ASU Scholarship Showcase

Modeling of transcriptional regulatory networks (TRNs) has been increasingly used to dissect the nature of gene regulation. Inference of regulatory relationships among transcription factors (TFs) and genes, especially among multiple TFs, is still challenging. In this study, we introduced an integrative method, LogicTRN, to decode TF–TF interactions that form TF logics in regulating target genes. By combining cis-regulatory logics and transcriptional kinetics into one single model framework, LogicTRN can naturally integrate dynamic gene expression data and TF-DNA-binding signals in order to identify the TF logics and to reconstruct the underlying TRNs. We evaluated the newly developed methodology using simulation, comparison and application studies, and the results not only show their consistence with existing knowledge, but also demonstrate its ability to accurately reconstruct TRNs in biological complex systems.

Although audiovisual (AV) training has been shown to improve overall speech perception in hearing-impaired listeners, there has been a lack of direct brain imaging data to help elucidate the neural networks and neural plasticity associated with hearing aid (HA) use and auditory training targeting speechreading. For this purpose, the current clinical case study reports functional magnetic resonance imaging (fMRI) data from two hearing-impaired patients who were first-time HA users. During the study period, both patients used HAs for 8 weeks; only one received a training program named ReadMyQuips[superscxript TM] (RMQ) targeting speechreading during the second half of the study period for 4 weeks. Identical fMRI tests were administered at pre-fitting and at the end of the 8 weeks. Regions of interest (ROI) including auditory cortex and visual cortex for uni-sensory processing, and superior temporal sulcus (STS) for AV integration, were identified for each person through independent functional localizer task. The results showed experience-dependent changes involving ROIs of auditory cortex, STS and functional connectivity between uni-sensory ROIs and STS from pretest to posttest in both cases. These data provide initial evidence for the malleable experience-driven cortical functionality for AV speech perception in elderly hearing-impaired people and call for further studies with a much larger subject sample and systematic control to fill in the knowledge gap to understand brain plasticity associated with auditory rehabilitation in the aging population.

In the visual domain, a stationary object that is difficult to detect usually becomes far more salient if it moves while the objects around it do not. This “pop out” effect is important for parsing the visual world into figure/ground relationships that allow creatures to detect food, threats, etc. We tested for an auditory correlate to this visual effect by asking listeners to identify a single word, spoken by a female, embedded with two or four masking words spoken by males. Percentage correct scores were analyzed and compared between conditions where target and maskers were presented from the same position vs. when the target was presented from one position while maskers were presented from different positions. In some trials, the target word was moved across the speaker array using amplitude panning, while in other trials that target was played from a single, static position. Results showed a spatial release from masking for all conditions where the target and maskers were not located at the same position, but there was no statistically significant difference between identification performance when the target was moving vs. when it was stationary. These results suggest that, at least for short stimulus durations (0.75 s for the stimuli in this experiment), there is unlikely to be a “pop out” effect for moving target stimuli in the auditory domain as there is in the visual domain.

Dexterous manipulation relies on modulation of digit forces as a function of digit placement. However, little is known about the sense of position of the vertical distance between finger pads relative to each other. We quantified subjects' ability to match perceived vertical distance between the thumb and index finger pads (d_y) of the right hand (“reference” hand) using the same or opposite hand (“test” hand) after a 10-second delay without vision of the hands. The reference hand digits were passively placed non-collinearly so that the thumb was higher or lower than the index finger (d_y = 30 or –30 mm, respectively) or collinearly (d_y = 0 mm). Subjects reproduced reference hand d_y by using a congruent or inverse test hand posture while exerting negligible digit forces onto a handle. We hypothesized that matching error (reference hand d_y minus test hand d_y) would be greater (a) for collinear than non-collinear d_ys, (b) when reference and test hand postures were not congruent, and (c) when subjects reproduced dy using the opposite hand. Our results confirmed our hypotheses. Under-estimation errors were produced when the postures of reference and test hand were not congruent, and when test hand was the opposite hand. These findings indicate that perceived finger pad distance is reproduced less accurately (1) with the opposite than the same hand and (2) when higher-level processing of the somatosensory feedback is required for non-congruent hand postures. We propose that erroneous sensing of finger pad distance, if not compensated for during contact and onset of manipulation, might lead to manipulation performance errors as digit forces have to be modulated to perceived digit placement.

Mobile devices are a promising channel for delivering just-in-time guidance and support for improving key daily health behaviors. Despite an explosion of mobile phone applications aimed at physical activity and other health behaviors, few have been based on theoretically derived constructs and empirical evidence. Eighty adults ages 45 years and older who were insufficiently physically active, engaged in prolonged daily sitting, and were new to smartphone technology, participated in iterative design development and feasibility testing of three daily activity smartphone applications based on motivational frames drawn from behavioral science theory and evidence. An “analytically” framed custom application focused on personalized goal setting, self-monitoring, and active problem solving around barriers to behavior change. A “socially” framed custom application focused on social comparisons, norms, and support.

An “affectively” framed custom application focused on operant conditioning principles of reinforcement scheduling and emotional transference to an avatar, whose movements and behaviors reflected the physical activity and sedentary levels of the user. To explore the applications' initial efficacy in changing regular physical activity and leisure-time sitting, behavioral changes were assessed across eight weeks in 68 participants using the CHAMPS physical activity questionnaire and the Australian sedentary behavior questionnaire. User acceptability of and satisfaction with the applications was explored via a post-intervention user survey. The results indicated that the three applications were sufficiently robust to significantly improve regular moderate-to-vigorous intensity physical activity and decrease leisure-time sitting during the 8-week behavioral adoption period. Acceptability of the applications was confirmed in the post-intervention surveys for this sample of midlife and older adults new to smartphone technology. Preliminary data exploring sustained use of the applications across a longer time period yielded promising results. The results support further systematic investigation of the efficacy of the applications for changing these key health-promoting behaviors.

The apolipoprotein E (APOE) e4 genotype is a powerful risk factor for late-onset Alzheimer’s disease (AD). In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we previously reported significant baseline structural differences in APOE e4 carriers relative to non-carriers, involving the left hippocampus more than the right—a difference more pronounced in e4 homozygotes than heterozygotes. We now examine the longitudinal effects of APOE genotype on hippocampal morphometry at 6-, 12- and 24-months, in the ADNI cohort. We employed a new automated surface registration system based on conformal geometry and tensor-based morphometry. Among different hippocampal surfaces, we computed high-order correspondences, using a novel inverse-consistent surface-based fluid registration method and multivariate statistics consisting of multivariate tensor-based morphometry (mTBM) and radial distance. At each time point, using Hotelling’s T² test, we found significant morphological deformation in APOE e4 carriers relative to non-carriers in the full cohort as well as in the non-demented (pooled MCI and control) subjects at each follow-up interval. In the complete ADNI cohort, we found greater atrophy of the left hippocampus than the right, and this asymmetry was more pronounced in e4 homozygotes than heterozygotes. These findings, combined with our earlier investigations, demonstrate an e4 dose effect on accelerated hippocampal atrophy, and support the enrichment of prevention trial cohorts with e4 carriers.

High-density electroencephalography was used to evaluate cortical activity during speech comprehension via a sentence verification task. Twenty-four participants assigned true or false to sentences produced with 3 noise-vocoded channel levels (1-unintelligible, 6-decipherable, 16-intelligible), during simultaneous EEG recording. Participant data were sorted into higher- (HP) and lower-performing (LP) groups. The identification of a late-event related potential for LP listeners in the intelligible condition and in all listeners when challenged with a 6-Ch signal supports the notion that this induced potential may be related to either processing degraded speech, or degraded processing of intelligible speech. Different cortical locations are identified as neural generators responsible for this activity; HP listeners are engaging motor aspects of their language system, utilizing an acoustic–phonetic based strategy to help resolve the sentence, while LP listeners do not. This study presents evidence for neurophysiological indices associated with more or less successful speech comprehension performance across listening conditions.

Many children born preterm exhibit frontal executive dysfunction, behavioral problems including attentional deficit/hyperactivity disorder and attention related learning disabilities. Anomalies in regional specificity of cortico-striato-thalamo-cortical circuits may underlie deficits in these disorders. Nonspecific volumetric deficits of striatal structures have been documented in these subjects, but little is known about surface deformation in these structures. For the first time, here we found regional surface morphological differences in the preterm neonatal ventral striatum. We performed regional group comparisons of the surface anatomy of the striatum (putamen and globus pallidus) between 17 preterm and 19 term-born neonates at term-equivalent age. We reconstructed striatal surfaces from manually segmented brain magnetic resonance images and analyzed them using our in-house conformal mapping program. All surfaces were registered to a template with a new surface fluid registration method. Vertex-based statistical comparisons between the two groups were performed via four methods: univariate and multivariate tensor-based morphometry, the commonly used medial axis distance, and a combination of the last two statistics. We found statistically significant differences in regional morphology between the two groups that are consistent across statistics, but more extensive for multivariate measures. Differences were localized to the ventral aspect of the striatum. In particular, we found abnormalities in the preterm anterior/inferior putamen, which is interconnected with the medial orbital/prefrontal cortex and the midline thalamic nuclei including the medial dorsal nucleus and pulvinar. These findings support the hypothesis that the ventral striatum is vulnerable, within the cortico-stiato-thalamo-cortical neural circuitry, which may underlie the risk for long-term development of frontal executive dysfunction, attention deficit hyperactivity disorder and attention-related learning disabilities in preterm neonates.

Background: Prior research shows that work in agriculture and construction/extraction occupations increases the risk of environmental heat-associated death.

Purpose: To assess the risk of environmental heat-associated death by occupation.

Methods: This was a case-control study. Cases were heat-caused and heat-related deaths occurring from May-October during the period 2002–2009 in Maricopa County, Arizona. Controls were selected at random from non-heat-associated deaths during the same period in Maricopa County. Information on occupation, age, sex, and race-ethnicity was obtained from death certificates. Logistic regression analysis was used to estimate odds ratios for heat-associated death.

Results: There were 444 cases of heat-associated deaths in adults (18+ years) and 925 adult controls. Of heat-associated deaths, 332 (75%) occurred in men; a construction/extraction or agriculture occupation was described on the death certificate in 115 (35%) of these men. In men, the age-adjusted odds ratios for heat-associated death were 2.32 (95% confidence interval 1.55, 3.48) in association with construction/extraction and 3.50 (95% confidence interval 1.94, 6.32) in association with agriculture occupations. The odds ratio for heat-associated death was 10.17 (95% confidence interval 5.38, 19.23) in men with unknown occupation. In women, the age-adjusted odds ratio for heat-associated death was 6.32 (95% confidence interval 1.48, 27.08) in association with unknown occupation. Men age 65 years and older in agriculture occupations were at especially high risk of heat-associated death.

Conclusion: The occurrence of environmental heat-associated death in men in agriculture and construction/extraction occupations in a setting with predictable periods of high summer temperatures presents opportunities for prevention.

Our previous studies show reduced abundance of the β-subunit of mitochondrial H+-ATP synthase (β-F1-ATPase) in skeletal muscle of obese individuals. The β-F1-ATPase forms the catalytic core of the ATP synthase, and it is critical for ATP production in muscle. The mechanism(s) impairing β-F1-ATPase metabolism in obesity, however, are not completely understood. First, we studied total muscle protein synthesis and the translation efficiency of β-F1-ATPase in obese (BMI, 36±1 kg/m²) and lean (BMI, 22±1 kg/m²) subjects. Both total protein synthesis (0.044±0.006 vs 0.066±0.006%·h^-1) and translation efficiency of β-F1-ATPase (0.0031±0.0007 vs 0.0073±0.0004) were lower in muscle from the obese subjects when compared to the lean controls (P<0.05). We then evaluated these same responses in a primary cell culture model, and tested the specific hypothesis that circulating non-esterified fatty acids (NEFA) in obesity play a role in the responses observed in humans. The findings on total protein synthesis and translation efficiency of β-F1-ATPase in primary myotubes cultured from a lean subject, and after exposure to NEFA extracted from serum of an obese subject, were similar to those obtained in humans. Among candidate microRNAs (i.e., non-coding RNAs regulating gene expression), we identified miR-127-5p in preventing the production of β-F1-ATPase. Muscle expression of miR-127-5p negatively correlated with β-F1-ATPase protein translation efficiency in humans (r = – 0.6744; P<0.01), and could be modeled in vitro by prolonged exposure of primary myotubes derived from the lean subject to NEFA extracted from the obese subject. On the other hand, locked nucleic acid inhibitor synthesized to target miR-127-5p significantly increased β-F1-ATPase translation efficiency in myotubes (0.6±0.1 vs 1.3±0.3, in control vs exposure to 50 nM inhibitor; P<0.05). Our experiments implicate circulating NEFA in obesity in suppressing muscle protein metabolism, and establish impaired β-F1-ATPase translation as an important consequence of obesity.