov 13;:
PMID: 19917300
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Suga H,Ehlert FJ
Department of Pharmacology, School of Medicine, University of California Irvine, Irvine, CA, United States, 92697-4625.
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Investigating the Interaction of McN-A-343 with the M(2) Muscarinic Receptor Using its Nitrogen Mustard Derivative.
Biochem Pharmacol. 2009 Nov 11;:
We investigated whether the aziridinium ion formed from a nitrogen mustard derivative (4-[(2-bromoethyl)methyl-amino]-2-butynyl N-(3-chlorophenyl)carbamate; BR384) structurally related to McN-A-343 (4-(trimethyl-amino)-2-butynyl N-(3-chlorophenyl)carbamate) interacts allosterically or orthosterically with the M(2) muscarinic receptor. Chinese hamster ovary cells expressing the human M(2) muscarinic receptor were incubated with the aziridinium ion of BR384 in combination with McN-A-343 or other known orthosteric and allosteric ligands for various incubation times. After removing unreacted ligands, we measured the binding of [(3)H]N-methylscopolamine to residual unalkylated receptors. Affinity constants, rate constants for alkylation, and cooperativity constants were estimated for the interacting ligands using a mathematical model. Receptor alkylation by BR384 was consistent with a two-step process. After rapidly equilibrating with the receptor (step one), the aziridinium ion-receptor complex became covalently linked with a first order rate constant of about 0.95min(-1) (step two). McN-A-343, acetylcholine and N-methylscopolamine competitively protected the M(2) receptor from irreversible alkylation by BR384. In contrast, the allosteric modulators, gallamine and WIN 51,708 (17-ss-hydroxy-17-alpha-ethynyl-5-alpha-androstano[3,2-ss]pyrimido [1,2-alpha]benzimidazole), allosterically inhibited or had no effect on, respectively, receptor alkylation by BR384. There was good agreement between affinity constants estimated from the kinetics of receptor alkylation and by displacement of [(3)H]N-methylscopolamine binding. Our results suggest that BR384 covalently binds to the orthosteric site of the M(2) receptor and that McN-A-343 binds reversibly at the same locus. Our method of analyzing allosteric interactions does not suffer from the limitations of more conventional approaches and can be adapted to detect allosteric interactions at receptors other than the muscarinic subtypes.
PMID: 19913516
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Alted López E,Bermejo S,Chico M
Servicio de Medicina Intensiva, UCI de Trauma, Hospital 12 de Octubre de Madrid, Spain.
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[Letter of reply.]
Med Intensiva. 2009 Nov;33(8):409-10
PMID: 19912974
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Anderson KD,Sharp KG,Hofstadter M,Irvine KA,Murray M,Steward O
Reeve-Irvine Research Center, University of California at Irvine School of Medicine, Irvine, 1113 Hewitt Hall, Irvine, CA 92697-1385, USA. kanderso@uci.edu
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Forelimb locomotor assessment scale (FLAS): novel assessment of forelimb dysfunction after cervical spinal cord injury.
Exp Neurol. 2009 Nov;220(1):23-33
We describe here a novel forelimb locomotor assessment scale (FLAS) that assesses forelimb use during locomotion in rats injured at the cervical level. A quantitative scale was developed that measures movements of shoulder, elbow, and wrist joints, forepaw position and digit placement, forelimb-hindlimb coordination, compensatory behaviors adopted while walking, and balance. Female Sprague-Dawley rats received graded cervical contusions ranging from 200 to 230 ("mild," n=11) and 250-290 kdyn ("moderate," n=13) between C5 and C8. Rats were videotaped post-injury as they walked along an alley to determine deficits and recovery of forelimb function. Recovery of shoulder and elbow joint movement occurred rapidly (within 1-7 days post-injury), whereas recovery of wrist joint movement was slower and more variable. Most rats in all groups displayed persistent deficits in forepaw and digit movement, but developed compensatory behaviors to allow functional forward locomotion within 1-2 weeks post-injury. Recovery of forelimb function as measured by the FLAS reached a plateau by 3 weeks post-injury in all groups. Rats with mild contusions displayed greater locomotor recovery than rats with moderate contusions, but exhibited persistent deficits compared to sham controls. Reliability was tested by having seven raters (three internal, four external) from different laboratories, independently and blindly score videos of all rats. The multivariate correlation between all raters, all animals, and all time points ranged from r(2)=0.88-0.96 (p<0.0001), indicating a high inter-rater reliability. Thus, the FLAS is a simple, inexpensive, sensitive, and reliable measure of forelimb function during locomotion following cervical SCI.
PMID: 19733168
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Konecky SD,Mazhar A,Cuccia D,Durkin AJ,Schotland JC,Tromberg BJ
Laser Microbeam and Medical Program (LAMMP), Beckman Laser Institute, University of California - Irvine, 1002 Health Sciences Road, Irvine, CA 92617, USA.
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Quantitative optical tomography of sub-surface heterogeneities using spatially modulated structured light.
Opt Express. 2009 Aug 17;17(17):14780-90
We present a wide-field method for obtaining three-dimensional images of turbid media. By projecting patterns of light of varying spatial frequencies on a sample, we reconstruct quantitative, depth resolved images of absorption contrast. Images are reconstructed using a fast analytic inversion formula and a novel correction to the diffusion approximation for increased accuracy near boundaries. The method provides more accurate quantification of optical absorption and higher resolution than standard diffuse reflectance measurements.
PMID: 19687956
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Anderson KD,Sharp KG,Steward O
Reeve-Irvine Research Center, University of California, Irvine College of Medicine, Irvine, CA 92697-1385, USA. kanderso@uci.edu
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Bilateral cervical contusion spinal cord injury in rats.
Exp Neurol. 2009 Nov;220(1):9-22
There is increasing motivation to develop clinically relevant experimental models for cervical SCI in rodents and techniques to assess deficits in forelimb function. Here we describe a bilateral cervical contusion model in rats. Female Sprague-Dawley rats received mild or moderate cervical contusion injuries (using the Infinite Horizons device) at C5, C6, or C7/8. Forelimb motor function was assessed using a grip strength meter (GSM); sensory function was assessed by the von Frey hair test; the integrity of the corticospinal tract (CST) was assessed by biotinylated dextran amine (BDA) tract tracing. Mild contusions caused primarily dorsal column (DC) and gray matter (GM) damage while moderate contusions produced additional damage to lateral and ventral tissue. Forelimb and hindlimb function was severely impaired immediately post-injury, but all rats regained the ability to use their hindlimbs for locomotion. Gripping ability was abolished immediately after injury but recovered partially, depending upon the spinal level and severity of the injury. Rats exhibited a loss of sensation in both fore- and hindlimbs that partially recovered, and did not exhibit allodynia. Tract tracing revealed that the main contingent of CST axons in the DC was completely interrupted in all but one animal whereas the dorsolateral CST (dlCST) was partially spared, and dlCST axons gave rise to axons that arborized in the GM caudal to the injury. Our data demonstrate that rats can survive significant bilateral cervical contusion injuries at or below C5 and that forepaw gripping function recovers after mild injuries even when the main component of CST axons in the dorsal column is completely interrupted.
PMID: 19559699
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Roca AI,Almada AE,Abajian AC
Department of Molecular Biology and Biochemistry, 560 Steinhaus Hall, University of California, Irvine, California 92697-3900, USA. aroca@uci.edu
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ProfileGrids as a new visual representation of large multiple sequence alignments: a case study of the RecA protein family.
BMC Bioinformatics. 2008;9:554
BACKGROUND: Multiple sequence alignments are a fundamental tool for the comparative analysis of proteins and nucleic acids. However, large data sets are no longer manageable for visualization and investigation using the traditional stacked sequence alignment representation. RESULTS: We introduce ProfileGrids that represent a multiple sequence alignment as a matrix color-coded according to the residue frequency occurring at each column position. JProfileGrid is a Java application for computing and analyzing ProfileGrids. A dynamic interaction with the alignment information is achieved by changing the ProfileGrid color scheme, by extracting sequence subsets at selected residues of interest, and by relating alignment information to residue physical properties. Conserved family motifs can be identified by the overlay of similarity plot calculations on a ProfileGrid. Figures suitable for publication can be generated from the saved spreadsheet output of the colored matrices as well as by the export of conservation information for use in the PyMOL molecular visualization program.We demonstrate the utility of ProfileGrids on 300 bacterial homologs of the RecA family - a universally conserved protein involved in DNA recombination and repair. Careful attention was paid to curating the collected RecA sequences since ProfileGrids allow the easy identification of rare residues in an alignment. We relate the RecA alignment sequence conservation to the following three topics: the recently identified DNA binding residues, the unexplored MAW motif, and a unique Bacillus subtilis RecA homolog sequence feature. CONCLUSION: ProfileGrids allow large protein families to be visualized more effectively than the traditional stacked sequence alignment form. This new graphical representation facilitates the determination of the sequence conservation at residue positions of interest, enables the examination of structural patterns by using residue physical properties, and permits the display of rare sequence features within the context of an entire alignment. JProfileGrid is free for non-commercial use and is available from http://www.profilegrid.org. Furthermore, we present a curated RecA protein collection that is more diverse than previous data sets; and, therefore, this RecA ProfileGrid is a rich source of information for nanoanatomy analysis.
PMID: 19102758
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Przulj N,Kuchaiev O,Stevanovi? A,Hayes W
Department of Computer Science, University of California, Irvine, CA, 92697-3425, USA. natasha@ics.uci.edu.
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Geometric evolutionary dynamics of protein interaction networks.
Pac Symp Biocomput. 2010;:178-89
Understanding the evolution and structure of protein-protein interaction (PPI) networks is a central problem of systems biology. Since most processes in the cell are carried out by groups of proteins acting together, a theoretical model of how PPI networks develop based on duplications and mutations is an essential ingredient for understanding the complex wiring of the cell. Many different network models have been proposed, from those that follow power-law degree distributions and those that model complementarity of protein binding domains, to those that have geometric properties. Here, we introduce a new model for PPI network (and thus gene) evolution that produces well-fitting network models for currently available PPI networks. The model integrates geometric network properties with evolutionary dynamics of PPI network evolution.
PMID: 19908370
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Jamal MM,Yoon EJ,Vega KJ,Hashemzadeh M,Chang KJ
Division of Gastroenterology, Veterans Affairs (VA) Medical Center, 5901 E. 7th St. Long Beach, CA 90822, United States. jamalm@uci.edu.
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Diabetes mellitus as a risk factor for gastrointestinal cancer among American veterans.
World J Gastroenterol. 2009 Nov 14;15(42):5274-8
AIM: To assess the risk of biliary and pancreatic cancers in a large cohort of patients with type 2 diabetes mellitus (DM). METHODS: Eligibility for this study included patients with type 2 DM (ICD-9 code 250.0) who were discharged from Department of Veteran Affairs hospitals between 1990 and 2000. Non-matched control patients without DM were selected from the same patient treatment files during the same period. Demographic information included age, sex and race. Secondary diagnoses included known risk factors based on their ICD-9 codes. By multivariate logistic regression, the occurrence of biliary and pancreatic cancer was compared between case subjects with DM and controls without DM. RESULTS: A total of 1 172 496 case and control subjects were analyzed. The mean age for study and control subjects was 65.8 +/- 11.3 and 64.8 +/- 12.6 years, respectively. The frequency of pancreatic cancer in subjects with DM was increased (0.9%) in comparison to control subjects (0.3%) with an OR of 3.22 (95% CI: 3.03-3.42). The incidence of gallbladder and extrahepatic biliary cancers was increased by twofold in diabetic patients when compared to controls. The OR and 95% CI were 2.20 (1.56-3.00) and 2.10 (1.61-2.53), respectively. CONCLUSION: Our study demonstrated that patients with DM have a threefold increased risk for developing pancreatic cancer and a twofold risk for developing biliary cancer.
PMID: 19908334
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Wong RC,Pébay A
Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
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Study of gap junctions in human embryonic stem cells.
Methods Mol Biol. 2010;584:211-28
Gap junctional intercellular communication (GJIC) has been described in different cell types including stem cells and has been involved in different biological events. GJIC is required for mouse embryonic stem cell maintenance and proliferation, and various studies suggest that functional GJIC is a common characteristic of human embryonic stem cells (hESC) maintained in different culture conditions. This chapter introduces methods to study gap junctions in hESC, from expression of gap junction proteins to functional study of GJIC in hESC proliferation, apoptosis, colony growth, and pluripotency.
PMID: 19907980
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Rex CS,Colgin LL,Jia Y,Casale M,Yanagihara TK,Debenedetti M,Gall CM,Kramar EA,Lynch G
Department of Anatomy & Neurobiology, University of California Irvine, Irvine California, United States of America.
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Origins of an intrinsic hippocampal EEG pattern.
PLoS One. 2009;4(11):e7761
Sharp waves (SPWs) are irregular waves that originate in field CA3 and spread throughout the hippocampus when animals are alert but immobile or as a component of the sleep EEG. The work described here used rat hippocampal slices to investigate the factors that initiate SPWs and govern their frequency. Acute transection of the mossy fibers reduced the amplitude but not the frequency of SPWs, suggesting that activity in the dentate gyrus may enhance, but is not essential for, the CA3 waves. However, selective destruction of the granule cells and mossy fibers by in vivo colchicine injections profoundly depressed SPW frequency. Reducing mossy fiber release with an mGluR2 receptor agonist or enhancing it with forskolin respectively depressed or increased the incidence of SPWs. Collectively, these results indicate that SPWs can be triggered by constitutive release from the mossy fibers. The waves were not followed by large after-hyperpolarizing potentials and their frequency was not strongly affected by blockers of various slow potassium channels. Antagonists of GABA-B mediated IPSCs also had little effect on incidence. It appears from these results that the spacing of SPWs is not dictated by slow potentials. However, modeling work suggests that the frequency and variance of large mEPSCs from the mossy boutons can account for the temporal distribution of the waves. Together, these results indicate that constitutive release from the mossy fiber terminal boutons regulates the incidence of SPWs and their contribution to information processing in hippocampus.
PMID: 19907647
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Kather A,Raftery MJ,Devi-Rao G,Lippmann J,Giese T,Sandri-Goldin RM,Schönrich G
Institute of Virology, CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA 92697-4025, USA; Institute of Immunology, University of Heidelberg, D-69120 Heidelberg, Germany.
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Herpes Simplex Virus Type 1 (HSV-1)-Induced Apoptosis in Human Dendritic Cells as a Result of Downregulation of Cellular FLICE-Inhibitory Protein (c-FLIP) and Reduced Expression of HSV-1 Antiapoptotic Latency-Associated Transcript (LAT) Sequences.
J Virol. 2009 Nov 11;:
Herpes simplex virus type 1 (HSV-1) is one of the most frequent and successful human pathogens. It targets immature dendritic cells (iDCs) to interfere with the antiviral immune response. The mechanisms underlying apoptosis of HSV-1 infected iDCs are not fully understood. Previously, we have shown that HSV-1-induced apoptosis of iDCs is associated with downregulation of the cellular FLICE-inhibitory protein (c-FLIP), a potent inhibitor of caspase-8-mediated apoptosis. In this study we prove that HSV-1 induces degradation of c-FLIP in a proteasome-independent manner. In addition, by using c-FLIP specific siRNA we show for the first time that downregulation of c-FLIP expression is sufficient to drive uninfected iDCs into apoptosis underlining the importance of this molecule for iDC survival. Surprisingly, we also observed virus-induced c-FLIP downregulation in epithelial cells and many other cell types that do not undergo apoptosis after HSV-1 infection. Microarray analyses revealed that HSV-1 encoded latency-associated transcript (LAT) sequences, which can substitute for c-FLIP as an inhibitor of caspase-8-mediated apoptosis, are much less abundant in iDCs as compared to epithelial cells. Finally, iDCs infected with a HSV-1 LAT knock-out mutant showed increased apoptosis when compared to iDCs infected with the corresponding wild type HSV-1. Taken together, our results demonstrate that apoptosis of HSV-1 infected iDCs requires both c-FLIP downregulation and diminished expression of viral LAT.
PMID: 19906927
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Nguyen D,Sa S,Pegan JD,Rich B,Xiang G,McCloskey KE,Manilay JO,Khine M
Department of Biomedical Engineering, University of California, Irvine, CA, USA. mkhine@uci.edu.
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Tunable shrink-induced honeycomb microwell arrays for uniform embryoid bodies.
Lab Chip. 2009 Dec 7;9(23):3338-3344
Embryoid body (EB) formation closely recapitulates early embryonic development with respect to lineage commitment. Because it is greatly affected by cell-cell and cell-substrate interactions, the ability to control the initial number of cells in the aggregates and to provide an appropriate substrate are crucial parameters for uniform EB formation. Here we report of an ultra-rapid fabrication and culture method utilizing a laser-jet printer to generate closely arrayed honeycomb microwells of tunable sizes for the induction of uniform EBs from single cell suspension. By printing various microwell patterns onto pre-stressed polystyrene sheets, and through heat induced shrinking, high aspect micromolds are generated. Notably, we achieve rounded bottom polydimethylsiloxane (PDMS) wells not easily achievable with standard microfabrication methods, but critical to achieve spherical EBs. Furthermore, by simply controlling the size of the microwells and the concentration of the cell suspension we can control the initial size of the cell aggregate, thus influencing lineage commitment. In addition, these microwells are easily adaptable and scalable to most standard well plates and easily integrated into commercial liquid handling systems to provide an inexpensive and easy high throughput compound screening platform.
PMID: 19904398
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Colt HG,Murgu SD
Pulmonary and Critical Care Division, UCI Medical Center, 101 the City Drive, Bldg. 53, Rm. 119, Orange, California 91916, USA.
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Closure of pneumonectomy stump fistula using custom Y and cuff-link-shaped silicone prostheses.
Ann Thorac Cardiovasc Surg. 2009 Oct;15(5):339-42
Large postpneumonectomy stump fistulas pose a significant problem for thoracic surgeons and interventional bronchoscopists. We present a case of successful rigid bronchoscopic repair of a complete right pneumonectomy stump dehiscence using a custom-built stent made of a sculpted silicone Y stent sutured to a new cuff-link-shaped DJ-Fistula stent. This resulted in rapid symptom resolution, weaning from mechanical ventilation and discharge home in a patient with bronchogenic carcinoma, respiratory failure, and significant other comorbidities that precluded repeat thoracotomy.
PMID: 19901891
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Ogunseitan OA,Schoenung JM,Saphores JD,Shapiro AA
Program in Public Health and School of Social Ecology, University of California, Irvine, CA 92697, USA. Oladele.Ogunseitan@uci.edu
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Science and regulation. The electronics revolution: from e-wonderland to e-wasteland.
Science. 2009 Oct 30;326(5953):670-1
PMID: 19900918
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Tan Z,Shi L,Schreiber SS
Department of Neurology, University of California Irvine School of Medicine, Irvine, CA 92697, USA.
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Differential Expression of Redox Factor-1 Associated with Beta-Amyloid-Mediated Neurotoxicity.
Open Neurosci J. 2009 Jan 1;3:26-34
Redox factor-1 (Ref-1), also known as HAP1, APE or APEX, is a multifunctional protein that regulates gene transcription as well as the response to oxidative stress. By interacting with transcription factors such as AP-1, NF-kappaB and p53, and directly participating in the cleavage of apurininic/apyrimidinic DNA lesions, Ref-1 plays crucial roles in both cell death signaling pathways and DNA repair, respectively. Oxidative stress induced by aggregated beta-amyloid (Abeta) peptide, altered DNA repair and transcriptional activation of cell death pathways have been implicated in the pathophysiology of Alzheimer's disease (AD). Here we show that varying concentrations of Abeta(1-42) differentially regulate Ref-1 expression, Ref-1 function and neuronal survival in vitro. Abeta (5.0 muM) caused a relatively rapid decrease in Ref-1 expression and activity associated with extensive DNA damage and neuronal degeneration. In contrast, Ref-1 induction occurred in cells exposed to Abeta (1.0 muM) without significant neuronal cell death. Abeta-induced attenuation of Ref-1 expression and endonuclease activity, and neuronal cell death were prevented by the anti-oxidant, catalase. Similar differential effects on Ref-1 expression and cell viability were observed in N2A neuroblastoma cells treated with either high or low dose hydrogen peroxide. These findings demonstrate the differential regulation of Ref-1 expression by varying degrees of oxidative stress. Parallels between the Ref-1 response to Abeta and H(2)O(2) suggest similarities between DNA repair pathways activated by different inducers of oxidative stress. In AD brain, colocalization of Ref-1 and Abeta the absence of significant DNA damage are consistent with the cell culture results and suggests that Ref-1 may play a more neuroprotective role under these conditions. Modulation of Ref-1 expression and activity by local variations in Abeta concentration may be an important determinant of neuronal vulnerability to oxidative stress in AD.
PMID: 19898678
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Tanaka H,Yi TM
Department of Developmental and Cell Biology, University of California Irvine, Irvine, California, USA.
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Reverse engineering a signaling network using alternative inputs.
PLoS One. 2009;4(10):e7622
One of the goals of systems biology is to reverse engineer in a comprehensive fashion the arrow diagrams of signal transduction systems. An important tool for ordering pathway components is genetic epistasis analysis, and here we present a strategy termed Alternative Inputs (AIs) to perform systematic epistasis analysis. An alternative input is defined as any genetic manipulation that can activate the signaling pathway instead of the natural input. We introduced the concept of an "AIs-Deletions matrix" that summarizes the outputs of all combinations of alternative inputs and deletions. We developed the theory and algorithms to construct a pairwise relationship graph from the AIs-Deletions matrix capturing both functional ordering (upstream, downstream) and logical relationships (AND, OR), and then interpreting these relationships into a standard arrow diagram. As a proof-of-principle, we applied this methodology to a subset of genes involved in yeast mating signaling. This experimental pilot study highlights the robustness of the approach and important technical challenges. In summary, this research formalizes and extends classical epistasis analysis from linear pathways to more complex networks, facilitating computational analysis and reconstruction of signaling arrow diagrams.
PMID: 19898612
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Seo YK,Zhu B,Jeon TI,Osborne TF
Department of Molecular Biology and Biochemistry, 3244 McGaugh Hall, University of California, UC Irvine, Irvine, CA 92697-3900, USA.
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Regulation of steroid 5-alpha reductase type 2 (Srd5a2) by sterol regulatory element binding proteins and statin.
Exp Cell Res. 2009 Nov 1;315(18):3133-9
In this study, we show that sterol regulatory element binding proteins (SREBPs) regulate expression of Srd5a2, an enzyme that catalyzes the irreversible conversion of testosterone to dihydroxytestosterone in the male reproductive tract and is highly expressed in androgen-sensitive tissues such as the prostate and skin. We show that Srd5a2 is induced in livers and prostate from mice fed a chow diet supplemented with lovastatin plus ezitimibe (L/E), which increases the activity of nuclear SREBP-2. The three fold increase in Srd5a2 mRNA mediated by L/E treatment was accompanied by the induction of SREBP-2 binding to the Srd5a2 promoter detected by a ChIP-chip assay in liver. We identified a SREBP-2 responsive region within the first 300 upstream bases of the mouse Srd5a2 promoter by co-transfection assays which contain a site that bound SREBP-2 in vitro by an EMSA. Srd5a2 protein was also induced in cells over-expressing SREBP-2 in culture. The induction of Srd5a2 through SREBP-2 provides a mechanistic explanation for why even though statin therapy is effective in reducing cholesterol levels in treating hypercholesterolemia it does not compromise androgen production in clinical studies.
PMID: 19500568
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Bonizzoni M,Afrane Y,Baliraine FN,Amenya DA,Githeko AK,Yan G
Program in Public Health, College of Health Sciences, University of California, Irvine 92697, USA. mbonizzo@uci.edu
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Genetic structure of Plasmodium falciparum populations between lowland and highland sites and antimalarial drug resistance in Western Kenya.
Infect Genet Evol. 2009 Sep;9(5):806-12
Human travel to malaria endemic lowlands from epidemic highlands has been shown to increase the risk of malaria infections in the highlands. In order to gain insight on the impact of human travel, we examined prevalence, genetic variability and population genetic structure of Plasmodium falciparum in asymptomatic children from one highland site and three surrounding malaria endemic lowland sites in Western Kenya, using multilocus microsatellite genotyping. We further analyzed the frequencies of mutations at the genes conferring resistance to chloroquine and sulfadoxine-pyrimethamine. We found a significant decrease in malaria prevalence in the highland site from 2006 to 2007, 1 year after the introduction of the artemisinin-based combination therapy as first-line treatment for uncomplicated malaria and the scale-up of insecticide-treated bed nets. Population genetic diversity, measured by the number of observed and effective microsatellite alleles and Nei's unbiased genetic diversity, was high and comparable for both highland and lowland populations. Analysis of molecular variance did not detect a significant genetic structure across highland and lowland regions. Similarly, mutations at key antimalarial-resistance codons of the pfcrt, pfmdr1, pfdhfr and pfdhps genes were found at comparable high frequencies in all four sites. High level of gene flow and lack of significant genetic structure in malaria parasites between highland and lowland areas suggest the importance of human travel in shaping parasite population structure.
PMID: 19398039
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Eshuis H,van Voorhis T
School of Chemistry, University of Bristol, Cantock's Close, Bristol, UKBS8 1TS. Henk.Eshuis@uci.edu.
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The influence of initial conditions on charge transfer dynamics.
Phys Chem Chem Phys. 2009 Nov 28;11(44):10293-8
In this work we address the influence of the initial state on electron transfer dynamics by comparing two different ways of setting up the initial state, namely by taking an electron from the HOMO of a DFT ground state, or by using constrained DFT to self-consistently create the initial state. We solve the TDKS equations for the benzyl-pentafluorobenzene cation. The neutral molecule has a localised HOMO, which gives a natural partitioning in donor and acceptor group. We compare the electronic dynamics for varying angle between donor and acceptor and for varying basis set. We show that the methods lead to essentially equivalent results, but that the use of cDFT gives higher currents and a more consistent initial state with respect to variation of basis set and geometry.
PMID: 19890512
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