• Analysis of multiplex gene expression maps obtained by voxelation

      An, Li; Xie, Hongbo; Chin, Mark H; Obradovic, Zoran; Smith, Desmond J; Megalooikonomou, Vasileios (2009-04-29)
      BACKGROUND: Gene expression signatures in the mammalian brain hold the key to understanding neural development and neurological disease. Researchers have previously used voxelation in combination with microarrays for acquisition of genome-wide atlases of expression patterns in the mouse brain. On the other hand, some work has been performed on studying gene functions, without taking into account the location information of a gene's expression in a mouse brain. In this paper, we present an approach for identifying the relation between gene expression maps obtained by voxelation and gene functions. RESULTS: To analyze the dataset, we chose typical genes as queries and aimed at discovering similar gene groups. Gene similarity was determined by using the wavelet features extracted from the left and right hemispheres averaged gene expression maps, and by the Euclidean distance between each pair of feature vectors. We also performed a multiple clustering approach on the gene expression maps, combined with hierarchical clustering. Among each group of similar genes and clusters, the gene function similarity was measured by calculating the average gene function distances in the gene ontology structure. By applying our methodology to find similar genes to certain target genes we were able to improve our understanding of gene expression patterns and gene functions. By applying the clustering analysis method, we obtained significant clusters, which have both very similar gene expression maps and very similar gene functions respectively to their corresponding gene ontologies. The cellular component ontology resulted in prominent clusters expressed in cortex and corpus callosum. The molecular function ontology gave prominent clusters in cortex, corpus callosum and hypothalamus. The biological process ontology resulted in clusters in cortex, hypothalamus and choroid plexus. Clusters from all three ontologies combined were most prominently expressed in cortex and corpus callosum. CONCLUSION: The experimental results confirm the hypothesis that genes with similar gene expression maps might have similar gene functions. The voxelation data takes into account the location information of gene expression level in mouse brain, which is novel in related research. The proposed approach can potentially be used to predict gene functions and provide helpful suggestions to biologists.
    • Cancer survival disparities by health insurance status

      Niu, Xiaoling; Roche, Lisa M; Pawlish, Karen S; Henry, Kevin A (2013-06)
      Previous studies found that uninsured and Medicaid insured cancer patients have poorer outcomes than cancer patients with private insurance. We examined the association between health insurance status and survival of New Jersey patients 18-64 diagnosed with seven common cancers during 1999-2004. Hazard ratios (HRs) with 95% confidence intervals for 5-year cause-specific survival were calculated from Cox proportional hazards regression models; health insurance status was the primary predictor with adjustment for other significant factors in univariate chi-square or Kaplan-Meier survival log-rank tests. Two diagnosis periods by health insurance status were compared using Kaplan-Meier survival log-rank tests. For breast, colorectal, lung, non-Hodgkin lymphoma (NHL), and prostate cancer, uninsured and Medicaid insured patients had significantly higher risks of death than privately insured patients. For bladder cancer, uninsured patients had a significantly higher risk of death than privately insured patients. Survival improved between the two diagnosis periods for privately insured patients with breast, colorectal, or lung cancer and NHL, for Medicaid insured patients with NHL, and not at all for uninsured patients. Survival from cancer appears to be related to a complex set of demographic and clinical factors of which insurance status is a part. While ensuring that everyone has adequate health insurance is an important step, additional measures must be taken to address cancer survival disparities.
    • Evolutionary Changes of the Target Sites of Two MicroRNAs Encoded in the Hox Gene Cluster of Drosophila and Other Insect Species

      Miura, Sayaka; Nozawa, Masafumi; Nei, Masatoshi (2011)
      MicroRNAs (miRs) are noncoding RNAs that regulate gene expression at the post-transcriptional level. In animals, the target sites of a miR are generally located in the 3' untranslated regions (UTRs) of messenger RNAs. However, how the target sites change during evolution is largely unknown. MiR-iab-4 and miR-iab-4as are known to regulate the expression of two Hox genes, Abd-A and Ubx, in Drosophila melanogaster. We have therefore studied the evolutionary changes of these two miR genes and their target sites of the Hox genes in Drosophila, other insect species, and Daphnia. Our homology search identified a single copy of each miR gene located in the same genomic position of the Hox gene cluster in all species examined. The seed nucleotide sequence was also the same for all species. Searching for the target sites in all Hox genes, we found several target sites of miR-iab-4 and miR-iab-4as in Antp in addition to Abd-A and Ubx in most insect species examined. Our phylogenetic analysis of target sites in Abd-A, Ubx, and Antp showed that the old target sites, which existed before the divergence of the 12 Drosophila species, have been well maintained in most species under purifying selection. By contrast, new target sites, which were generated during Drosophila evolution, were often lost in some species and mostly located in unalignable regions of the 3' UTRs. These results indicate that these regions can be a potential source of generating new target sites, which results in multiple target genes for each miR in animals.
    • Infants’ Somatotopic Neural Responses to Seeing Human Actions: I’ve Got You under My Skin

      Saby, Joni N; Meltzoff, Andrew N; Marshall, Peter J (2013)
      Human infants rapidly learn new skills and customs via imitation, but the neural linkages between action perception and production are not well understood. Neuroscience studies in adults suggest that a key component of imitation-identifying the corresponding body part used in the acts of self and other-has an organized neural signature. In adults, perceiving someone using a specific body part (e.g., hand vs. foot) is associated with activation of the corresponding area of the sensory and/or motor strip in the observer's brain-a phenomenon called neural somatotopy. Here we examine whether preverbal infants also exhibit somatotopic neural responses during the observation of others' actions. 14-month-old infants were randomly assigned to watch an adult reach towards and touch an object using either her hand or her foot. The scalp electroencephalogram (EEG) was recorded and event-related changes in the sensorimotor mu rhythm were analyzed. Mu rhythm desynchronization was greater over hand areas of sensorimotor cortex during observation of hand actions and was greater over the foot area for observation of foot actions. This provides the first evidence that infants' observation of someone else using a particular body part activates the corresponding areas of sensorimotor cortex. We hypothesize that this somatotopic organization in the developing brain supports imitation and cultural learning. The findings connect developmental cognitive neuroscience, adult neuroscience, action representation, and behavioral imitation.
    • Meta-analysis of reward processing in major depressive disorder reveals distinct abnormalities within the reward circuit

      Ng, Tommy H; Alloy, Lauren B; Smith, David V (2019-11-11)
      <jats:title>Abstract</jats:title> <jats:p>Many neuroimaging studies have investigated reward processing dysfunction in major depressive disorder. These studies have led to the common idea that major depressive disorder is associated with blunted responses within the reward circuit, particularly in the ventral striatum. Yet, the link between major depressive disorder and reward-related responses in other regions remains inconclusive, thus limiting our understanding of the pathophysiology of major depressive disorder. To address this issue, we performed a coordinate-based meta-analysis of 41 whole-brain neuroimaging studies encompassing reward-related responses from a total of 794 patients with major depressive disorder and 803 healthy controls. Our findings argue against the common idea that major depressive disorder is primarily linked to deficits within the reward system. Instead, our results demonstrate that major depressive disorder is associated with opposing abnormalities in the reward circuit: hypo-responses in the ventral striatum and hyper-responses in the orbitofrontal cortex. The current findings suggest that dysregulated corticostriatal connectivity may underlie reward-processing abnormalities in major depressive disorder, providing an empirical foundation for a more refined understanding of abnormalities in the reward circuitry in major depressive disorder.</jats:p>
    • One-year postpartum anthropometric outcomes in mothers and children in the LIFE-Moms lifestyle intervention clinical trials

      Phelan, Suzanne; Clifton, Rebecca G; Haire-Joshu, Debra; Redman, Leanne M; Van Horn, Linda; Evans, Mary; Joshipura, Kaumudi; Couch, Kimberly A; Arteaga, S Sonia; Cahill, Alison G; Drews, Kimberly L; Franks, Paul W; Gallagher, Dympna; Josefson, Jami L; Klein, Samuel; Knowler, William C; Martin, Corby K; Peaceman, Alan M; Thom, Elizabeth A; Wing, Rena R; Yanovski, Susan Z; Pi-Sunyer, Xavier; Phelan, S; Wing, RR; Hagobian, TA; Schaffner, A; Hart, C; Yin, EK; Phipps, MG; Abrams, B; Scholl, TO; Savitz, DA; Gallagher, D; Pi-Sunyer, X; Thornton, J; Rosenn, B; Paley, C; Gidwani, S; Horowitz, M; Joshipura, K; Franks, PW; Palacios, C; Campos, M; Rivera, J; Willett, WC; Zorrilla, C; Soltero, S; Hu, F; Cordero, J; Trak, MA; Melendez, M; Cahill, AG; Klein, S; Haire-Joshu, D; Stein, R; Mathur, A; Cade, WT; Moley, K; Peaceman, AM; Van Horn, L; Kwasny, M; Josefson, JL; Neff, L; Spring, B; Redman, LM; Martin, CK; Elkind-Hirsh, K; Breaux, J; Johnson, W; Frost, EA; Knowler, WC; Couch, KA; Curtis, JM; Dunnigan, DL; Hanson, RL; Hoskin, M; Kavena, K; Kishi, GY; Moffett, C; Murphy, S; Nelson, RG; Pomeroy, J; Shovestull, L; Williams, Rachel; Clifton, RG; Thom, EA; Drews, K; Boekhoudt, T; Evans, M; Yanovski, SZ; Arteaga, S; Alekel, DL; Grp, LIFE-Moms Res (2020-01)
      BACKGROUND/OBJECTIVES: Excess gestational weight gain (GWG) is a risk factor for maternal postpartum weight retention and excessive neonatal adiposity, especially in women with overweight or obesity. Whether lifestyle interventions to reduce excess GWG also reduce 12-month maternal postpartum weight retention and infant weight-for-length z score is unknown. Randomized controlled trials from the LIFE-Moms consortium investigated lifestyle interventions that began in pregnancy and tested whether there was benefit through 12 months on maternal postpartum weight retention (i.e., the difference in weight from early pregnancy to 12 months) and infant-weight-for-length z scores. SUBJECTS/METHODS: In LIFE-Moms, women (N = 1150; 14.1 weeks gestation at enrollment) with overweight or obesity were randomized within each of seven trials to lifestyle intervention or standard care. Individual participant data were combined and analyzed using generalized linear mixed models with trial entered as a random effect. The 12-month assessment was completed by 83% (959/1150) of women and 84% (961/1150) of infants. RESULTS: Compared with standard care, lifestyle intervention reduced postpartum weight retention (2.2 ± 7.0 vs. 0.7 ± 6.2 kg, respectively; difference of -1.6 kg (95% CI -2.5, -0.7; p = 0.0003); the intervention effect was mediated by reduction in excess GWG, which explained 22% of the effect on postpartum weight retention. Lifestyle intervention also significantly increased the odds (OR = 1.68 (95% CI, 1.26, 2.24)) and percentage of mothers (48.2% vs. 36.2%) at or below baseline weight at 12 months postpartum (yes/no) compared with standard care. There was no statistically significant treatment group effect on infant anthropometric outcomes at 12 months. CONCLUSIONS: Compared with standard care, lifestyle interventions initiated in pregnancy and focused on healthy eating, increased physical activity, and other behavioral strategies resulted in significantly less weight retention but similar infant anthropometric outcomes at 12 months postpartum in a large, diverse US population of women with overweight and obesity.
    • Origins and Evolution of MicroRNA Genes in Drosophila Species

      Nozawa, Masafumi; Miura, Sayaka; Nei, Masatoshi (2010)
      MicroRNAs (miRs) regulate gene expression at the posttranscriptional level. To obtain some insights into the origins and evolutionary patterns of miR genes, we have identified miR genes in the genomes of 12 Drosophila species by bioinformatics approaches and examined their evolutionary changes. The results showed that the extant and ancestral Drosophila species had more than 100 miR genes and frequent gains and losses of miR genes have occurred during evolution. Although many miR genes appear to have originated from random hairpin structures in intronic or intergenic regions, duplication of miR genes has also contributed to the generation of new miR genes. Estimating the rate of nucleotide substitution of miR genes, we have found that newly arisen miR genes have a substitution rate similar to that of synonymous nucleotide sites in protein-coding genes and evolve almost neutrally. This suggests that most new miR genes have not acquired any important function and would become inactive. By contrast, old miR genes show a substitution rate much lower than the synonymous rate. Moreover, paired and unpaired nucleotide sites of miR genes tend to remain unchanged during evolution. Therefore, once miR genes acquired their functions, they appear to have evolved very slowly, maintaining essentially the same structures for a long time.
    • Origins and Evolution of MicroRNA Genes in Plant Species

      Nozawa, Masafumi; Miura, Sayaka; Nei, Masatoshi (2012)
      MicroRNAs (miRNAs) are among the most important regulatory elements of gene expression in animals and plants. However, their origin and evolutionary dynamics have not been studied systematically. In this paper, we identified putative miRNA genes in 11 plant species using the bioinformatic technique and examined their evolutionary changes. Our homology search indicated that no miRNA gene is currently shared between green algae and land plants. The number of miRNA genes has increased substantially in the land plant lineage, but after the divergence of eudicots and monocots, the number has changed in a lineage-specific manner. We found that miRNA genes have originated mainly by duplication of preexisting miRNA genes or protein-coding genes. Transposable elements also seem to have contributed to the generation of species-specific miRNA genes. The relative importance of these mechanisms in plants is quite different from that in Drosophila species, where the formation of hairpin structures in the genomes seems to be a major source of miRNA genes. This difference in the origin of miRNA genes between plants and Drosophila may be explained by the difference in the binding to target mRNAs between plants and animals. We also found that young miRNA genes are less conserved than old genes in plants as well as in Drosophila species. Yet, nearly half of the gene families in the ancestor of flowering plants have been lost in at least one species examined. This indicates that the repertoires of miRNA genes have changed more dynamically than previously thought during plant evolution.
    • PreMeta: a tool to facilitate meta-analysis of rare-variant associations

      Tang, Zheng-Zheng; Bunn, Paul; Tao, Ran; Liu, Zhouwen; Lin, Dan-Yu; Tao, Rongjia|0000-0001-5058-4401 (2017-02-14)
      BACKGROUND: Meta-analysis is essential to the discovery of rare variants that influence complex diseases and traits. Four major software packages, namely MASS, MetaSKAT, RAREMETAL, and seqMeta, have been developed to perform meta-analysis of rare-variant associations. These packages first generate summary statistics for each study and then perform the meta-analysis by combining the summary statistics. Because of incompatible file formats and non-equivalent summary statistics, the output files from the study-level analysis of one package cannot be directly used to perform meta-analysis in another package. RESULTS: We developed a computationally efficient software program, PreMeta, to resolve the non-compatibility of the four software packages and to facilitate meta-analysis of large-scale sequencing studies in a consortium setting. PreMeta reformats the output files of study-level summary statistics generated by the four packages (text files produced by MASS and RAREMETAL, binary files produced by MetaSKAT, and R data files produced by seqMeta) and translates the summary statistics from one form to another, such that the summary statistics from any package can be used to perform meta-analysis in any other package. With this tool, consortium members are not required to use the same software for study-level analyses. In addition, PreMeta checks for allele mismatches, corrects summary statistics, and allows the rescaled inverse normal transformation to be performed at the meta-analysis stage by rescaling summary statistics. CONCLUSIONS: PreMeta processes summary statistics from the four packages to make them compatible and avoids the need to redo study-level analyses. PreMeta documentation and executable are available at: http://dlin.web.unc.edu/software/premeta .