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1.  Spatiotemporal dynamics of speech sound perception in chronic developmental stuttering 
Brain and language  2010;115(2):141-147.
High-density ERPs were recorded in eight adults with persistent developmental stuttering (PERS) and eight matched normally fluent (CONT) control volunteers while participants either repeatedly uttered the vowel ‘ah’ or listened to their own previously recorded vocalizations.
The frontocentral N1 auditory wave was reduced in response to spoken vowels relative to heard vowels (auditory-vocal gating), but no difference in the extent of such modulation was found in the PERS group. Abnormalities in the PERS group were restricted to the LISTEN condition, in the form of early N1 and late N3 amplitude changes. Voltage of the N1 wave was significantly reduced over right inferior temporo-occipital scalp in the PERS group. A laterality index derived from N1 voltage moderately correlated with the PERS group's assessed pre-experiment stuttering frequency. Source localization with sLORETA (Pascual-Marqui, 2002) revealed that at the peak of the N1 the PERS group displayed significantly greater current density in right primary motor cortex than the CONT group, suggesting abnormal early speech motor activation. Finally, the late N3 wave was reduced in amplitude over inferior temporo-occipital scalp, more so over the right hemisphere. SLORETA revealed that in the time window of the N3 the PERS group showed significantly less current density in right secondary auditory cortex than the CONT group, suggesting abnormal speech sound perception. These results point to a deficit in auditory processing of speech sounds in persistent developmental stuttering, stemming from early increased activation of right rolandic area and late reduced activation in right auditory cortex.
PMCID: PMC4334906  PMID: 20810160
chronic developmental stuttering; ERPs; speech perception; primary motor cortex; cortex; sLORETA; auditory-vocal gating
2.  Evidence for specificity of ERP abnormalities during response inhibition in ADHD children: A comparison with Reading Disorder children without ADHD 
Brain and cognition  2009;72(2):228-237.
Executive function and working memory deficits are not only present in ADHD, but also in Reading Disorder (RD). Here, high-density ERPs were recorded during the Stop Signal Task in 53 children and adolescents: An ADHD-combined type group, a group with RD, and a healthy control group. The ADHD-C group displayed unique abnormalities of the frontal N200. Both healthy controls and RD groups showed a success-related right frontal N200 modulation, which was absent in the ADHD group. Second, for Success Inhibition trials, the ADHD-C had smaller right frontal N200 waves relative to healthy controls, while the RD group didn't. In contrast, NoGo-P3 abnormalities were present both in the ADHD-C and RD groups. Impaired early response inhibition mechanisms, indexed by the frontal N200, appear to be limited to ADHD-C. In contrast, deficits in later cognitive control and error monitoring mechanisms, indexed by the NoGo-P3, appear to be present in both conditions.
PMCID: PMC4321824  PMID: 19850394
ADHD; Reading Disorder; Event-Related Potentials; Stop Signal Task; Inhibitory Control; N200; NoGo-P3
3.  TRIP-1 via AKT modulation drives lung fibroblast/myofibroblast trans-differentiation 
Respiratory Research  2014;15(1):19.
Myofibroblasts are the critical effector cells in the pathogenesis of pulmonary fibrosis which carries a high degree of morbidity and mortality. We have previously identified Type II TGFβ receptor interacting protein 1 (TRIP-1), through proteomic analysis, as a key regulator of collagen contraction in primary human lung fibroblasts—a functional characteristic of myofibroblasts, and the last, but critical step in the process of fibrosis. However, whether or not TRIP-1 modulates fibroblast trans-differentiation to myofibroblasts is not known.
TRIP-1 expression was altered in primary human lung fibroblasts by siRNA and plasmid transfection. Transfected fibroblasts were then analyzed for myofibroblast features and function such as α-SMA expression, collagen contraction ability, and resistance to apoptosis.
The down-regulation of TRIP-1 expression in primary human lung fibroblasts induces α-SMA expression and enhances resistance to apoptosis and collagen contraction ability. In contrast, TRIP-1 over-expression inhibits α-SMA expression. Remarkably, the effects of the loss of TRIP-1 are not abrogated by blockage of TGFβ ligand activation of the Smad3 pathway or by Smad3 knockdown. Rather, a TRIP-1 mediated enhancement of AKT phosphorylation is the implicated pathway. In TRIP-1 knockdown fibroblasts, AKT inhibition prevents α-SMA induction, and transfection with a constitutively active AKT construct drives collagen contraction and decreases apoptosis.
TRIP-1 regulates fibroblast acquisition of phenotype and function associated with myofibroblasts. The importance of this finding is it suggests TRIP-1 expression could be a potential target in therapeutic strategy aimed against pathological fibrosis.
PMCID: PMC3946032  PMID: 24528651
Type II TGFβ receptor interacting protein 1 (TRIP-1); Eukaryotic translation initiation factor-3 (eIF3); Pulmonary fibroblasts; α-smooth muscle actin (α-SMA); Fibrosis
4.  Functional Mimicry of the Acetylated C-Terminal Tail of p53 by a SUMO-1 Acetylated Domain, SAD 
Journal of cellular physiology  2010;225(2):371-384.
The ubiquitin-like molecule, SUMO-1, a small protein essential for a variety of biological processes, is covalently conjugated to many intracellular proteins, especially to regulatory components of the transcriptional machinery, such as histones and transcription factors. Sumoylation provides either a stimulatory or an inhibitory signal for proliferation and for transcription, but the molecular mechanisms by which SUMO-1 achieves such versatility of effects are incompletely defined. The tumor suppressor and transcription regulator p53 is a relevant SUMO-1 target. Particularly, the C-terminal tail of p53 undergoes both sumoylation and acetylation. While the effects of sumoylation are still controversial, acetylation modifies p53 interaction with chromatin embedded promoters, and enforces p53 apoptotic activity. In this study, we show that the N-terminal region of SUMO-1 might functionally mimic this activity of the p53 C-terminal tail. We found that this SUMO-1 domain possesses similarity with the C-terminal acetylable p53 tail as well as with acetylable domains of other transcription factors. SUMO-1 is, indeed, acetylated when conjugated to its substrates and to p53. In the acetylable form SUMO-1 tunes the p53 response by modifying p53 transcriptional program, by promoting binding onto selected promoters and by favoring apoptosis. By contrast, when non-acetylable, SUMO-1 enforces cell-cycle arrest and p53 binding to a different sets of genes. These data demonstrate for the first time that SUMO-1, a post-translational modification is, in turn, modified by acetylation. Further, they imply that the pleiotropy of effects by which SUMO-1 influences various cellular outcomes and the activity of p53 depends upon its acetylation state.
PMCID: PMC3614007  PMID: 20458745
5.  Restoration of DNA-Binding and Growth-Suppressive Activity of Mutant Forms of p53 Via a PCAF-Mediated Acetylation Pathway 
Journal of cellular physiology  2010;225(2):394-405.
Tumor-derived mutant forms of p53 compromise its DNA binding, transcriptional, and growth regulatory activity in a manner that is dependent upon the cell-type and the type of mutation. Given the high frequency of p53 mutations in human tumors, reactivation of the p53 pathway has been widely proposed as beneficial for cancer therapy. In support of this possibility p53 mutants possess a certain degree of conformational flexibility that allows for re-induction of function by a number of structurally different artificial compounds or by short peptides. This raises the question of whether physiological pathways for p53 mutant reactivation also exist and can be exploited therapeutically. The activity of wild-type p53 is modulated by various acetyl-transferases and deacetylases, but whether acetylation influences signaling by p53 mutant is still unknown. Here, we show that the PCAF acetyl-transferase is down-regulated in tumors harboring p53 mutants, where its re-expression leads to p53 acetylation and to cell death. Furthermore, acetylation restores the DNA-binding ability of p53 mutants in vitro and expression of PCAF, or treatment with deacetylase inhibitors, promotes their binding to p53-regulated promoters and transcriptional activity in vivo. These data suggest that PCAF-mediated acetylation rescues activity of at least a set of p53 mutations. Therefore, we propose that dis-regulation of PCAF activity is a pre-requisite for p53 mutant loss of function and for the oncogenic potential acquired by neoplastic cells expressing these proteins. Our findings offer a new rationale for therapeutic targeting of PCAF activity in tumors harboring oncogenic versions of p53.
PMCID: PMC3614009  PMID: 20589832
6.  Two 4N Cell-Cycle Arrests Contribute to Cisplatin-Resistance 
PLoS ONE  2013;8(4):e59848.
Cisplatin is a platinum-based drug that is used for the treatment of a wide-variety of primary human cancers. However, the therapeutic efficacy of cisplatin is often limited by intrinsic or acquired drug resistance. An important goal, therefore, is to identify mechanisms that lead to cisplatin resistance in cancer, and then use this information to more effectively target resistant cells. Cisplatin-resistant clones of the HCT116 cell line underwent a prolonged G2 arrest after cisplatin treatment while sensitive clones did not. The staurosporine analog UCN-01 abrogated this G2 arrest and sensitized the resistant clones to cisplatin. At later time points, 4N arrested cells assumed a tetraploid G1 state that was characterized by depletion of Cyclin A, Cyclin B, and CDC2, and increased expression of p53 and p21, in 4N cells. siRNA-mediated knockdown of p21 abrogated the tetraploid G1 arrest and induced killing that was dependent on p53. The results identify two targetable 4N arrests that can contribute to cisplatin resistance: First, a prolonged G2 arrest that can be targeted by UCN-01, and second, a tetraploid G1 arrest that can be targeted by siRNA against p21.
PMCID: PMC3613405  PMID: 23560058
7.  186Re-Liposomal Doxorubicin (Doxil): In Vitro Stability, Pharmacokinetics, Imaging and Biodistribution in a Head and Neck Squamous Cell Carcinoma Xenograft Model 
Nuclear medicine and biology  2009;36(5):515-524.
PMCID: PMC2696057  PMID: 19520292
Rhenium-186; Doxil; biodistribution; pharmacokinetics; SPECT/CT; liposome; nanoparticle
8.  The Temporal Dynamics of Implicit Processing of Non-Letter, Letter, and Word-Forms in the Human Visual Cortex 
The decoding of visually presented line segments into letters, and letters into words, is critical to fluent reading abilities. Here we investigate the temporal dynamics of visual orthographic processes, focusing specifically on right hemisphere contributions and interactions between the hemispheres involved in the implicit processing of visually presented words, consonants, false fonts, and symbolic strings. High-density EEG was recorded while participants detected infrequent, simple, perceptual targets (dot strings) embedded amongst a of character strings. Beginning at 130 ms, orthographic and non-orthographic stimuli were distinguished by a sequence of ERP effects over occipital recording sites. These early latency occipital effects were dominated by enhanced right-sided negative-polarity activation for non-orthographic stimuli that peaked at around 180 ms. This right-sided effect was followed by bilateral positive occipital activity for false-fonts, but not symbol strings. Moreover the size of components of this later positive occipital wave was inversely correlated with the right-sided ROcc180 wave, suggesting that subjects who had larger early right-sided activation for non-orthographic stimuli had less need for more extended bilateral (e.g., interhemispheric) processing of those stimuli shortly later. Additional early (130–150 ms) negative-polarity activity over left occipital cortex and longer-latency centrally distributed responses (>300 ms) were present, likely reflecting implicit activation of the previously reported ‘visual-word-form’ area and N400-related responses, respectively. Collectively, these results provide a close look at some relatively unexplored portions of the temporal flow of information processing in the brain related to the implicit processing of potentially linguistic information and provide valuable information about the interactions between hemispheres supporting visual orthographic processing.
PMCID: PMC2796900  PMID: 20046826
word reading; ERPs; visual cortex; visual orthography
9.  The Central American Network for Disaster and Health Information 
Purpose: This paper describes an international outreach program to support rebuilding Central America's health information infrastructure after several natural disasters in the region, including Hurricane Mitch in 1998 and two major earthquakes in 2001.
Setting, Participants, and Description: The National Library of Medicine joined forces with the Pan American Health Organization/World Health Organization, the United Nations International Strategy for Disaster Reduction, and the Regional Center of Disaster Information for Latin America and the Caribbean (CRID) to strengthen libraries and information centers in Central America and improve the availability of and access to health and disaster information in the region by developing the Central American Network for Disaster and Health Information (CANDHI). Through CRID, the program created ten disaster health information centers in medical libraries and disaster-related organizations in six countries.
Results/Outcome: This project served as a catalyst for the modernization of several medical libraries in Central America. The resulting CANDHI provides much needed electronic access to public health “gray literature” on disasters, as well as access to numerous health information resources. CANDHI members assist their institutions and countries in a variety of disaster preparedness activities through collecting and disseminating information.
PMCID: PMC1924936  PMID: 17641767
10.  Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate 
The Journal of Cell Biology  2006;173(4):533-544.
The activity of the p53 gene product is regulated by a plethora of posttranslational modifications. An open question is whether such posttranslational changes act redundantly or dependently upon one another. We show that a functional interference between specific acetylated and phosphorylated residues of p53 influences cell fate. Acetylation of lysine 320 (K320) prevents phosphorylation of crucial serines in the NH2-terminal region of p53; only allows activation of genes containing high-affinity p53 binding sites, such as p21/WAF; and promotes cell survival after DNA damage. In contrast, acetylation of K373 leads to hyperphosphorylation of p53 NH2-terminal residues and enhances the interaction with promoters for which p53 possesses low DNA binding affinity, such as those contained in proapoptotic genes, leading to cell death. Further, acetylation of each of these two lysine clusters differentially regulates the interaction of p53 with coactivators and corepressors and produces distinct gene-expression profiles. By analogy with the “histone code” hypothesis, we propose that the multiple biological activities of p53 are orchestrated and deciphered by different “p53 cassettes,” each containing combination patterns of posttranslational modifications and protein–protein interactions.
PMCID: PMC2063863  PMID: 16717128

Results 1-10 (10)