Examination of aminophenol-containing compounds designed as antiproliferative agents and potential atypical retinoids.

Retinoic acid (RA, 1), an oxidized form of vitamin A, binds to retinoic acid receptors (RAR) and retinoid X receptors (RXR) to regulate gene expression and has important functions such as cell proliferation and differentiation. Synthetic ligands regarding RAR and RXR have been devised for the treatment of various diseases, particularly promyelocytic leukemia, but their side effects have led to the development of new, less toxic therapeutic agents. Fenretinide (4-HPR, 2), an aminophenol derivative of RA, exhibits potent antiproliferative activity without binding to RAR/RXR, but its clinical trial was discontinued due to side effects of impaired dark adaptation. Assuming that the cyclohexene ring of 4-HPR is the cause of the side effects, methylaminophenol was discovered through structure-activity relationship research, and p-dodecylaminophenol (p-DDAP, 3), which has no side effects or toxicity and is effective against a wide range of cancers, was developed. Therefore, we thought that introducing the motif carboxylic acid found in retinoids, could potentially enhance the anti-proliferative effects. Introducing chain terminal carboxylic functionality into potent p-alkylaminophenols significantly attenuated antiproliferative potencies, while a similar structural modification of weakly potent p-acylaminophenols enhanced growth inhibitory potencies. However, conversion of the carboxylic acid moieties to their methyl esters completely abolished the cell growth inhibitory effects of both series. Insertion of a carboxylic acid moiety, which is important for binding to RA receptors, abolishes the action of p-alkylaminophenols, but enhances the action of p-acylaminophenols. This suggests that the amido functionality may be important for the growth inhibitory effects of the carboxylic acids.

Engineering artificial photosynthetic life-forms through endosymbiosis.

The evolutionary origin of the photosynthetic eukaryotes drastically altered the evolution of complex lifeforms and impacted global ecology. The endosymbiotic theory suggests that photosynthetic eukaryotes evolved due to endosymbiosis between non-photosynthetic eukaryotic host cells and photosynthetic cyanobacterial or algal endosymbionts. The photosynthetic endosymbionts, propagating within the cytoplasm of the host cells, evolved, and eventually transformed into chloroplasts. Despite the fundamental importance of this evolutionary event, we have minimal understanding of this remarkable evolutionary transformation. Here, we design and engineer artificial, genetically tractable, photosynthetic endosymbiosis between photosynthetic cyanobacteria and budding yeasts. We engineer various mutants of model photosynthetic cyanobacteria as endosymbionts within yeast cells where, the engineered cyanobacteria perform bioenergetic functions to support the growth of yeast cells under defined photosynthetic conditions. We anticipate that these genetically tractable endosymbiotic platforms can be used for evolutionary studies, particularly related to organelle evolution, and also for synthetic biology applications.

Cellular uptake of protic ruthenium complexes is influenced by pH dependent passive diffusion and energy dependent efflux.

The lipophilic vs. hydrophilic properties of three protic ruthenium compounds were studied as a function of pH. Specifically, we measured Log(Do/w) values for [(N,N)2Ru(6,6'-dhbp)]2+ complexes (where N,N = 2,2'-bipyridine (1A), 1,10-phenanthroline (2A), 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (3A) and 6,6'-dhbp is the diprotic 6,6'-dihydroxy-2,2'-bipyridine ligand) from pH 4.0 to 8.0. This study allowed us to demonstrate that as the ligand is deprotonated at higher pH values the resulting neutral charge on the complex improves its lipophilic properties. Thus, improved uptake by passive diffusion is expected with protic ligands on Ru(II). Furthermore, cellular studies have demonstrated that passive diffusion is the dominant pathway for cellular uptake. However, metabolic inhibition has also shown that energy dependent efflux reduces the amount of the ruthenium complex (as measured by mean fluorescence intensity) in the cells. These compounds have been shown by fluorescence microscopy to accumulate in the nuclei of cancer cells (MCF7, MDA-MB-231, and HeLa). Taken together, this data shows that uptake is required for toxicity but uptake alone is not sufficient. The greatest light activated toxicity appears to occur in breast cancer cell lines with relatively moderate uptake (MCF7 and MDA-MB-231) rather than the cell line with the greatest uptake of complex 3A (normal breast cell line MCF-10A).

Are individual differences in appetitive and defensive motivation related? A psychophysiological examination in two samples.

Appetitive and defensive motivation account for a good deal of variance in personality and mental health, but whether individual differences in these systems are correlated or orthogonal has not been conclusively established. Previous investigations have generally relied on self-report and have yielded conflicting results. We therefore assessed the relation between psychophysiological indices of appetitive and defensive motivation during elicitation of these motivational states: specifically, frontal electroencephalogram asymmetry during reward anticipation and startle response during anticipation of predictable or unpredictable threat of shock. Results in a sample of psychopathology-free community members (n=63), an independent sample of undergraduates with a range of internalising symptoms (n=64), and the combination of these samples (n=127) revealed that differences in responding to the two tasks were not significantly correlated. Average coefficients approached zero in all three samples (community: .04, undergraduate: -.01, combined: .06). Implications of these findings for research on normal and abnormal personality are discussed.

The relation between symptoms of bulimia nervosa and obsessive-compulsive disorder: a startle investigation.

Bulimia nervosa (BN) and obsessive-compulsive disorder (OCD) co-occur at greater rates than chance and may have shared mechanisms of dysfunction. One of these proposed mechanisms is a hyper-responsive aversive system as indicated by heightened startle response to aversive stimuli. The present study examined this hypothesis using 2 types of aversive stimuli: disorder specific (e.g., high-caloric food pictures for BN, contamination pictures for OCD) and nondisorder specific (e.g., knife). Temporal parameters of aversive responding were also examined by assessing startle response in anticipation of and following picture presentation. The sample consisted of 114 undergraduate women selected to have a broad range of BN and/or OCD symptomatology. OCD symptoms were associated with increased startle potentiation during the anticipation and presentation of contamination pictures, and BN symptoms were associated with increased startle potentiation during disorder-related contamination pictures (e.g., sink, toilet). BN symptoms were also associated with increased startle potentiation during and following the presentation of food pictures (though the former effect was only a trend). Additionally, the interaction of BN and OCD symptoms was associated with elevated startle responding during the presentation of contamination and threat stimuli. Overall, the present study provides evidence that BN and OCD symptoms are associated with heightened aversive responding to disorder-specific stimuli, and comorbid BN and OCD symptoms are associated with heightened aversive responding across disorder-specific and nonspecific aversive stimuli. Clinical and theoretical implications are discussed.

Biomarkers of threat and reward sensitivity demonstrate unique associations with risk for psychopathology.

Two emotional/motivational constructs that have been posited to underlie anxiety and depressive disorders are heightened sensitivity to threat and reduced sensitivity to reward, respectively. It is unclear, though, whether these constructs are only epiphenomena or also connote risk for these disorders (and relatedly, whether they connote risk for separate disorders). Using family history of psychopathology as an indicator of risk, the present study examined whether biomarkers of sensitivity to threat (startle potentiation) and reward (frontal EEG asymmetry) were associated with similar or different familial liabilities. In addition, the present study examined whether these biomarkers were associated with risk independent of proband DSM-IV diagnosis. One-hundred and seventy-three individuals diagnosed with panic disorder (PD), early onset major depressive disorder (MDD), both (comorbids), or controls completed two laboratory paradigms assessing sensitivity to predictable/unpredictable threat (measured via startle response) and reward (measured via frontal EEG asymmetry during a gambling task). Results indicated that across all participants: (a) startle potentiation to unpredictable threat was associated with family history of PD (but not MDD); and (b) frontal EEG asymmetry while anticipating reward was associated with family history of MDD (but not PD). Additionally, both measures continued to be associated with family history of psychopathology after controlling for proband DSM-IV diagnosis. Results suggest that the proposed biomarkers of sensitivity to unpredictable threat and reward exhibit discriminant validity and may add to the predictive validity of the DSM-IV defined constructs of PD and MDD, respectively.

A psychophysiological investigation of threat and reward sensitivity in individuals with panic disorder and/or major depressive disorder.

Heightened sensitivity to threat and reduced sensitivity to reward are potential mechanisms of dysfunction in anxiety and depressive disorders, respectively. However, few studies have simultaneously examined whether these mechanisms are unique or common to these disorders. In this study, sensitivity to predictable and unpredictable threat (measured by startle response during threat anticipation) and sensitivity to reward (measured by frontal electroencephalographic [EEG] asymmetry during reward anticipation) were assessed in 4 groups (N = 191): those with (1) panic disorder (PD) without a lifetime history of depression, (2) major depression (MDD) without a lifetime history of an anxiety disorder, (3) comorbid PD and MDD, and (4) controls. General distress/negative temperament (NT) was also assessed via self-report. Results indicated that PD (with or without comorbid MDD) was uniquely associated with heightened startle to predictable and unpredictable threat, and MDD (with or without comorbid PD) was uniquely associated with reduced frontal EEG asymmetry. Both psychophysiological measures of threat and reward sensitivity were stable on retest approximately 9 days later in a subsample of participants. Whereas the comorbid group did not respond differently on the tasks relative to the PD-only and MDD-only groups, they did report greater NT than these 2 groups (which did not differ from each other). Results suggest that heightened sensitivity to threat and reduced sensitivity to reward may be specific components of PD and MDD, respectively. In addition, relative to noncomorbid depression and PD, comorbid MDD and PD may be characterized by heightened NT, but not abnormal levels of these "specific" components.

Frontal brain asymmetry in depression with comorbid anxiety: a neuropsychological investigation.

The approach-withdrawal model posits that depression and anxiety are associated with a relative right asymmetry in frontal brain activity. Most studies have tested this model using measures of cortical brain activity such as electroencephalography. However, neuropsychological tasks that differentially use left versus right frontal cortical regions can also be used to test hypotheses from the model. In two independent samples (Study 1 and 2), the present study investigated the performance of currently depressed individuals with or without a comorbid anxiety disorder and healthy controls on neuropsychological tasks tapping primarily left (verbal fluency) or right (design fluency) frontal brain regions. Across both samples, results indicated that comorbid participants performed more poorly than depressed only and control participants on design fluency, while all groups showed equivalent performance on verbal fluency. Moreover, comorbid participants showed "asymmetrical" performance on these two tasks (i.e., poorer design [right frontal] relative to verbal [left frontal] fluency), whereas depressed only and control participants showed approximately symmetrical profiles of performance. Results from these two samples suggest an abnormal frontal asymmetry in neurocognitive performance driven primarily by right frontal dysfunction among anxious-depressed individuals and highlight the importance of considering comorbid anxiety when examining frontal brain functioning in depression.

Effects of predictability of shock timing and intensity on aversive responses.

An important characteristic of aversive stimuli that determines emotional responses is whether the stimuli are predictable. Human laboratory studies in this area have typically operationalized predictability as being able to predict the occurrence of aversive events, but animal studies suggest that being able to predict other characteristics of the stimuli may also play a role in aversive responding. To examine this, the present study examined two characteristics: the timing and intensity of aversive stimuli. Specifically, participants were randomly assigned to receive shocks that were either predictable or unpredictable in terms of when they would occur (timing) and/or their intensity. Indicators of aversive emotional responses were EMG startle responses and subjective anxiety ratings. Results revealed that aversive responding was elevated for unpredictable timing and intensity suggesting that the predictability of both characteristics play a role in aversive responding (though the effects for timing were stronger). In sum, the anxiogenic effects of unpredictability may generalize to situations beyond unpredictable timing.

Effect of acute tryptophan depletion on emotions in individuals with personal and family history of depression following a mood induction.

BACKGROUND: Acute tryptophan depletion (ATD) has shown depletion-specific increases in depressed mood and overall depressive symptoms, especially in those with a family history and in remitted patients. However, its effect on a broad range of emotions beyond depressed mood has been inconsistent, and studies have rarely employed a negative mood induction. METHOD: The present double-blind study administered tryptophan-depleted and taste-matched placebo challenge drinks to individuals with a past diagnosis and family history of depression (i.e. depression-vulnerable subjects) and controls in order to investigate the effect of ATD on positive affect, anxiety, anger and depressed mood following a negative mood induction. RESULTS: Certain aspects of positive affect decreased due to ATD in the depression vulnerables but not in the controls. No differential effects were found on depressed mood and anxiety. CONCLUSIONS: A stress-induced blunted hedonic capacity may increase vulnerability to ATD and may be a core emotional abnormality in depression. Additionally, serotonin may have a stronger influence on positive affect than on other depression-related emotions during periods of stress.

What is the association between obsessive-compulsive disorder and eating disorders?

Because eating disorders (EDs) and obsessive compulsive disorder (OCD) co-occur at high rates and can have functionally similar clinical presentations, it has been suggested that both constructs might be part of a common spectrum of disorders. Identifying the relationship between EDs and OCD may lead to the discovery of important shared core disease processes and/or mechanisms for maintenance. The objective of this paper is to understand the relationship between EDs and OCD by systematically reviewing epidemiological, longitudinal and family studies guided by five models of comorbidity posited by Klein and Riso (1993) and others. Though this literature is relatively small, the preponderance of evidence from these studies largely suggests that OCD/ED co-occur because of a shared etiological relationship. Limitations to extant literature, and suggestions for future research are discussed.

Subthreshold conditions as precursors for full syndrome disorders: a 15-year longitudinal study of multiple diagnostic classes.

BACKGROUND: There has been increasing interest in the distinction between subthreshold and full syndrome disorders and specifically whether subthreshold conditions escalate or predict the onset of full syndrome disorders over time. Most of these studies, however, examined whether a single subthreshold condition escalates into the full syndrome form of that disorder. Equally important, though, is whether subthreshold conditions are likely to develop other full syndrome disorders and whether these associations are maintained after adjusting for comorbidity. METHODS: A 15-year longitudinal study of subthreshold psychiatric conditions was conducted with 1,505 community-drawn young adults. We examined whether 1) subthreshold major depression, bipolar, anxiety disorders, alcohol use, substance use, conduct disorder and/or ADHD were precursors for the corresponding (homotypic) full syndrome disorder; 2) subthreshold conditions were precursors for other (heterotypic) full syndrome disorders; and 3) these homotypic and heterotypic precursors persisted after adjusting for comorbidity. RESULTS: Subthreshold major depression, anxiety, alcohol use, substance use, and conduct all escalated into their corresponding full syndrome and nearly all homotypic developments were maintained after adjusting for comorbid subthreshold and full syndrome conditions. Many heterotypic associations were also observed and most remained after controlling for comorbidity, particularly among externalizing disorders (e.g., alcohol, substance, conduct/antisocial personality disorder). CONCLUSIONS: Many subthreshold conditions have predictive validity as they may represent precursors for full syndrome disorders. Alternatively, dimensional conceptualizations of psychopathology which include these more minor conditions may yield greater validity. Subthreshold conditions may represent good targets for preventive interventions.

Recurrent abdominal pain, anxiety, and depression in primary care.

OBJECTIVE: The prevalence of psychiatric disorder in children and adolescents with functional recurrent abdominal pain (RAP) is unknown. Our aim was to determine whether RAP is associated with psychiatric symptoms and disorders, anxious temperament, and functional impairment in pediatric primary care. METHODS: Children and adolescents who were 8 to 15 years of age, inclusive, and presented with RAP (N = 42) or for routine care in the absence of recurrent pain (N = 38) were identified by a screening procedure in pediatric primary care office waiting rooms and recruited to participate in a case-control study. Outcome measures were psychiatric diagnoses generated by standardized psychiatric interview administered blind to subject status and self, parent, and clinician ratings of child psychiatric symptoms, temperamental traits, and functional status. RESULTS: RAP patients were significantly more likely to receive a diagnosis of a psychiatric disorder, with a categorical anxiety disorder in 33 (79%) and a depressive disorder in 18 patients (43%), and higher levels of anxiety and depressive symptoms, temperamental harm avoidance, and functional impairment than control subjects. Anxiety disorders (mean age of onset: 6.25 [standard deviation: 2.17] years) were significantly more likely to precede RAP (mean age of onset: 9.17 [standard deviation: 2.75] years) in patients with associated anxiety. CONCLUSIONS: Youths who present with RAP in primary care deserve careful assessment for anxiety and depressive disorders. Future studies should examine treatments that are proved to be efficacious for pediatric anxiety and/or depressive disorders as potential interventions for RAP. Longitudinal, family, and psychobiological studies are needed to illuminate the nature of observed associations among RAP, anxiety, and depression.