Impairment in the achievement domain in bipolar spectrum disorders: role of behavioral approach system hypersensitivity and impulsivity.

AIM: Research indicates that bipolar disorder is characterized by both high levels of impairment and high levels of achievement. A critical, and yet largely unexamined question, is: what psychological mechanisms promote high accomplishment (and low impairment) among bipolar spectrum individuals? The aim of this study was to examine this question. The Authors also conceptually explore how the answer to this question can enhance the development of intervention and prevention strategies for adolescents with a bipolar spectrum condition. METHODS: Academic transcript data were obtained for 120 college students who had either a bipolar spectrum disorder (N=54) or no major psychopathology (N=66). RESULTS: Bipolar spectrum individuals obtained a lower cumulative grade point average (GPA, t=-2.9, P=0.005) and dropped more classes (t=2.1, P=or<0.04) than normal controls. The findings also have relevance to the behavioral approach system (BAS) dysregulation theory of bipolar disorder, as well as research on impulsivity among bipolar individuals. Specifically, follow-up analyses revealed that bipolar individuals exhibiting a combination of high BAS drive and low impulsivity earned higher GPAs than the remaining bipolar individuals. Thus, high BAS sensitivity, when paired with low impulsivity, may not be impairing and may contribute to the high achievement sometimes observed among bipolar individuals. CONCLUSION: Such information is important for the development of prevention and intervention programs designed adolescents that lower risk for bipolar impairment without decreasing achievement.

Competitive binding of triplex-forming oligonucleotides in the two alternate promoters of the PMP22 gene.

Overexpression of the 22-kDa peripheral myelin protein (PMP22) causes the inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 1A (CMT1A). In an attempt to alter PMP22 gene expression as a possible therapeutic strategy for CMT1A, antiparallel triplex-forming oligonucleotides (TFO) were designed to bind to purine-rich target sequences in the two PMP22 gene promoters, P1 and P2. Target region I in P1 and region V in P2 were also shown to specifically bind proteins in mammalian nuclear extracts. Competition for binding of these targets by TFO vs. protein(s) was compared by exposing proteins to their target sequences after triplex formation (passive competition) or by allowing TFO and proteins to simultaneously compete for the same targets (active competition). In both formats, TFO were shown to competitively interfere with the binding of protein to region I. Oligonucleotides directed to region V competed for protein binding by a nontriplex-mediated mechanism, most likely via the formation of higher-order, manganese-destabilizable structures. Given that the activity of the P1 promoter is closely linked to peripheral nerve myelination, TFO identified here could serve as useful reagents in the investigation of promoter function, the role of PMP22 in myelination, and possibly as rationally designed drugs for the therapy of CMT1A. The nontriplex-mediated action of TFO directed at the P2 promoter may have wider implications for the use of such oligonucleotides in vivo.

Negative priming from activation of counting and addition knowledge.

In two experiments, subjects were presented with digit pairs (e.g., 32) and asked to respond to the rightmost number. Negative priming, that is, slowed processing, was evident when the rightmost number was a counting-string (e.g., 43 following 12) or addition-sum (e.g., 65 following 32) associate of the number pair from the preceding trial. The studies are the first to demonstrate negative priming with counting and arithmetical memory representations and suggest the obligatory activation of these representations with the presentation of number pairs. The results are also consistent with the view that negative priming often occurs at the semantic level.

Childhood maltreatment and college students' current suicidal ideation: a test of the hopelessness theory.

Few studies have examined the relation between childhood maltreatment and adult suicidality within the context of a coherent theoretical model. The current study evaluates the ability of the hopelessness theory of depression's (Abramson, Metalsky, & Alloy, 1989) etiological chain to account for this relation in a sample of 297 undergraduates. Supporting the model, emotional, but not physical or sexual, maltreatment was uniquely related to average levels of suicidal ideation across a 2.5-year follow-up. Further, students' cognitive styles and average levels of hopelessness partially mediated this relation. Although these results cannot speak to causality, they support the developmental model evaluated.

The Temple-Wisconsin Cognitive Vulnerability to Depression Project: lifetime history of axis I psychopathology in individuals at high and low cognitive risk for depression.

The authors tested the cognitive vulnerability hypotheses of depression with a retrospective behavioral high-risk design. Individuals without current Axis I diagnoses who exhibited either negative or positive cognitive styles were compared on lifetime prevalence of depressive and other disorders and the clinical parameters of depressive episodes. Consistent with predictions, cognitively high-risk participants had higher lifetime prevalence than low-risk participants of major and hopelessness depression and marginally higher prevalence of minor depression. These group differences were specific to depressive disorders. The high-risk group also had more severe depressions than the low-risk group, but not longer duration or earlier onset depressions. The risk group differences in prevalence of depressive disorders were not mediated by current depressive symptoms.

Mechanism of inhibition of HIV-1 integrase by G-tetrad-forming oligonucleotides in Vitro.

The G-tetrad-forming oligonucleotides and have been identified as potent inhibitors of human immunodeficiency virus type 1 integrase (HIV-1 IN) activity (Rando, R. F., Ojwang, J., Elbaggari, A., Reyes, G. R., Tinder, R., McGrath, M. S., and Hogan, M. E. (1995) J. Biol. Chem. 270, 1754-1760; Mazumder, A., Neamati, N., Ojwang, J. O., Sunder, S., Rando, R. F., and Pommier, Y. (1996) Biochemistry 35, 13762-13771; Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992-34999). To understand the inhibition of HIV-1 IN activity by the G-quartet inhibitors, we have designed the oligonucleotides and, composed of three and four G-quartets with stem lengths of 19 and 24 A, respectively. The fact that increasing the G-quartet stem length from 15 to 24 A kept inhibition of HIV-1 IN activity unchanged suggests that the binding interaction occurs between a GTGT loop domain of the G-quartet inhibitors and a catalytic site of HIV-1 IN, referred to as a face-to-face interaction. Docking the NMR structure of (Jing and Hogan (1998)) into the x-ray structure of the core domain of HIV-1 IN, HIV-1 IN-(51-209) (Maignan, S., Guilloteau, J.-P. , Qing, Z.-L., Clement-Mella, C., and Mikol, V. (1998) J. Mol. Biol. 282, 359-368), was performed using the GRAMM program. The statistical distributions of hydrogen bonding between HIV-1 IN and were obtained from the analyses of 1000 random docking structures. The docking results show a high probability of interaction between the GTGT loop residues of the G-quartet inhibitors and the catalytic site of HIV-1 IN, in agreement with the experimental observation.

Stability-activity relationships of a family of G-tetrad forming oligonucleotides as potent HIV inhibitors. A basis for anti-HIV drug design.

Recently, we have demonstrated that T30695, a G-tetrad-forming oligonucleotide, is a potent inhibitor of human immunodeficiency virus, type I (HIV-1) integrase and the K(+)-induced loop folding of T30695 plays a key role in the inhibition of HIV-1 integrase (Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992-34999). Here we have modified T30695 by introducing a hydrophobic bulky group, propynyl dU, or a positively charged group, 5-amino dU, into the bases of T residues of the loops, and by substitution of the T-G loops by T-T loops. Physical measurements have demonstrated that the substitution of propynyl dU or 5-amino dU for T in the T residues of the loops did not alter the structure of T30695, and these derivatives also formed an intramolecular G-quartet structure, which is an essential requirement for anti-HIV activity. Measured IC(50) and EC(50) values show that these substitutions did not induce an apparent decrease in the ability to inhibit HIV-1 integrase activity and in the inhibition of HIV-1 replication in cell culture. However, the substitution of T-T loops for T-G loops induced a substantial decrease in both thermal stability and anti-HIV activity. The data analysis of T30695 and the 21 derivatives shows a significant, functional correlation between thermal stability of the G-tetrad structure and the capacity to inhibit HIV-1 integrase activity and between thermal stability of the G-tetrad structure and the capacity to inhibit HIV-1 replication, as assessed with the virus strains HIV-1 RF, IIIB, and MN in cell culture. This relationship between thermostability and activity provides a basis for improving the efficacy of these compounds to inhibit HIV-1 integrase activity and HIV-1 replication in cell culture.

Depressogenic cognitive styles: predictive validity, information processing and personality characteristics, and developmental origins.

Two of the major cognitive theories of depression, the theory of Beck [Beck, A. T. (1967). Depression: clinical, experimental and theoretical aspects. New York: Harper & Row. and Beck, A. T. (1987) Cognitive models of depression. Journal of Cognitive Psychotherapy: an International Quarterly, 1, 5-37] and the hopelessness theory [Abramson, Metalsky, & Alloy, (1989) Hopelessness depression: a theory-based subtype of depression. Psychological Review, 96, 358-372], include the hypothesis that particular negative cognitive styles increase individuals' likelihood of developing episodes of depression, in particular, a cognitively mediated subtype of depression, when they encounter negative life events. The Temple-Wisconsin Cognitive Vulnerability to Depression (CVD) project is a two-site, prospective longitudinal study designed to test this cognitive vulnerability hypothesis, as well as the other etiological hypotheses of Beck's and the hopelessness theories of depression. In this article, based on CVD project findings to date, we review evidence that the hypothesized depressogenic cognitive styles do indeed confer vulnerability for clinically significant depressive disorders and suicidality. In addition, we present evidence regarding moderators of these depressogenic cognitive styles, the information processing and personality correlates of these styles and the possible developmental antecedents of these styles. We end with a consideration of future research directions and the clinical implications of cognitive vulnerability to depression.

Structure-activity of tetrad-forming oligonucleotides as a potent anti-HIV therapeutic drug.

Recently, we have described the design and characterization of oligonucleotides containing only G and T bases, i.e. T30695 and T30177, that are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in culture (Jing, N., Rando, R. F., Pommier, Y., and Hogan, M. E. (1997) Biochemistry 36, 12498-12505). To understand that observation and to rationalize the generally high thermal stability of oligonucleotide folding for these compounds, we have used NMR methods, coupled to molecular modeling, to obtain a high resolution structure model for T30695, which is the most potent of the integrase inhibitors that have been identified thus far. Modeling and NMR data obtained in the presence of Li+ ions show that T30695 assumes an intramolecular fold with a distorted G-octet core and a set of three open, partially disordered loops. This is referred to as Li+-form structure. The NMR-based model suggests that, upon coordination with three K+ equivalents, the central G-octet becomes more regular and that the loop domains become orderly and compact. This is referred to as K+-form structure. Based upon the assay of inhibition of HIV-1 integrase, T30695 demonstrated a strong inhibition of HIV-1 integrase activity as the K+-form structure, but a poor inhibition of HIV-1 integrase activity as the Li+-form structure. The structure/activity analysis suggests that the K+-induced conformation transition of the tetrad-forming oligonucleotides, such as T30695 and T30177, plays a key role in inhibition of HIV-1 integrase activity.

Suicidality and cognitive vulnerability to depression among college students: a prospective study.

Using a behavioral high-risk two-site prospective design, we tested the cognitive vulnerability hypotheses about suicidality. Consistent with prediction, the high cognitive risk (HR) participants were more likely than the low cognitive risk (LR) participants to exhibit suicidality, measured by both structured diagnostic interview and questionnaire self-report, during the 2 1/2 year prospective follow-up period. Moreover, when the prospective period was examined as a whole, the mediation hypothesis derived from the cognitive theories was strongly supported. Hopelessness appeared to mediate the obtained relationship between cognitive vulnerability and suicidality. Finally, the obtained relationship between cognitive vulnerability and suicidality was not mediated by other hypothesized risk factors for suicidality not specified in the cognitive theories, such as past suicidality, personal history of depressive disorders, borderline and antisocial personality dysfunction, and parental history of depression.

The dynamic self: how the content and structure of the self-concept change with mood.

Change in the content and structure of the self-concept was examined in a 2-year prospective study of depression. A self-descriptive card-sorting task measured the self-concepts of participants who were either high or low in cognitive vulnerability to depression at 2 times, once when their mood was low and once when it was not. Analyses examined change in the positive and negative content of the self-concept and in 3 features of self-structure: differential importance, compartmentalization, and self-complexity. Findings suggest that change in the content of the self-concept simply reflects life circumstances, whereas change in self-structure may help to counteract stress and negative mood.

Comparison of four diagnostic methods for detection of Helicobacter species in laboratory mice.

Four species of Helicobacter--H. muridarum, "H. rappini," H. hepaticus, and H. bilis--have been identified in the gastrointestinal tract of rodents. The association of Helicobacter species with chronic gastrointestinal diseases in mice has raised concern about their impact on research results. In this study, different methods for detection of Helicobacter species in the mouse intestinal tract were compared: polymerase chain reaction (PCR) amplification of 16S rRNA gene sequences, bacterial culture, electron microscopy, and histologic examination (Steiner stain). The PCR method was more sensitive in detecting murine Helicobacter species than was culture, electron microscopy, or histologic examination. Of the cecal specimens identified as Helicobacter species-positive by PCR, approximately 60% were identified as positive by each of the other methods. An 87.5% concordance was obtained by PCR screening of DNA from fecal and cecal specimens. Differentiation among murine Helicobacter species by colony morphologic or histologic features was not possible. Scanning electron microscopy and histologic examination indicated greater numbers of helical microorganisms, specifically H. hepaticus, in the cecum than in the colon. These results indicate that the PCR assays used can be performed on feces as a noninvasive means for rapidly screening large numbers of colony mice for murine Helicobacter species.

Ion selective folding of loop domains in a potent anti-HIV oligonucleotide.

Previously, we have described inhibition of HIV-1 infection by T30177, 5'-(GTGGTGGGTGGGTGGGT)-3', an oligonucleotide that is a potent inhibitor of HIV-1 integrase in vitro (Mazumder et al. (1996) Biochemistry 35, 13762). Here a family of oligonucleotides, analogs of T30177, has been studied. On the basis of thermal denaturation, we show that a folded structure of T30177 is much more stable than that of the thrombin binding aptamer, which only differs with T30177 in the loop sequence. Sequence changes reveal that loop interactions are solely responsible for this observed stability difference. In the presence of K+ ion, the fold of T30695, a designed 16mer derivative, is indeed more stable than T30177. Loop folding within T30695 is very ion selective. Quantitative analysis of thermal denaturation suggests that the loops of T30695, 5'-(GGGTGGGTGGGTGGGT)-3', and T30177 confer the ability to coordinate three equivalents of K+ ion (one bound to the core octet and two bound to the loops); however, the thrombin binding aptamer is shown to bind only one K+ equivalent. Folding kinetics and CD titration demonstrate that K+-induced folding of T30695 and T30177 is a two-step process, consistent with a sequential model in which a first equivalent of K+ binds to the octet core, followed by slow K+-induced rearrangement of the loop domains. Comparing structural stability with the capacity of the folded oligomers to inhibit the HIV-1 integrase enzyme in vitro or HIV-1 infection in cell culture, we have found that the folding and activity data are highly correlated, suggesting that formation of an orderly, ion-coordinated loop structure similar to that in T30177 or T30695 may be a prerequisite for both integrase inhibition and anti-HIV-1 activity.

Sequence-specific inhibition of the tumor necrosis factor-alpha receptor I gene by oligodeoxynucleotides containing N7 modified 2'-deoxyguanosine.

Tumor necrosis factor-alpha (TNF-alpha) is a highly pleiotropic cytokine produced mainly by activated macrophages. This cytokine has been found to mediate the growth of certain tumors, the replication of HIV-1, septic shock, cachexia, graft-versus-host disease, and autoimmune diseases. The binding of TNF-alpha to the p55 tumor necrosis factor receptor type I (TNFRI) is considered one of the initial steps responsible for the multiple physiologic effects mediated by TNF-alpha. The role of TNF-alpha as an inflammatory mediator through TNFRI makes both of these genes attractive targets for intervention in both acute and chronic inflammatory diseases. We have designed antisense oligodeoxynucleotides (ODNs) containing chemically modified purine and pyrimidine bases that specifically inhibit TNFRI expression and functions. These ODNs were designed to hybridize to the 3'-polyadenylation signal region of the TNFRI gene. In cell-based assays, gene-specific antisense inhibition occurred in a dose-dependent fashion at submicromolar concentrations in the presence of cellular uptake enhancing agents. Within ODN sets with a common pattern of stabilizing backbone substitution, the inhibition of the gene expression is found to be correlated with the affinity of the ODNs for their cognate mRNA target sites, providing direct evidence for an antisense mechanism of action. In addition, events triggered by the binding of TNF-alpha to TNFRI, such as the production of IL-6 and IL-8, were significantly reduced by treatment of cells with the anti-TNFRI ODN. Therefore, antisense ODNs can be used to control biologic processes mediated by TNF-alpha and may be useful as therapeutic agents to treat conditions resulting from overproduction of TNF-alpha.

Harlequin ichthyosis (ichq): a juvenile lethal mouse mutation with ichthyosiform dermatitis.

The harlequin ichthyosis (ichq) mouse mutation arose spontaneously in 1989 in a colony of BALB/cJ mice at The Jackson Laboratory. Affected mice developed thick skin due to formation of compact, orthokeratotic scales that fractured over articular surfaces, secondary to bending. Harlequin ichthyosis mice on the inbred BALB/cJ background died between 9 and 12 days of age. Onset of the clinical phenotype corresponded with emergence of hair fibers from follicles at 5 days of age. There was marked proliferation of the root sheaths of anagen hair follicles, limited to the region within the dermis. Sebaceous glands were present but small compared with those of littermate controls. Emerging hair fibers were surrounded by a thick, compact sheath of cornified cells. Mutant skin contained large mitochondria with lamellar-shaped, electron-dense structures at the ultrastructural level. Keratohyalin granules were smaller and less pleomorphic than those in control mice. Lamellar bodies were not evident in either mutant or littermate control mice. Using a panel of antibodies to evaluate changes in keratinocyte differentiation, mouse-specific keratin 6 was overexpressed in the suprabasilar, hyperplastic epidermis. Loricrin expression, within the cytoplasm of cells in the stratum granulosum, decreased rapidly postmortem, unlike that in normal mice where it was stable for over 24 hours postmortem. Filaggrin expression, within granules of cells in the stratum granulosum, was prominent, corresponding to hypergranulosis evident by light microscopy in mutant mouse skin. Skin grafts from harlequin ichthyosis mice grafted onto immunodeficient nude mice maintained the phenotype for the 10-week observation period. The mutant gene locus mapped to the proximal end of mouse chromosome 19 and is inherited as a fully penetrant autosomal recessive gene. The harlequin ichthyosis mouse mutation is very similar to human type 2 harlequin ichthyosis for which it may be a good model.

Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.

Mice harboring a targeted disruption of the epidermal growth factor receptor (EGFR) allele exhibit a severely disorganized hair follicle phenotype, fuzzy coat, and systemic disease resulting in death before 3 weeks. This skin phenotype was reproduced in whole skin grafts and in grafts of EGFR null hair follicle buds onto nude mice, providing a model to evaluate the natural evolution of skin lacking the EGFR. Hair follicles in grafts of null skin did not progress from anagen to telogen and scanning electron micrografts revealed wavy, flattened hair fibers with cuticular abnormalities. Many of the EGFR null hair follicles in the grafted skin were consumed by an inflammatory reaction resulting in complete hair loss in 67% of the grafts by 10 weeks. Localization of follicular differentiation markers including keratin 6, transglutaminase, and the hair keratins mHa2 and hacl-1 revealed a pattern of premature differentiation within the null hair follicles. In intact EGFR null mice, proliferation in the interfollicular epidermis, but not hair follicles, was greatly decreased in the absence of EGFR. In contrast, grafting of EGFR null skin resulted in a hyperplastic response in the epidermis that did not resolve even after 10 weeks, although the wound-induced hyperplasia in EGFR wild-type grafts had resolved within 3 to 4 weeks. Thus, epithelial expression of the EGFR has complex functions in the skin. It is important in delaying follicular differentiation, may serve to protect the hair follicle from immunological reactions, and modifies both normal and wound-induced epidermal proliferation but seems dispensable for follicular proliferation.

Modified antisense oligonucleotides directed against tumor necrosis factor receptor type I inhibit tumor necrosis factor alpha-mediated functions.

Tumor necrosis factor alpha (TNF alpha), a polypeptide produced by activated macrophages, is a highly pleiotropic cytokine which elicits inflammatory and immunological reactions. The binding of TNF alpha to tumor necrosis factor receptor type I (TNFRI) is considered the initial step responsible for some of the multiple biological functions mediated by TNF alpha. The role of TNF alpha as an inflammatory mediator through human TNFRI makes TNFRI an attractive target for intervention in both acute and chronic inflammatory diseases. In this study, we have identified partial phosphorothioate oligodeoxyribonucleotides (ODNs) containing C-5 propynyl or hexynyl derivatives of 2'-deoxyuridine which specifically inhibited TNFRI and subsequently inhibited the functions of TNF alpha mediated through TNFRI. The most active ODNs were directed against the 3'-poly adenylation signal site on the TNFRI mRNA, and in a cellular assay, gene-specific antisense inhibition occurred in a dose-dependent fashion at submicromolar concentrations, in the presence of Cellfectin. The inhibition of gene expression correlated with the binding affinity of the ODN for the target mRNA. The ODNs lowered TNFRI protein levels and TNF alpha-mediated functions by specifically reducing levels of TNFRI mRNA. These anti-TNFRI ODNs offer a novel approach for controlling biological functions of TNF alpha and may be useful as human therapeutic agents for treating diseases in which TNF alpha has been implicated.

Angora mouse mutation: altered hair cycle, follicular dystrophy, phenotypic maintenance of skin grafts, and changes in keratin expression.

Angora is an autosomal recessive mouse mutation caused by a deletion of approximately 2 kilobases in the fibroblast growth factor 5 (Fgf5) gene. Phenotypically, homozygous angora (Fgf5go/Fgf5go) mice have excessively long truncal hair and can be differentiated from heterozygous (+/Fgf5go) and wild-type (+/+) littermates by 21 days of age. Abnormal hair length is due to a prolongation of the anagen phase of the hair cycle of approximately 3 days. In addition, widely scattered hair follicles produce structurally defective hair shafts that twist within the follicle, presumably causing secondary hyperplasia of the outer root sheath and epidermis adjacent to the follicle. These follicular abnormalities were accentuated by immunohistochemical detection of mouse specific keratin 6, a nonspecific marker of epidermal hyperplasia. These abnormalities could be identified from birth throughout life in angora mice genotyped by polymerase chain reaction techniques. Moreover, the long truncal hair phenotype was maintained in skin grafted onto C.B-17/Sz-scid/scid mice that had normal pelage hairs and hair cycles, suggesting that circulating or diffusible humoral factors regulating the mouse hair cycle are not involved in this mutation. The angora mutation provides another useful mouse model for studying the hair cycle and its modulation.

Structural analysis of DNA bending induced by tethered triple helix forming oligonucleotides.

In order to monitor DNA flexibility, we have recently reported the design of an artificial DNA bending system consisting of two triple helix forming oligonucleotides (TFOs) connected by a flexible linker [Akiyama, T., & Hogan, M. E. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 12122-12127], which spans a single turn of DNA helix. Those data suggested that up to 60 degrees of bending deformation could be induced with an expenditure of energy which is much smaller than predicted from bulk flexibility parameters. In this report, the detailed structure of the bend has been investigated by three different methods: circular permutation analysis, phasing analysis, and ring closure. Circular permutation and phasing analysis suggest that the magnitude of the bend is dependent on linker length. The apparent location of the bend was estimated from circular permutation analysis to be at the duplex region intervening the two sites of triple helix formation. The electrophoretic mobility of the bent complex appears to vary with the sequence of the intervening duplex region of the binding site complex, in the order of AT-rich > random > or = GC-rich sequence. Detailed fitting of the phasing data has shown that bending is not accompanied by significant twisting deformation. Ring closure analysis with T4 DNA ligase has confirmed the general magnitude of the TFO-induced bend and has additionally suggested that formation of the simple linear antiparallel triple helix does not enhance DNA flexibility.