Faculty Bibliography

DNA must be synthesized for purposes of genome duplication and DNA repair. While the former is a highly accurate process, short-patch synthesis associated with repair of DNA damage is often error-prone. Break-induced replication (BIR) is a unique cellular process that mimics normal DNA replication in its processivity, rate, and capacity to duplicate hundreds of kilobases, but is initiated at double-strand breaks (DSBs) rather than at replication origins. Here we employed a series of frameshift reporters to measure mutagenesis associated with BIR in Saccharomyces cerevisiae. We demonstrate that BIR DNA synthesis is intrinsically inaccurate over the entire path of the replication fork, as the rate of frameshift mutagenesis during BIR is up to 2,800-fold higher than during normal replication. Importantly, this high rate of mutagenesis was observed not only close to the DSB where BIR is less stable, but also far from the DSB where the BIR replication fork is fast and stabilized. We established that polymerase proofreading and mismatch repair correct BIR errors. Also, dNTP levels were elevated during BIR, and this contributed to BIR-related mutagenesis. We propose that a high level of DNA polymerase errors that is not fully compensated by error-correction mechanisms is largely responsible for mutagenesis during BIR, with Pol delta generating many of the mutagenic errors. We further postulate that activation of BIR in eukaryotic cells may significantly contribute to accumulation of mutations that fuel cancer and evolution.

The brain's energy economy excessively favors intrinsic, spontaneous neural activity over extrinsic, evoked activity, presumably to maintain its internal organization. Emerging hypotheses capable of explaining such an investment posit that the brain's intrinsic functional architecture encodes a blueprint for its repertoire of responses to the external world. Yet, there is little evidence directly linking intrinsic and extrinsic activity in the brain. Here we relate differences among individuals in the magnitude of task-evoked activity during performance of an Eriksen flanker task, to spontaneous oscillatory phenomena observed during rest. Specifically, we focused on the amplitude of low-frequency oscillations (LFO, 0.01-0.1Hz) present in the BOLD signal. LFO amplitude measures obtained during rest successfully predicted the magnitude of task-evoked activity in a variety of regions that were all activated during performance of the flanker task. In these regions, higher LFO amplitude at rest predicted higher task-evoked activity. LFO amplitude measures obtained during rest were also found to have robust predictive value for behavior. In midline cingulate regions, LFO amplitudes predicted not only the speed and consistency of performance but also the magnitude of the behavioral congruency effect embedded in the flanker task. These results support the emerging hypothesis that the brain's repertoire of responses to the external world are represented and updated in the brain's intrinsic functional architecture

Sleep and wake have a homeostatic relation that influences most aspects of physiology and waking behavior. Sleep disturbance has a detrimental effect on sleepiness and psychomotor vigilance. The purpose of this study was to identify which actual or perceived sleep characteristics accounted for the most variance in daytime functioning among postpartum mothers. Seventy first-time postpartum mothers' actual sleep (actigraphically estimated: total sleep time, number of wake bouts, length of nocturnal wake, and sleep efficiency) and perceived sleep (self-reported: number of awakenings, wake time, and sleep quality) were measured along with their daytime functioning (Stanford Sleepiness Scale [SSS], Epworth Sleepiness Scale [ESS], Visual Analogue of Fatigue Scale [VAFS], and morning Psychomotor Vigilance Test [PVT]). Data were repeatedly collected from the same sample during postpartum weeks 2, 7, and 13. Four stepwise linear regressions were calculated for each postpartum week to examine which objective and/or subjective variable(s) accounted for the most variance in daytime functioning. The SSS and VAFS were both most consistently associated with perceived sleep quality. The ESS was most consistently associated with actual total sleep time. PVT performance was most consistently associated with estimates of actual and perceived sleep efficiency. Actual and perceived sleep profiles were differentially associated with specific daytime functions. These results from postpartum mothers may indicate that populations who experience specific forms of sleep disturbance (e.g. fragmentation and/or deprivation) may also experience specific daytime conditions.

The renal vasopressin V(2) receptor (V(2)R) plays a critical role in physiological and pathophysiological processes associated with arginine vasopressin (AVP)-induced antidiuresis. Because clinical data suggests that females may be more prone to hyponatremia from AVP-mediated antidiuresis, we investigated whether there are sex differences in the expression and function of the renal V(2)R. In normal Sprague-Dawley rat kidneys, V(2)R mRNA and protein expression was 2.6- and 1.7-fold higher, respectively, in females compared with males. To investigate the potential physiological implications of this sex difference, we studied changes in urine osmolality induced by the AVP V(2)R agonist desmopressin. In response to different doses of desmopressin, there was a graded increase in urine osmolality and decrease in urine volume during a 24-h infusion. Females showed greater mean increases in urine osmolality and greater mean decreases in urine volume at 0.5 and 5.0 ng/h infusion rates. We also studied renal escape from antidiuresis produced by water loading in rats infused with desmopressin (5.0 ng/h). After 5 days of water loading, urine osmolality of both female and male rats escaped to the same degree physiologically, but V(2)R mRNA and protein in female kidneys was reduced to a greater degree (-63% and -73%, respectively) than in males (-32% and -48%, respectively). By the end of the 5-day escape period, renal V(2)R mRNA and protein expression were reduced to the same relative levels in males and females, thereby abolishing the sex differences in V(2)R expression seen in the basal state. Our results demonstrate that female rats express significantly more V(2)R mRNA and protein in kidneys than males, and that this results physiologically in a greater sensitivity to V(2)R agonist administration. The potential pathophysiological implications of these results are that females may be more susceptible to the development of dilutional hyponatremia because of a greater sensitivity to endogenously secreted AVP.

The present study compared blood oxygen level dependent (BOLD) response in behaviorally inhibited and behaviorally non-inhibited adolescents to positive and negative feedback following their choice in a reward task. Previous data in these same subjects showed enhanced activation in striatal areas in behaviorally inhibited subjects to cues predicting gain or a loss. However, no analyses had examined responses following actual gains or losses. Relative to non-inhibited subjects, behaviorally inhibited subjects in the current study showed enhanced caudate response to negative but not positive feedback, indicating that striatal sensitivity to feedback may be specific to aversive information. In addition, compared to non-inhibited subjects, behaviorally inhibited subjects exhibited reduced differentiation between positive and negative feedback in ventromedial prefrontal cortex (vmPFC). This suggests a perturbed ability to encode reward value.

PURPOSE/OBJECTIVE:The obesity epidemic raises concerns about the impact of excessive and insufficient weight gain during pregnancy. METHODS:We examined the association between gestational weight gain (GWG) and preterm birth, term small- and large-for-gestational-age (SGA and LGA), term birthweight, and term primary Cesarean delivery, considering prepregnancy body mass index (BMI) and ethnicity in a cohort of 33,872 New York City residents who gave birth between 1995 and 2003 and delivered in hospitals elsewhere in New York State. RESULTS:Preterm birth (<37 weeks' gestation) showed a modest U-shaped relationship, with projected GWG of <10 kg and 20+ kg associated with odds ratios of 1.4 and 1.3, respectively, relative to 10 to 14 kg. The pattern was stronger for preterm birth <32 weeks' and for underweight women with low GWG and overweight/obese women with high GWG. Term SGA decreased and term LGA and birthweight increased monotonically with increasing GWG. Primary Cesarean delivery followed the same pattern as LGA, but less strongly. CONCLUSIONS:Although the study is limited by potential selection bias and measurement error, our findings support the contention that GWG may be a modifiable predictor of pregnancy outcome that warrants further investigation, particularly randomized trials, to assess whether the relation is causal.

OBJECTIVE: The objective of this blinded, prospective, longitudinal study was to determine whether new group A beta hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or OC disorder without a PANDAS history served as the comparison (non-PANDAS) group. METHOD: Consecutive clinical ratings of tic and OC symptom severity were obtained for 31 PANDAS subjects and 53 non-PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25-month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results. RESULTS: No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group. CONCLUSIONS: This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria

OBJECTIVE: To test the hypothesis that aerobic, but not strength, training would lead to attenuated reactivity to and more rapid recovery from cognitive and orthostatic challenge and that deconditioning would reverse this effect. METHODS: We conducted a randomized controlled trial contrasting the effects of aerobic versus strength training on heart rate, four indices of RR interval variability, and blood pressure reactivity to and recovery from psychological and orthostatic challenge in 149 healthy, young, sedentary adults. Subjects were randomized to 12-week aerobic or strength training programs and studied before and after training and again after 4 weeks of sedentary deconditioning. The data were analyzed by performing a Group (aerobic versus strength) by Session (study entry, post training, and deconditioning), by Period (baseline, speech, Stroop, math, tilt) three-way analysis of variance with prespecified contrasts of the effect of group assignment on reactivity and recovery. RESULTS: Aerobic capacity increased in response to conditioning and decreased after deconditioning in the aerobic, but not the strength, training group. However, the two groups did not differ on heart rate, RR interval variability, or blood pressure reactivity to or recovery from laboratory challenge. CONCLUSIONS: These findings, from the largest randomized controlled trial to address this matter to date, raise doubts about attenuation of reactivity or enhancement of recovery as a putative mechanism underlying the cardioprotective effects of aerobic exercise. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00365196.

OBJECTIVE: Valproate is associated with polycystic ovary syndrome as well as congenital malformations and developmental delays of infants who were prenatally exposed. The frequency of valproate use for mental health conditions among women of childbearing age was determined. METHODS: Using New York State Medicaid claims for persons with psychiatric disorders, 40,526 individuals with active prescriptions for mood stabilizers (non-antipsychotic) on May 1, 2009, were identified. Chi square tests were used to compare valproate use among women of childbearing age with similarly aged men and older women. RESULTS: Valproate was the most commonly prescribed agent for young women (23.4%). Men were more likely than women, and older women more likely than younger women, to take valproate. CONCLUSIONS: Over 20% of childbearing-aged women receiving mood stabilizers were treated with valproate, although increasing data on the reproductive toxicity of this agent compel consideration of other non-antipsychotic mood stabilizers as first-line choices.

BACKGROUND: The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous opioidergic regulation increases sensitivity to CO2, separation distress and panic attacks. In panic disorder (PD) patients, both spontaneous clinical panics and lactate-induced panics markedly increase tidal volume (TV), whereas normals have a lesser effect, possibly due to their intact endogenous opioid system. We hypothesized that impairing the opioidergic system by naloxone could make normal controls parallel PD patients' response when lactate challenged. Whether actual separations and losses during childhood (childhood parental loss, CPL) affected naloxone-induced respiratory contrasts was explored. Subjective panic-like symptoms were analyzed although pilot work indicated that the subjective aspect of anxious panic was not well modeled by this specific protocol. METHOD: Randomized cross-over sequences of intravenous naloxone (2 mg/kg) followed by lactate (10 mg/kg), or saline followed by lactate, were given to 25 volunteers. Respiratory physiology was objectively recorded by the LifeShirt. Subjective symptomatology was also recorded. RESULTS: Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL. CONCLUSIONS: Opioidergic dysregulation may underlie respiratory pathophysiology and suffocation sensitivity in PD. Comparing specific anti-panic medications with ineffective anti-panic agents (e.g. propranolol) can test the specificity of the naloxone+lactate model. A screen for putative anti-panic agents and a new pharmacotherapeutic approach are suggested. Heuristically, the experimental unveiling of the endogenous opioid system impairing effects of CPL and separation in normal adults opens a new experimental, investigatory area