bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a novel blocker of IκBα kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-κB
Authors: Sung Bokyung , Pandey Manoj K. , Nakajima Yuki , Nishida Hiroshi , Konishi Tetsuya , Chaturvedi Madan M. , Aggarwal Bharat B.
Published: January 2008

3,4-Dihydroxybenzalacetone (DBL) is a polyphenol derived from the medicinal plant Chaga [Inonotus obliquus (persoon) Pilat]. Although Chaga is used in Russia folk medicine to treat tumors, very little is known about its mechanism of action. Because most genes involved in inflammation, antiapoptosis, and cell proliferation are regulated by the transcription factor nuclear factor-κB (NF-κB), we postulated that DBL activity is mediated via modulation of the NF-κB activation pathway. We investigated the effects of DBL on NF-κB activation by electrophoretic mobility shift assay and on NF-κB-regulated gene expression by Western blot analysis. We found that DBL suppressed NF-κB activation by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1β, epidermal growth factor, okadaic acid, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific and inhibited both inducible and constitutive NF-κB activation. DBL did not interfere with the binding of NF-κB to DNA but rather inhibited IκBα kinase activity, IκBα phosphorylation and degradation, p65 phosphorylation, and translocation. DBL also suppressed the expression of TNF-induced and NF-κB-regulated proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of TNF-induced apoptosis and suppression of TNF-induced invasion. Together, our results indicate that DBL inhibits NF-κB activation and NF-κB-regulated gene expression, which may explain the ability of DBL to enhance apoptosis and inhibit invasion. [Mol Cancer Ther 2008;7(1):191–201]
Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α
Authors: Koh Mei Y. , Spivak-Kroizman Taly , Venturini Sara , Welsh Sarah , Williams Ryan R. , Kirkpatrick D. Lynn , Powis Garth
Published: January 2008

We have reported previously that PX-478 (S-2-amino-3-[4′-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1α (HIF-1α) within the tumor. We now report that PX-478 inhibits HIF-1α protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1α inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1α mRNA and inhibits translation as determined by 35S labeling experiments and reporter assays using the 5′ untranslated region of HIF-1α. Moreover, to a lesser extent, PX-478 also inhibits HIF-1α deubiquitination resulting in increased levels of polyubiquitinated HIF-1α. The inhibitory effect of PX-478 on HIF-1α levels is primarily due to its inhibition of translation because HIF-1α translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1α at multiple levels that together or individually may contribute to its antitumor activity against HIF-1α-expressing tumors. [Mol Cancer Ther 2008;7(1):90–100]
Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth
Authors: Clem Brian , Telang Sucheta , Clem Amy , Yalcin Abdullah , Meier Jason , Simmons Alan , Rasku Mary Ann , Arumugam Sengodagounder , Dean William L. , Eaton John , Lane Andrew , Trent John O. , Chesney Jason
Published: January 2008

6-Phosphofructo-1-kinase, a rate-limiting enzyme of glycolysis, is activated in neoplastic cells by fructose-2,6-bisphosphate (Fru-2,6-BP), a product of four 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isozymes (PFKFB1-4). The inducible PFKFB3 isozyme is constitutively expressed by neoplastic cells and required for the high glycolytic rate and anchorage-independent growth of ras-transformed cells. We report herein the computational identification of a small-molecule inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), which suppresses glycolytic flux and is cytostatic to neoplastic cells. 3PO inhibits recombinant PFKFB3 activity, suppresses glucose uptake, and decreases the intracellular concentration of Fru-2,6-BP, lactate, ATP, NAD+, and NADH. 3PO markedly attenuates the proliferation of several human malignant hematopoietic and adenocarcinoma cell lines (IC50, 1.4-24 μmol/L) and is selectively cytostatic to ras-transformed human bronchial epithelial cells relative to normal human bronchial epithelial cells. The PFKFB3 enzyme is an essential molecular target of 3PO because transformed cells are rendered resistant to 3PO by ectopic expression of PFKFB3 and sensitive to 3PO by heterozygotic genomic deletion of PFKFB3. Importantly, i.p. administration of 3PO (0.07 mg/g) to tumor-bearing mice markedly reduces the intracellular concentration of Fru-2,6-BP, glucose uptake, and growth of established tumors in vivo. Taken together, these data support the clinical development of 3PO and other PFKFB3 inhibitors as chemotherapeutic agents. [Mol Cancer Ther 2008;7(1):110–20]
A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells
Authors: Zhang Tao , Hamza Adel , Cao Xianhua , Wang Bing , Yu Shuwen , Zhan Chang-Guo , Sun Duxin
Published: January 2008

Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu33 (Hsp90) and Arg167 (Cdc37). Immunoprecipitation confirmed that celastrol (10 μmol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 μmol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 μmol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells. [Mol Cancer Ther 2008;7(1):162–70]
2-[(1-Methylpropyl)dithio]-1H-imidazole inhibits tubulin polymerization through cysteine oxidation
Authors: Huber Kelly , Patel Poulam , Zhang Lei , Evans Helen , Westwell Andrew D. , Fischer Peter M. , Chan Stephen , Martin Stewart
Published: January 2008

2-[(1-Methylpropyl)dithio]-1H-imidazole (IV-2) is a known inhibitor of the thioredoxin system. It causes the oxidation of cysteine residues from both thioredoxin reductase and thioredoxin, with only the latter leading to irreversible inhibition of protein function. Although IV-2 is considered to be the first specific inhibitor of thioredoxin to undergo evaluation in cancer patients (under the name PX-12), it is unclear whether the oxidative ability of IV-2 is limited to proteins of the thioredoxin family. The current study investigated the specificity of IV-2 by examining its interaction with tubulin, a protein in which cysteine oxidation causes loss of polymerization competence. The cellular effects of IV-2 were examined in MCF-7 breast cancer and endothelial cells (human umbilical vein endothelial cells). Immunocytochemistry revealed a loss of microtubule structure with Western blot analysis confirming that treated cells contained a higher proportion of unpolymerized tubulin. Cell-free tubulin polymerization assays showed a dose-dependent inhibition of tubulin polymerization and depolymerization of preformed microtubules, confirming a direct interaction between IV-2 and tubulin. Further investigation of the tubulin interaction, through analysis of sulfhydryl reactivity and disulfide bond formation, suggested that IV-2 acts through the oxidation of cysteines in tubulin. Biochemical assays indicated that the oxidative properties of IV-2 are not limited to thioredoxin and tubulin, as cysteine-dependent proteases were also inhibited. Breast cancer cells with thioredoxin silenced by short interfering RNA remained sensitive to IV-2, albeit at higher antiproliferative GI50 values than in cells with normal thioredoxin function. These findings show that modulation of targets other than thioredoxin contribute to the effects of IV-2 on proliferating cells. [Mol Cancer Ther 2008;7(1):143–51]
β-Ionone inhibits colonic aberrant crypt foci formation in rats, suppresses cell growth, and induces retinoid X receptor-α in human colon cancer cells
Authors: Janakiram Naveena B. , Cooma Indranie , Mohammed Altaf , Steele Vernon E. , Rao Chinthalapally V.
Published: January 2008

β-Ionone, an end-ring analogue of β-carotenoid, which is a constituent of vegetables and fruits, has been analyzed for colon cancer chemoprevention and treatment. β-Ionone induced cell growth inhibition and apoptosis in human colon cancer HCT116 cell line. We tested the in vivo chemopreventive efficacy in rat colon carcinogenesis model using aberrant crypt foci (ACF) as endpoint marker. HCT116 cells treated with subtoxic concentrations of β-ionone resulted dose-dependent cell growth suppression with G1-S-phase growth arrest and significant induction of apoptosis. β-Ionone up-regulated expression of retinoid X receptor-α mRNA dose-dependently in HCT116 cells. To evaluate inhibitory properties of β-ionone on colonic ACF, 7-week-old male F344 rats were fed experimental diets containing 0%, 0.1%, or 0.2% β-ionone. After 1 week, rats received s.c. injections of azoxymethane, 15 mg/kg body weight, once weekly for 2 weeks. Rats were continued on respective experimental diets and sacrificed 8 weeks after the azoxymethane treatment. Colons were evaluated histopathologically for ACF. Administration of dietary 0.1% and 0.2% β-ionone significantly suppressed total colonic ACF formation up to 34% to 38% (P < 0.0002 to P < 0.0009), respectively, when compared with control group. Importantly, rats fed β-ionone showed >55% inhibition (P < 0.0001) of foci containing four or more aberrant crypts. Results from in vitro and in vivo bioassay clearly suggest that β-ionone could be further developed for prevention and treatment of colon cancer. [Mol Cancer Ther 2008;7(1):181–90]
Synergistic effect of a novel antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro
Authors: Schayowitz Adam , Sabnis Gauri , Njar Vincent C.O. , Brodie Angela M.H.
Published: January 2008

This study was carried out to determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer. We investigated the role of the androgen receptor and its relationship to other signal transduction proteins. A hormone-refractory prostate cancer cell line [high-passage LNCaP (HP-LNCaP)] was established in vitro. Cells were treated with inhibitors of mammalian target of rapamycin and tyrosine kinase receptors. Expression of these proteins and the androgen receptor were measured by Western immunoblotting. Analysis of the model and various treatments was also assessed through proliferation assays, luciferase activation assays, binding assays, and ELISA. Our novel antiandrogen, VN/124-1, effectively inhibited proliferation of hormone-resistant prostate cancer cell lines (HP-LNCaP), which were no longer sensitive to bicalutamide and had increased expression of the androgen receptor. Treatment with everolimus or gefitinib resulted in an increase in protein expression and activation of the androgen receptor. Conversely, inhibition of the androgen receptor resulted in increased expression of IGFR1β, pHER2, pmTOR, and pAkt. The addition of bicalutamide to everolimus or gefitinib inhibited cell proliferation in HP-LNCaP cells. However, the addition of VN/124-1 has proven to be superior to bicalutamide, and the combination was synergistic (P < 0.05) compared with either agent alone. This study suggests that compensatory cross-talk between the androgen receptor and various signaling pathways may account for decreased sensitivity to androgen receptor antagonists and the progression to hormone-resistant prostate cancer. Furthermore, these findings suggest that inhibition of both pathways may provide effective control in hormone-resistant prostate cancer and restore sensitivity to androgen antagonists in hormone-refractory patients. [Mol Cancer Ther 2008;7(1):121–32]
Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib
Authors: Ma Jie , Waxman David J.
Published: January 2008

The promising but still limited efficacy of angiogenesis inhibitors as monotherapies for cancer treatment indicates a need to integrate these agents into existing therapeutic regimens. Presently, we investigate the antitumor activity of the small-molecule angiogenesis inhibitor axitinib (AG-013736) and its potential for combination with metronomic cyclophosphamide. Axitinib significantly inhibited angiogenesis in rat 9L tumors grown s.c. in scid mice but only moderately delayed tumor growth. Combination of axitinib with metronomic cyclophosphamide fully blocked 9L tumor growth on initiation of drug treatment. In contrast, metronomic cyclophosphamide alone required multiple treatment cycles to halt tumor growth. However, in contrast to the substantial tumor regression that is ultimately induced by metronomic cyclophosphamide, the axitinib/cyclophosphamide combination was tumor growth static. Axitinib did not inhibit hepatic activation of cyclophosphamide or export of its activated metabolite, 4-hydroxy-cyclophosphamide (4-OH-CPA), to extrahepatic tissues; rather, axitinib selectively decreased 9L tumor uptake of 4-OH-CPA by 30% to 40%. The reduced tumor penetration of 4-OH-CPA was associated with a decrease in cyclophosphamide-induced tumor cell apoptosis and a block in the induction of the endogenous angiogenesis inhibitor thrombospondin-1 in tumor-associated host cells, which may contribute to the absence of tumor regression with the axitinib/cyclophosphamide combination. Finally, axitinib transiently increased 9L tumor cell apoptosis, indicating that its effects are not limited to the endothelial cell population. These findings highlight the multiple effects that may characterize antiangiogenic agent/metronomic chemotherapy combinations and suggest that careful optimization of drug scheduling and dosages will be required to maximize antitumor responses. [Mol Cancer Ther 2008;7(1):79–89]
Increased Response-time Variability is Associated with Reduced Inferior Parietal Activation during Episodic Recognition in Aging
Authors: MacDonald Stuart W. S. , Nyberg Lars , Sandblom Johan , Fischer Håkan , Bäckman Lars
Published: January 2008

Intraindividual variability (IIV) in cognitive performance shares systematic associations with aging-related processes, brain injury, and neurodegenerative pathology. However, little research has examined the neural underpinnings of IIV, with no studies investigating brain correlates of IIV in relation to retrieval success. Using functional magnetic resonance imaging, we examined links between IIV, recognition memory performance, and blood oxygenation level dependent activations. Nineteen older adults (70–79 years) were presented with 80 words at encoding, with brain scans and response latencies obtained during subsequent recognition. An index of IIV, the intraindividual standard deviation (ISD), was computed across successful latency trials. Decreasing ISDs were systematically associated with better recognition, faster latencies, and increased activation in the inferior parietal cortex (BA 40). Demonstrated links between less behavioral variability and parietal activations are consistent with the known importance of the parietal cortex for retrieval success. In support of extant findings and theory from neuroscience, neuropsychology, and cognitive aging, the present results suggest that behavioral IIV represents a proxy for neural integrity.
Differential Modulation of Word Recognition by Semantic and Spatial Orienting of Attention
Authors: Cristescu Tamara C. , Nobre Anna Christina
Published: January 2008

In the present study, we investigated the ability to orient attention to abstract associative features of complex stimuli, more specifically, to the semantic categories of visual word stimuli. We compared the behavioral and electrophysiological effects of semantic orienting with those elicited by spatial orienting to word stimuli. Two parallel, cued lexical-decision tasks, with semantic- or spatial-orienting cues, were used. Results showed that both semantic and spatial orienting facilitated behavioral performance. The event-related potential analysis revealed different and non-overlapping patterns of modulation of word processing by semantic and spatial orienting. Modulation by semantic orienting started later, affecting only the potentials linked to conceptual or semantic processing (N300 and N400). The pattern of N300/N400 modulation in the semantic-orienting condition was similar to that observed in semantic-priming tasks, and was compatible with the operation of controlled semantic processes. Spatial orienting significantly enhanced the amplitude of the early visual potential P1 as well as the language-related N400 potential. These findings showed that the similar end-result of behavioral facilitation by semantic and spatial orienting is achieved through largely distinct mechanisms acting upon separate levels of stimulus analysis.
Learning through Hand- or Typewriting Influences Visual Recognition of New Graphic Shapes: Behavioral and Functional Imaging Evidence
Authors: Longcamp Marieke , Boucard Céline , Gilhodes Jean-Claude , Anton Jean-Luc , Roth Muriel , Nazarian Bruno , Velay Jean-Luc
Published: January 2008

Fast and accurate visual recognition of single characters is crucial for efficient reading. We explored the possible contribution of writing memory to character recognition processes. We evaluated the ability of adults to discriminate new characters from their mirror images after being taught how to produce the characters either by traditional pen-and-paper writing or with a computer keyboard. After training, we found stronger and longer lasting (several weeks) facilitation in recognizing the orientation of characters that had been written by hand compared to those typed. Functional magnetic resonance imaging recordings indicated that the response mode during learning is associated with distinct pathways during recognition of graphic shapes. Greater activity related to handwriting learning and normal letter identification was observed in several brain regions known to be involved in the execution, imagery, and observation of actions, in particular, the left Broca's area and bilateral inferior parietal lobules. Taken together, these results provide strong arguments in favor of the view that the specific movements memorized when learning how to write participate in the visual recognition of graphic shapes and letters.
Evidence for Anticipatory Motor Control within a Cerebello-Diencephalic-Parietal Network
Authors: Pollok Bettina , Gross Joachim , Kamp Daniel , Schnitzler Alfons
Published: January 2008

The posterior parietal cortex and the cerebellum are assumed to contribute to anticipatory motor control. Thus, it is reasonable that these areas act as a functional unit. To identify a neural signature of anticipatory motor control, 11 healthy volunteers performed a bimanual finger-tapping task with respect to isochronous (i.e., regular) and randomized (i.e., irregular) auditory pacing. Neuromagnetic activity was recorded using a 122-channel whole-head neuromagnetometer. Functional interaction between spatially distributed brain areas was determined by measures of tap-related phase synchronization. Assuming that (i) the cerebellum predicts sensory events by an internal model and (ii) the PPC maintains this prediction, we hypothesized that functional interaction between both structures varies depending on the predictability of the pacing signal. During isochronous pacing, functional connectivity within a cerebello-diencephalic-parietal network before tap onset was evident, suggesting anticipatory motor control. During randomized pacing, however, functional connectivity after tap onset was increased within a parietal-cerebellar loop, suggesting mismatch detection and update of the internal model. Data of the present study imply that anticipatory motor control is implemented in a network-like manner. Our data agree well with the hypothesis that functional connectivity in a cerebello-diencephalic-parietal loop might be crucial for anticipatory motor control, whereas parietal-cerebellar interaction might be critical for feedback processing.
Refreshing One of Several Active Representations: Behavioral and Functional Magnetic Resonance Imaging Differences between Young and Older Adults
Authors: Raye Carol L. , Mitchell Karen J. , Reeder John A. , Greene Erich J. , Johnson Marcia K.
Published: January 2008

We explored age-related differences in executive function during selection of a target from among active representations. Refreshing (thinking briefly of a just-activated representation) is an executive process that foregrounds a target relative to other active representations. In a behavioral study, participants saw one or three words, then saw a cue to refresh one of the words, saw one word again and read it, or read a new word. Increasing the number of active representations increased response times (RTs) only in the refresh condition for young adults but increased RTs equally in all conditions for older adults, suggesting that they experienced interference from activated irrelevant information during perception and reflection. Consistent with this interpretation, in a functional magnetic resonance imaging study, young adults showed two areas of the left dorsolateral frontal cortex and a medial area of frontal cortex, including anterior cingulate, that were relatively more sensitive to number of active representations during refresh than read trials; for older adults these areas were equally sensitive to number of active items for refresh and read trials. Young and older adults showed activity associated with refreshing on trials requiring selection in left mid-ventral frontal cortex (an area associated with selection from active representations); older adults also showed activity in left anterior ventral frontal cortex (an area associated with controlled semantic activation). Our results support the hypothesis of an age-related decrease in ability to gate out activated but currently irrelevant information, and are consistent with a dissociation of function between eft mid-ventral and left anterior ventral frontal cortex.
Brain Responses to Biological Relevance
Authors: Tipper Christine M. , Handy Todd C. , Giesbrecht Barry , Kingstone Alan
Published: January 2008

This study examines whether orienting attention to biologically based social cues engages neural mechanisms distinct from those engaged by orienting to nonbiologically based nonsocial cues. Participants viewed a perceptually ambiguous stimulus presented centrally while performing a target detection task. By having participants alternate between viewing this stimulus as an eye in profile or an arrowhead, we were able to directly compare the neural mechanisms of attentional orienting to social and nonsocial cues while holding the physical stimulus constant. The functional magnetic resonance imaging results indicated that attentional orienting to both eye gaze and arrow cues engaged extensive dorsal and ventral fronto-parietal networks. Eye gaze cues, however, more vigorously engaged two regions in the ventral frontal cortex associated with attentional reorienting to salient or meaningful stimuli, as well as lateral occipital regions. An event-related potential study demonstrated that this enhanced occipital response was attributable to a higher-amplitude sensory gain effect for targets appearing at locations cued by eye gaze than for those cued by an arrowhead. These results endorse the hypothesis that differences in attention to social and nonsocial cues are quantitative rather than qualitative, running counter to current models that assume enhanced processing for social stimuli reflects the involvement of a unique network of brain regions. An intriguing implication of the present study is the possibility that our ability to orient volitionally and reflexively to socially irrelevant stimuli, including arrowheads, may have arisen as a useful by-product of a system that developed first, and foremost, to promote social orienting to stimuli that are biologically relevant.
The Role of Pause Cues in Language Learning: The Emergence of Event-related Potentials Related to Sequence Processing
Authors: Mueller Jutta L. , Bahlmann Joerg , Friederici Angela D.
Published: January 2008

Humans can derive sequential dependencies from unfamiliar artificial speech within several of minutes of exposure. However, there is an ongoing debate about the nature of the underlying learning processes. In a widely discussed study Peña et al. [Peña, M., Bonatti, L. L., Nespor, M., & Mehler, J. Signal-driven computations in speech processing. Science, 298, 604–607, 2002] argued for the importance of subtle acoustic cues in the signal, such as pauses, in order to switch between two computational mechanisms, which are conceptualized as rule-based versus statistical. The present study was aimed to approach this problem by recording event-related potentials in response to correct and incorrect phrases consisting of bisyllabics after short exposure to either rule-based or random artificial speech streams. Rule-based streams contained dependencies of the form AXC, whereby A elements reliably predicted the C elements and X elements were variable. Participants were exposed to four input and test phases. Two of the input streams were rule-based and contained either only probabilistic information related to the distribution of the AXC stimuli or an additional acoustic cue indicating the boundaries of relevant units. The other two streams were random variations of the rule-based streams. During the test phase in the condition with pause cues, an early negativity and a later positivity emerged for correct and incorrect items in comparison to their acoustically identical counterparts, which were presented after the random control condition. In the noncued condition, only negativities were seen. The timing and the scalp distribution of the negativities were different for correct and incorrect sequences in both the cued and the noncued conditions. The results are interpreted in support of a view of grammatical learning in which both distributional and acoustic cues may contribute to different aspects of syntactic learning.
Brain Error–monitoring Activity is Affected by Semantic Relatedness: An Event-related Brain Potentials Study
Authors: Ganushchak Lesya Y. , Schiller Niels O.
Published: January 2008

Speakers continuously monitor what they say. Sometimes, self-monitoring malfunctions and errors pass undetected and uncorrected. In the field of action monitoring, an event-related brain potential, the error-related negativity (ERN), is associated with error processing. The present study relates the ERN to verbal self-monitoring and investigates how the ERN is affected by auditory distractors during verbal monitoring. We found that the ERN was largest following errors that occurred after semantically related distractors had been presented, as compared to semantically unrelated ones. This result demonstrates that the ERN is sensitive not only to response conflict resulting from the incompatibility of motor responses but also to more abstract lexical retrieval conflict resulting from activation of multiple lexical entries. This, in turn, suggests that the functioning of the verbal self-monitoring system during speaking is comparable to other performance monitoring, such as action monitoring.
The Application of Biosignal Feedback for Reducing Cybersickness from Exposure to a Virtual Environment
Authors: Kim Young Youn , Kim Eun Nam , Park Min Jae , Park Kwang Suk , Ko Hee Dong , Kim Hyun Taek
Published: January 2008

We examined the efficacy of a new method to reduce cybersickness. A real-time cybersickness detection system was constructed with an artificial neural network whose inputs were the electrophysiological signals of subjects in a virtual environment. The system was equipped with a means of feedback; it temporarily provided a narrow field of view and a message about navigation speed deceleration, both of which acted as feedback outputs whenever electrophysiological inputs signaled the occurrence of cybersickness. This system is named cybersickness relief virtual environment (CRVE). Forty-seven subjects experienced the VR for 9.5 min twice in CRVE and non-CRVE conditions. The results indicated that the frequency of cybersickness and simulator sickness questionnaire scores were lower in the CRVE condition than in the non-CRVE condition. Subjects also showed a higher net increase in tachyarrhythmia from the baseline period to the virtual navigation period in the CRVE condition compared to the non-CRVE condition. These results suggest that a CRVE condition may be a countermeasure against cybersickness.
MKM: A Global Framework for Animating Humans in Virtual Reality Applications
Authors: Multon Franck , Kulpa Richard , Bideau Benoit
Published: January 2008

Virtual humans are more and more used in VR applications, but their animation is still a challenge, especially if complex tasks must be carried out in interaction with the user. In many applications with virtual humans, credible virtual characters play a major role in presence. Motion editing techniques assume that the natural laws are intrinsically encoded in prerecorded trajectories and that modifications may preserve these natural laws, leading to credible autonomous actors. However, a complete knowledge of all the constraints is required to ensure continuity or to synchronize and blend several actions necessary to achieve a given task. We propose a framework capable of performing these tasks in an interactive environment that can change at each frame, depending on the user’s orders. This framework enables VR applications to animate from dozens of characters in real time for complex constraints, to hundreds of characters if only ground adaptation is performed. It offers the following capabilities: motion synchronization, blending, retargeting, and adaptation thanks to enhanced inverse kinetics and kinematics solver. To evaluate this framework, we have compared the motor behavior of subjects in real and in virtual environments.
Use of Simulated Thermal Cues for Material Discrimination and Identification with a Multi-Fingered Display
Authors: Yang Gi-Hun , Jones Lynette A. , Kwon Dong-Soo
Published: January 2008

Thermal cues provide information about the thermal properties of an object held in the hand. These cues can be simulated in a thermal display and used to assist in identifying the object. Two experiments were conducted using a thermal display that simulated the cues associated with contact with different materials. The thermal contact model was based on a semi-infinite body model that included thermal contact resistance and blood perfusion. Its performance was evaluated in two experiments, the first of which involved discriminating between simulated materials, and in the second, subjects were required to identify simulated materials based on the thermal cues presented to one, three, or five fingers. The results from the first experiment indicated that when the temperature profile associated with contact with a real material is presented to the finger, subjects can use this cue to discriminate between simulated materials. Their performance on this task is comparable to that achieved with real materials with similar thermal properties. In the second experiment, the accuracy with which subjects identified a simulated material based on thermal cues improved as the number of fingers stimulated increased, suggesting that spatial summation of cold occurs when the area stimulated is noncontiguous. However, most of the improvement in identifying materials occurred when the display presented thermal cues to three as compared to one finger, with little further enhancement in performance when five fingers were stimulated. These results indicate that thermal displays can be used effectively to present information about the material composition of objects in virtual environments.
A New Haptic Interaction and Visualization Approach for Rigid Molecular Docking in Virtual Environments
Authors: Subasi Erk , Basdogan Cagatay
Published: January 2008

Many biological activities take place through the physicochemical interaction of two molecules. This interaction occurs when one of the molecules finds a suitable location on the surface of the other for binding. This process is known as molecular docking, and it has applications to drug design. If we can determine which drug molecule binds to a particular protein, and how the protein interacts with the bonded molecule, we can possibly enhance or inhibit its activities. This information, in turn, can be used to develop new drugs that are more effective against diseases. In this paper, we propose a new approach based on a human-computer interaction paradigm for the solution of the rigid body molecular docking problem. In our approach, a rigid ligand molecule (i.e., drug) manipulated by the user is inserted into the cavities of a rigid protein molecule to search for the binding cavity, while the molecular interaction forces are conveyed to the user via a haptic device for guidance. We developed a new visualization concept, Active Haptic Workspace (AHW), for the efficient exploration of the large protein surface in high resolution using a haptic device having a small workspace. After the discovery of the true binding site and the rough alignment of the ligand molecule inside the cavity by the user, its final configuration is calculated off-line through time stepping molecular dynamics (MD) simulations. At each time step, the optimum rigid body transformations of the ligand molecule are calculated using a new approach, which minimizes the distance error between the previous rigid body coordinates of its atoms and their new coordinates calculated by the MD simulations. The simulations are continued until the ligand molecule arrives at the lowest energy configuration. Our experimental studies conducted with six human subjects testing six different molecular complexes demonstrate that given a ligand molecule and five potential binding sites on a protein surface, the subjects can successfully identify the true binding site using visual and haptic cues. Moreover, they can roughly align the ligand molecule inside the binding cavity such that the final configuration of the ligand molecule can be determined via the proposed MD simulations.
Moving Toward Dialogical Collaboration: A Critical Examination of a University— School—Community Partnership
Authors: Miller Peter M. , Hafner Madeline M.
Published: January 2008

Purpose: This study sought to deepen current understandings of collaboration and leadership in the context of partnerships between diverse universities, schools, and communities. Using a critical epistemological perspective, the project specifically attempted to learn more about the processes employed by one particular partnership in the Western United States. To inform this process evaluation, the study's conceptual framework was rooted in tenets of Paulo Freire's (1970) concept of dialogue. Specifically, the study sought to reveal the extent to which the Freirean dialogical tenets of humility, faith, hope, and critical thinking were embodied in this collaborative process.

Research Methods: Qualitative case study.

Data Collection and Analysis: Data were collected through semistructured interviews with 17 participants, 25 observations, and analysis of relevant documents and archival data. After a process of open and axial coding, the findings were deductively analyzed using tenets of Freire's (1970) dialogue.

Findings: The findings suggested that although the partnership's participants appeared to have intentions that were closely aligned with the tenets of dialogue, various factors inhibited the actual process from evolving as one that was comprehensively dialogical. Conclusions: It is asserted that in educational partnerships between diverse individuals and organizations, the onus is on those who occupy traditional leadership positions to ensure that equal participative opportunities are afforded to all interested parties. Several recommendations are offered to facilitate the creation of such collaborative structures.
Diagnosis and Treatment of Reading Disabilities Based on the Component Model of Reading
Authors: Aaron P.G. , Joshi R. Malatesha , Gooden Regina , Bentum Kwesi E.
Published: January 2008

Currently, learning disabilities (LD) are diagnosed on the basis of the discrepancy between students' IQ and reading achievement scores. Students diagnosed with LD often receive remedial instruction in resource rooms. The available evidence suggests that the educational policy based on this discrepancy model has not yielded satisfactory results. This has led researchers to try other paradigms, such as the component model and response to intervention, for dealing with children with reading disabilities. The component model of reading (CMR) described in the present article identifies the reading component that is the source of reading difficulty and targets instruction at that component. Study 1 describes the CMR and reports on its validity. Study 2 describes the successful outcome of a 7-year CMR-based reading instruction program. Compared to the discrepancy model, the CMR has demonstrated several advantages.
Peer Groups, Popularity, and Social Preference
Authors: Estell David B. , Jones Martin H. , Pearl Ruth , Van Acker Richard , Farmer Thomas W. , Rodkin Philip C.
Published: January 2008

The extant literature on the social functioning of students with learning disabilities (LD) has indicated that whereas a majority belong to peer groups, a higher proportion are isolated and most have lower social status among peers in general than their typically achieving classmates. Although some work has examined these issues over short-term longitudinal studies, none to date have examined them over extensive time periods. Toward this end, the current study examined a sample of 1,361 students (678 girls and 683 boys; 55 with LD) using multiple measures of peer social functioning assessed each semester from spring of third grade through fall of sixth grade. The results indicated that whereas students with LD were similar to their typically achieving peers in terms of group functioning and characteristics, they were viewed as lower in social standing among their classmates as a whole. These effects were maintained over time, indicating that long-term inclusion may not substantially affect peer social functioning among students with LD.
Computational Skills, Working Memory, and Conceptual Knowledge in Older Children With Mathematics Learning Disabilities
Authors: Mabbott Donald J. , Bisanz Jeffrey
Published: January 2008

Knowledge and skill in multiplication were investigated for late elementary-grade students with mathematics learning disabilities (MLD), typically achieving age-matched peers, low-achieving age-matched peers, and ability-matched peers by examining multiple measures of computational skill, working memory, and conceptual knowledge. Poor multiplication fact mastery and calculation fluency and general working memory discriminated children with MLD from typically achieving age-matched peers. Furthermore, children with MLD were slower in executing backup procedures than typically achieving age-matched peers. The performance of children with MLD on multiple measures of multiplication skill and knowledge was most similar to that of ability-matched younger children. MLD may be due to difficulties in computational skills and working memory. Implications for the diagnosis and remediation of MLD are discussed.
Learning Strategies and Study Approaches of Postsecondary Students With Dyslexia
Authors: Kirby John R. , Silvestri Robert , Allingham Beth H. , Parrila Rauno , La Fave Chantal B.
Published: January 2008

The present study describes the self-reported learning strategies and study approaches of college and university students with and without dyslexia and examines the relationship of those characteristics with reading ability. Students with ( n = 36) and without ( n = 66) dyslexia completed tests measuring reading rate, reading comprehension, reading history, learning strategies, and learning approaches. The results indicated that students without dyslexia obtained significantly higher scores than students with dyslexia in their reported use of selecting main ideas and test taking strategies. Students with dyslexia reported significantly greater use of study aids and time management strategies in comparison to students without dyslexia. Moreover, university students with dyslexia were significantly more likely to report a deep approach to learning in comparison to university students without dyslexia. Reading ability correlated positively with selecting main ideas and test taking strategies and negatively with use of study aids. The authors interpret the learning strategy results as consequences of and compensations for the difficulties that students with dyslexia have in word reading.
The Varieties of Pathways to Dysfluent Reading
Authors: Katzir Tami , Kim Young-Suk , Wolf Maryanne , Morris Robin , Lovett Maureen W.
Published: January 2008

The majority of work on the double-deficit hypothesis (DDH) of dyslexia has been done at the letter and word levels of reading. Key research questions addressed in this study are (a) do readers with different subtypes of dyslexia display differences in fluency at particular reading levels (e.g., letter, word, and connected text)? and (b) do children with dyslexia identified by either low-achievement or ability—achievement discrepancy criteria show similar differences when classified by the DDH? To address these questions, the authors assessed a sample of 158 children with severe reading impairments in second and third grades on an extensive battery and classified them into three reader subtypes using the DDH. The results demonstrated that the three DDH subtypes exhibited differences in fluency at different levels of reading (letter, word, and connected text), underscoring the separate reading profiles of these subtypes and the different possible routes to dysfluency in reading disabilities. Furthermore, the results suggest that the different patterns among DDH subtypes are primarily driven by the ability—achievement discrepancy group. The implications of these findings are discussed for intervention, reading theory, and a more refined understanding of heterogeneity.
A Comparative Pharmacokinetic Study of Recombinant Human Serum Albumin With Plasma‐derived Human Serum Albumin in Patients With Liver Cirrhosis
Authors: Ohnishi Kunihiko , Kawaguchi Atsuhiro , Nakajima Shunji , Mori Hiroyuki , Ueshima Takahiro
Published: January 2008

We conducted an open‐label, parallel‐group study of the high purity, mass‐produced recombinant human serum albumin (rHSA), derived from the methylotrophic yeast Pichia pastoris, to compare pharmacokinetics and ensure bioequivalence with plasma‐derived human serum albumin (pHSA) in 22 patients with liver cirrhosis. Both rHSA and pHSA groups enrolled 11 patients each, assigned according to predose serum albumin concentrations using the minimization method. Pharmacokinetic and safety profiles for 3‐day repeated intravenous infusions at a daily dose of 25 g were evaluated for 8 days. Geometric mean AUC0–168hr (g·hr/dL) was 637.12 and 635.93 in the rHSA and pHSA groups, respectively, with a 90% confidence interval (CI) for the difference (92.9%‐108.1%) lying within the bioequivalence range. The other major parameter, geometric mean Cmax (g/dL), was 4.16 and 4.19 in the rHSA and pHSA groups, respectively, with a 90% CI for the difference (92.7%‐106.4%). The pHSA group presented with 3 adverse events: 1 case of insomnia, and 2 laboratory abnormalities with no serious adverse events. Results from this study show similar pharmacokinetic profiles following intravenous administration of 25g/day of rHSA and pHSA for 3 days, indicating bioequivalence.
Leveraging Prior Quantitative Knowledge to Guide Drug Development Decisions and Regulatory Science Recommendations: Impact of FDA Pharmacometrics During 2004–2006
Authors: Wang Yaning , Bhattaram A. Venkatesh , Jadhav Pravin R. , Lesko Lawrence J. , Madabushi Rajanikanth , Powell J. Robert , Qiu Wei , Sun He , Yim Dong S. , Zheng Jenny J. , Gobburu Jogarao V. S.
Published: January 2008

The End‐of‐Phase 2A meetings are proposed to identify opportunities to make innovative medical products available sooner and to increase the quality of drug applications through early meetings between sponsors and the FDA. This article summarizes the overall experience across 11 pilot End‐of‐Phase 2A meetings since 2004. Four case studies are presented in more detail to demonstrate the various issues and methods encountered at these meetings. Overall, industry and FDA scientists ranked these meetings to be “very helpful” (average score of 4 on a scale of 1 to 5). In almost all the instances the sponsors changed their drug development plans subsequent to these extensive quantitative analyses‐based meetings. A draft Guidance is being developed to be issued in 2008, and we hope this initiative will be resourced by then.
The Stability of Psychopathy From Adolescence Into Adulthood
Authors: Lynam Donald R. , Loeber Rolf , Stouthamer-Loeber Magda
Published: January 2008

This study examines moderators of the relation between psychopathy assessed at age 13 using the mother-reported Childhood Psychopathy Scale and psychopathy assessed at age 24 using the interviewer-rated Psychopathy Checklist: Screening Version (PCL:SV). Data from more than 250 participants of the middle sample of the Pittsburgh Youth Study were used. Thirteen potential moderators were examined, including demographics (i.e., race, family structure, family socioeconomic status [SES], and neighborhood SES), parenting factors (physical punishment, inconsistent discipline, lax supervision, and positive parenting), peer delinquency, own delinquency, and other individual differences (i.e., verbal IQ, behavioral impulsivity, and cognitive impulsivity). Moderators were examined for the total psychopathy score at age 24 as well as for each of the four PCL:SV facets. After relaxing the criterion for statistical significance, 8 out of a possible 65 interactions were statistically significant. Implications of the present findings and future directions are discussed.