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1.  Global Methylation in the Placenta and Umbilical Cord Blood From Pregnancies With Maternal Gestational Diabetes, Preeclampsia, and Obesity 
Reproductive Sciences  2014;21(1):131-137.
Emerging evidence indicates that maternal medical risk during pregnancy, such as gestational diabetes mellitus (GDM), preeclampsia, and obesity, predisposes the offspring to suboptimal development. However, the underlying biological/epigenetic mechanism in utero is still unknown. The current pilot study (N = 50) compared the levels of global methylation in the placenta and umbilical cord blood among women with and without each risk condition (GDM, preeclampsia, and obesity) and explored whether the levels of global methylation were associated with fetal/infant growth. Results show that global methylation levels in the placenta were lower in patients with gestational diabetes (P = .003) and preeclampsia (P = .05) but higher with obesity (P = .01). Suggestive negative associations were found between global methylation level in the placenta and infant body length and head circumference. While preliminary, it is possible that the placenta tissue, but not umbilical cord blood, may be epigenetically programmed by maternal GDM, preeclampsia, and obesity to carry out its own specific functions that influence fetal growth.
PMCID: PMC3857768  PMID: 23765376
global methylation; fetal programming; placenta; umbilical cord blood; gestational diabetes mellitus; preeclampsia; obesity; birth outcomes
2.  Inhibition of autophagy induces retinal pigment epithelial cell damage by the lipofuscin fluorophore A2E 
FEBS Open Bio  2014;4:1007-1014.
•Autophagy was augmented in RPE cells in the presence of a lipofuscin pigment, A2E.•RPE cell death was induced in the presence of A2E with an autophagy inhibitor.•Inhibition of autophagy resulted in the accumulation of abnormal mitochondria.•Autophagy in RPE cells prevents the accumulation of damaged cellular molecules.
In this study, we show augmented autophagy in the retinal pigment epithelial cell line ARPE-19 when cultured in the presence of the lipofuscin pigment A2E. A2E alone does not induce RPE cell death, but cell death was induced in the presence of A2E with the autophagy inhibitor 3-methyladenine (3MA), with a concomitant increase in the generation of mitochondrial reactive oxygen species. On the other hand, the ATP production capacity of mitochondria was decreased in the presence of A2E, and pharmacological inhibition of autophagy had no additional effects. The altered mRNA expression level of mitochondrial function markers was confirmed by real-time polymerase chain reaction, which showed that the antioxidant enzymes SOD1 and SOD2 were not reduced in the presence of A2E alone, but significantly suppressed with the addition of 3MA. Furthermore, transmission electron micrography revealed autophagic vacuole formation in the presence of A2E, and inhibition of autophagy resulted in the accumulation of abnormal mitochondria with loss of cristae. Spheroid culture of human RPE cells demonstrated debris accumulation in the presence of A2E, and this accumulation was accelerated in the presence of 3MA. These results indicate that autophagy in RPE cells is a vital cytoprotective process that prevents the accumulation of damaged cellular molecules.
PMCID: PMC4250541  PMID: 25473597
3MA, 3-methyladenine; AMD, age-related macular degeneration; mROS, mitochondrial reactive oxygen species; RPE, retinal pigment epithelial cells; SEM, scanning electron microscopy; STGD, Stargardt disease; TEM, transmission electron microscopy; Autophagy; Retinal pigment epithelium; Lipofuscin; Mitochondria; Reactive oxygen species
3.  Controlling Mammalian Gene Expression by Allosteric Hepatitis Delta Virus Ribozymes 
ACS Synthetic Biology  2013;2(12):684-689.
We engineered small molecule responsive allosteric ribozymes based on the genomic hepatitis delta virus (HDV) ribozyme by replacing the P4-L4 stem-loop with an RNA aptamer through a connector stem. When embedded in the 3′ untranslated region of a reporter gene mRNA, these RNA devices enabled regulation of cis-gene expression by theophylline and guanine by up to 29.5-fold in mammalian cell culture. Furthermore, a NOR logic gate device was constructed by placing two engineered ribozymes in tandem, demonstrating the modularity of the RNA devices. The significant improvement in the regulatory dynamic range (ON/OFF ratio) of the RNA devices based on the HDV ribozyme should provide new opportunities for practical applications.
PMCID: PMC3874218  PMID: 23697539
ribozyme; HDV ribozyme; riboswitch; aptazyme; logic gate
4.  Childhood maltreatment and conduct disorder: Independent predictors of criminal outcomes in ADHD youth 
Child abuse & neglect  2012;36(0):782-789.
Children with attention-deficit/hyperactivity disorder (ADHD) are at heightened risk for maltreatment in childhood and criminality as they enter into adolescence and early adulthood. Here, we investigated the effect of moderate to severe childhood maltreatment on later criminality among adolescents/young adults diagnosed with ADHD in childhood while accounting for the contributions of other known risk factors such as early conduct disorder (CD).
Eighty-eight participants from a longitudinal study of children diagnosed with ADHD and screened for comorbid disorders at age 7–11 years were assessed for maltreatment histories at the time of the 10-year adolescent follow-up. Detailed juvenile and adult criminal records were obtained from the New York State Division of Criminal Justice Services approximately 3- years after commencement of the follow-up study. We used regression analyses to determine predictors of adolescent/young adult criminal behavior.
Moderate to severe childhood maltreatment increased the risk of adolescent/young adult arrest over and above the risk associated with childhood CD, while both childhood maltreatment and childhood CD significantly increased the risk of recidivism. ADHD youth classified as maltreated were three and a half times more likely to be arrested when compared to ADHD youth without a maltreatment classification.
We established maltreatment as a risk factor for criminality in ADHD youth and demonstrated that this relationship was independent of the contributions of CD, and established risk factor for antisocial behavior in this population. The findings highlight the need for maltreatment screening in children with ADHD in order to identify those at heightened risk for criminal activity, and target treatment to improve outcome in this high-risk group of children.
PMCID: PMC3514569  PMID: 23146580
5.  Diversified Microbiota of Meconium Is Affected by Maternal Diabetes Status 
PLoS ONE  2013;8(11):e78257.
This study was aimed to assess the diversity of the meconium microbiome and determine if the bacterial community is affected by maternal diabetes status.
The first intestinal discharge (meconium) was collected from 23 newborns stratified by maternal diabetes status: 4 mothers had pre-gestational type 2 diabetes mellitus (DM) including one mother with dizygotic twins, 5 developed gestational diabetes mellitus (GDM) and 13 had no diabetes. The meconium microbiome was profiled using multi-barcode 16S rRNA sequencing followed by taxonomic assignment and diversity analysis.
All meconium samples were not sterile and contained diversified microbiota. Compared with adult feces, the meconium showed a lower species diversity, higher sample-to-sample variation, and enrichment of Proteobacteria and reduction of Bacteroidetes. Among the meconium samples, the taxonomy analyses suggested that the overall bacterial content significantly differed by maternal diabetes status, with the microbiome of the DM group showing higher alpha-diversity than that of no-diabetes or GDM groups. No global difference was found between babies delivered vaginally versus via Cesarean-section. Regression analysis showed that the most robust predictor for the meconium microbiota composition was the maternal diabetes status that preceded pregnancy. Specifically, Bacteroidetes (phyla) and Parabacteriodes (genus) were enriched in the meconium in the DM group compared to the no-diabetes group.
Our study provides evidence that meconium contains diversified microbiota and is not affected by the mode of delivery. It also suggests that the meconium microbiome of infants born to mothers with DM is enriched for the same bacterial taxa as those reported in the fecal microbiome of adult DM patients.
PMCID: PMC3819383  PMID: 24223144
6.  Academic Achievement Varies With Gestational Age Among Children Born at Term 
Pediatrics  2012;130(2):e257-e264.
The goal of this study was to examine the degree to which children born within the “normal term” range of 37 to 41 weeks’ gestation vary in terms of school achievement.
This study analyzed data from 128 050 singleton births born between 37 and 41 weeks’ gestation in a large US city. Data were extracted from city birth records to assess a number of obstetric, social, and economic variables, at both the individual and community levels. Birth data were then matched with public school records of standardized city-wide third-grade reading and math tests. Specifically, we assessed (1) whether children born within the normal term range of 37 to 41 weeks’ gestation show differences in reading and/or math ability 8 years later as a function of gestational age, and (2) the degree to which a wide range of individual- and community-level social and biological factors mediate this effect.
Analyses revealed that gestational age within the normal term range was significantly and positively related to reading and math scores in third grade, with achievement scores for children born at 37 and 38 weeks significantly lower than those for children born at 39, 40, or 41 weeks. This effect was independent of birth weight, as well as a number of other obstetric, social, and economic factors.
Earlier normal term birth may be a characteristic considered by researchers, clinicians, and parents to help identify children who may be at risk for poorer school performance.
PMCID: PMC3408682  PMID: 22753563
gestational age; developmental outcomes; risk factors; school performance; reading achievement
7.  Cannabis-Dependence Risk Relates to Synergism between Neuroticism and Proenkephalin SNPs Associated with Amygdala Gene Expression: Case-Control Study 
PLoS ONE  2012;7(6):e39243.
Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown.
Methodology/Principal Findings
Healthy young adults (18–27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%–19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect.
Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk.
PMCID: PMC3382183  PMID: 22745721
8.  Prenatal Exposure to Maternal and Paternal Smoking on Attention Deficit Hyperactivity Disorders Symptoms and Diagnosis in Offspring 
The study examined the effect of maternal and paternal smoking during pregnancy on the child’s inattention and hyperactivity/impulsivity symptoms, and the risk for attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). Generalized estimating equations, incorporating data from multiple informants (parents and teachers), was used to evaluate levels of ADHD as a function of parental smoking. The risk for ADHD, ODD, and comorbid ADHD and ODD was evaluated using polytomous logistic regression. We found that maternal, but not paternal, smoking was significantly associated with elevated inattention, hyperactivity/impulsivity, and total ADHD symptoms in children. Children of smoking, relative to nonsmoking, mothers had a significant increased risk for comorbid ADHD and ODD and ADHD, but not ODD. Although father’s smoking was not associated with an increased risk, as it strongly influenced mothers’ smoking, intervention for both parents may be most effective in preventing the pathway to ADHD-related problems in the children.
PMCID: PMC3124822  PMID: 20823730
Smoking during pregnancy; inattention; hyperactivity/impulsivity; ADHD; ODD
9.  Impact of Maternal Posttraumatic Stress Disorder and Depression Following Exposure to the September 11 Attacks on Preschool Children’s Behavior 
Child development  2010;81(4):1129-1141.
To evaluate whether conjoined maternal posttraumatic stress disorder (PTSD) and depression are associated with increased behavioral problems among terrorism-exposed preschool children (N = 116; 18–54 months), this study compared clinically significant child behavioral problem rates among the preschool children of mothers with PTSD and depression, depression alone, and neither disorder. Behavioral problems were independently rated by mothers and preschool teachers. Maternal depression and PTSD, relative to maternal depression alone, and to neither disorder, were associated with substantially increased child problems. Notably, maternal depression and PTSD were associated with increased emotional reactivity (relative risk [RR] = 5.9 by mother’s and 3.4 by teacher’s reports) and aggressive behavior problems (RR = 11.0 by mother’s and RR = 5.9 by teacher’s reports). This was corroborated by teacher ratings. Implications for intervening with terrorism-exposed preschool children are discussed.
PMCID: PMC3124807  PMID: 20636686
10.  Selection of silk-binding peptides by phage display 
Biotechnology Letters  2011;33(5):1069-1073.
Peptides that bind to silkworm-derived silk fibroin fiber were selected from a phage-displayed random peptide library. The selected silk-binding peptides contained a consensus sequence QSWS which is important for silk-binding as confirmed by binding assays using phage and synthetic peptides. With further optimization, we anticipate that the silk-binding peptides will be useful for functionalization of silk for biomaterial applications.
PMCID: PMC3082026  PMID: 21259034
Fibroin fiber; Peptide; Phage display; Silk
11.  The Risk for Impaired Learning-related Abilities in Childhood and Educational Attainment Among Adults Born Near-term 
Journal of Pediatric Psychology  2008;34(4):406-418.
Objective To examine whether near-term births (NTB) and small-for-gestational-age (SGA) infants are at high risk for childhood learning-related problems and poor adult educational attainment, and whether poverty amplifies the adverse effects of NTB and SGA on those outcomes. Methods A randomly selected birth cohort (n = 1,619) was followed into adulthood. IQ and learning abilities were measured in childhood and educational attainment was measured in adulthood. Results NTB (n = 226) and SGA (n = 154) were associated with lower educational attainment mediated through learning-related abilities at age 7. Childhood poverty moderated the impact of NTB on educational attainment both directly and mediated through lower learning-related abilities. Poverty did not moderate the effect of SGA. Conclusions Poorer learning-related outcomes and educational attainment were not limited to children born very (<32 weeks) or extremely (<28 weeks) preterm, especially among those living in poverty. Targeted interventions such as remedial learning during childhood among NTB in poor families may yield higher educational attainment.
PMCID: PMC2722131  PMID: 18794190
educational attainment; learning abilities; near-term birth; poverty; small-for-gestational-age
12.  An efficient platform for genetic selection and screening of gene switches in Escherichia coli 
Nucleic Acids Research  2009;37(5):e39.
Engineered gene switches and circuits that can sense various biochemical and physical signals, perform computation, and produce predictable outputs are expected to greatly advance our ability to program complex cellular behaviors. However, rational design of gene switches and circuits that function in living cells is challenging due to the complex intracellular milieu. Consequently, most successful designs of gene switches and circuits have relied, to some extent, on high-throughput screening and/or selection from combinatorial libraries of gene switch and circuit variants. In this study, we describe a generic and efficient platform for selection and screening of gene switches and circuits in Escherichia coli from large libraries. The single-gene dual selection marker tetA was translationally fused to green fluorescent protein (gfpuv) via a flexible peptide linker and used as a dual selection and screening marker for laboratory evolution of gene switches. Single-cycle (sequential positive and negative selections) enrichment efficiencies of >7000 were observed in mock selections of model libraries containing functional riboswitches in liquid culture. The technique was applied to optimize various parameters affecting the selection outcome, and to isolate novel thiamine pyrophosphate riboswitches from a complex library. Artificial riboswitches with excellent characteristics were isolated that exhibit up to 58-fold activation as measured by fluorescent reporter gene assay.
PMCID: PMC2655682  PMID: 19190095
13.  Roles of perinatal problems on adolescent antisocial behaviors among children born after 33 completed weeks: a prospective investigation 
There is uncertainty about the extent to which mildly sub-optimal perinatal characteristics among individuals born near-term (>33 weeks of gestation) are associated with various subsequent childhood problems, including antisocial behavior. There is even more uncertainty about whether the pathway to antisocial behavior differs by gender.
A sample of 1689 infants, born near-term, was followed from birth for over 30 years. Using structural equation modeling (SEM), the study evaluated hypothesized mechanisms linking perinatal problems to antisocial behavior, mediated through the following variables in early and later childhood: neurological abnormalities at age 1; hearing, speech, and language problems at age 3; cognitive function at age 4; and academic performance at age 7. Childhood problems were assessed by trained research clinicians, blind to perinatal status. An ‘antisocial behavior’ variable was created, based on retrospective self-report of six antisocial incidences assessed in adulthood.
Path coefficients showed that birthweight, head circumference, and Apgar scores were indirectly associated with antisocial behavior in the presence of one or more of the following: neurological abnormalities, abnormality in language, speech, and hearing, cognitive function, or academic performance. We found gender differences only in the associations between hearing and IQ and between language perception and IQ. Poor academic performance was associated with antisocial behavior in both boys and girls.
Our hypothesis, that perinatal problems may progress to antisocial behavior when mediated by various markers of early childhood problems, was confirmed. Adverse perinatal events need to be considered in identifying infants who are at risk for academic problems and antisocial behavior, even when the infant is born relatively close to term (i.e., >33 weeks). Poor academic performance, which is indirectly influenced by a variety of neurological and cognitive problems during the perinatal period, infancy, and early childhood appear to increase antisocial behavioral problems in both girls and boys.
PMCID: PMC2585154  PMID: 18673404
Perinatal problems; birthweight; head circumference; Apgar scores; childhood problems; antisocial behavior; longitudinal study; hearing; language; intelligence; epidemiology
14.  Temperament among offspring at high and low risk for depression 
Psychiatry research  2007;153(2):145-151.
The purpose of this study was to examine relationships between parental depression, offspring temperament, and offspring major depressive disorder (MDD), and to determine whether difficult temperament, as measured by the Dimensions of Temperament Survey (DOTS), mediates the relation between parental MDD and offspring MDD. Offspring (n=169) of depressed or never depressed parents were followed over approximately 20 years and were blindly assessed up to 4 times (Waves 1 to 4) using semi-structured interviews. Offspring completed the DOTS at the time of first or second assessment. The results showed: (1) high-risk offspring with one or more depressed parent were significantly more likely than offspring with neither parent depressed parent to have a difficult temperament; (2) offspring with a difficult temperament were more than twice as likely as those with an easy temperament to develop a MDD; and (3) difficult temperament explained more than 10% of the association between parental depression and new onsets of MDD in offspring. The findings suggest that offspring temperament is associated with development of MDD and that difficult temperament at least partially mediates the relationship between parental depression and offspring depression. When identifying those at greatest risk for MDD, measures of temperament could serve as a useful supplement to family psychiatric history of MDD.
PMCID: PMC2128059  PMID: 17651814
Dimensions of Temperament Survey (DOTS); Major depressive disorder (MDD)
15.  The role of perinatal problems in risk of co-morbid psychiatric and medical disorders in adulthood 
Psychological medicine  2007;37(9):1323-1334.
Perinatal problems may be associated with an increased risk for psychological and physical health problems in adulthood, although it is unclear which perinatal problems (low birthweight, preterm birth, low Apgar scores, and small head circumference), or what clusters of problems, are more likely to be associated with later health problems. It is also not known whether perinatal problems (singly or together) are associated with co-morbidity between psychological and physical health problems.
A regional random sample (from Baltimore) of mothers and their children (n = 525) was followed from birth to adulthood (mean age 29 years). Perinatal conditions were measured at delivery. Psychological problems (depression and suicidal ideation) were measured with the General Health Questionnaire-28 (GHQ-28) and physical problems (asthma and hypertension) with the RAND-36 Health Status Inventory.
Children with perinatal problems were generally at increased risk for depression, suicidal ideation and hypertension, and co-morbid depression and hypertension even after controlling for confounders. One possible underlying condition, preterm low birthweight (LBW), extracted by cluster analysis, considering all of the four perinatal problems, was associated with increased risk for psychological and physical health outcomes as well as co-morbidity of the two.
LBW, preterm birth and small head circumference singly increased the risk for both psychological and physical health problems, as well as co-morbid depression and hypertension, while low Apgar scores were only associated with psychological problems. Delineating different etiological processes, such as preterm LBW, considering various perinatal problems simultaneously, might be of benefit to understanding the fetal origin of adult illness and co-morbidity.
PMCID: PMC2563431  PMID: 17472762
16.  Conjoined Effects of Low Birth Weight and Childhood Abuse on Adaptation and Well-being in Adolescence and Adulthood 
To characterize the conjoined effects of low birth weight (LBW) and childhood abuse on impaired adaptation and illness in adolescence and adulthood.
Longitudinal study of a birth cohort.
Baltimore, Md.
Children (N=1748) were followed from birth to adulthood (mean age, 26 years) as part of the Johns Hopkins Collaborative Perinatal Study.
Main Exposures
Childhood abuse and LBW.
Main Outcome Measures
Indicators of adaptation were delinquency, school suspension, repeating grades, academic honors, quality of life, and socioeconomic status. Indicators of psychiatric and medical problems were depression, social dysfunction, somatization, asthma, and hypertension.
Participants with both LBW and subsequent childhood abuse, relative to those with neither risk, were at a substantially elevated risk for psychological problems: 10-fold for depression; nearly 9-fold for social dysfunction, and more than 4-fold for somatization. However, they were not at an elevated risk for medical problems in adulthood. Those exposed to childhood abuse were more likely to report delinquency, school suspension, repeating grades during adolescence, and impaired well-being in adulthood, regardless of LBW status. For those with LBW alone, the prevalence of those problems was comparable with that of individuals without either risk factor.
Children with LBW and childhood abuse are at much greater risk for poor adaptation and psychiatric problems than those with LBW alone and those with neither risk. Preventive interventions should target families with LBW children who are at greater risk for childhood abuse.
PMCID: PMC2561199  PMID: 17283305
17.  Low birthweight and risk of affective disorders & selected medical illness in offspring at high and low risk for depression 
Comprehensive psychiatry  2007;48(5):470-4789.
Numerous studies have demonstrated that low birthweight (LBW) is associated with the development of medical conditions, such as hypertension and diabetes, and psychiatric disorders, such as depression. One possible mechanism through which LBW might increase risk for both medical and psychiatric disorders is by altering the biological systems, such as the HPA-axis function, that govern emotion regulation and physical reactivity. In this study, we conducted secondary data analyses in a longitudinal study originally designed to understand the intergenerational transmission of MDD. We examined risk for both medical and psychiatric illnesses known to be influenced by HPA-axis dysregulation in the context of parental depression. The study had two primary objectives: 1) to examine whether LBW increases the risk of selected adult illness that may be influenced by the HPA-axis; and 2) to examine whether the increased risk of illness varies by parental depression status.
We conducted longitudinal assessments of 244 offspring of depressed and non-depressed parents for over 20 years. Psychopathology and medical illness were assessed by direct interview conducted by clinicians blind to risk status and previous diagnosis. We examined the effect of birthweight in three categories: birthweight less than 2.5kg (LBW); 2.5kg-3.5kg; and greater than 3.5kg (reference group).
Offspring with LBW had a significantly increased risk of MDD, anxiety disorders, phobia, suicidal ideation, impaired functioning, allergies, and hypertension compared to those with BW greater than 3.5kg. The association between LBW and depression was stronger among children of depressed parents than among children of non-depressed parents, with an interaction term (birthweight and parental depression status) significant for MDD (p=.05), suggesting that parental depression may augment the impact of LBW on offspring depression:
PMCID: PMC2085442  PMID: 17707257

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