All-electrical skyrmionic magnetic tunnel junction.

Topological whirls or 'textures' of spins such as magnetic skyrmions represent the smallest realizable emergent magnetic entities1-5. They hold considerable promise as robust, nanometre-scale, mobile bits for sustainable computing6-8. A longstanding roadblock to unleashing their potential is the absence of a device enabling deterministic electrical readout of individual spin textures9,10. Here we present the wafer-scale realization of a nanoscale chiral magnetic tunnel junction (MTJ) hosting a single, ambient skyrmion. Using a suite of electrical and multimodal imaging techniques, we show that the MTJ nucleates skyrmions of fixed polarity, whose large readout signal-20-70% relative to uniformly magnetized states-corresponds directly to skyrmion size. The MTJ exploits complementary nucleation mechanisms to stabilize distinctly sized skyrmions at zero field, thereby realizing three non-volatile electrical states. Crucially, it can electrically write and delete skyrmions to both uniform states with switching energies 1,000 times lower than the state of the art. Here, the applied voltage emulates a magnetic field and, in contrast to conventional MTJs, it reshapes both the energetics and kinetics of the switching transition, enabling deterministic bidirectional switching. Our stack platform enables large readout and efficient switching, and is compatible with lateral manipulation of skyrmionic bits, providing the much-anticipated backbone for all-electrical skyrmionic device architectures9,10. Its wafer-scale realizability provides a springboard to harness chiral spin textures for multibit memory and unconventional computing8,11.

A synergistic combination of local tight binding theory and second harmonic generation elucidating surface properties of ZnO nanoparticles.

Zinc oxide (ZnO) in the form of nanoparticles (NPs) is an important nanomaterial due to its catalytic and optoelectronic properties. An interesting aspect of ZnO is that its crystal structure is anisotropic, which leads to a strong 2nd order nonlinear response, such as frequency doubling or second harmonic generation (SHG). In this article we show that not only the bulk but the surface of ZnO NPs in contact with a liquid medium can contribute to the overall SHG. We have developed and applied a synergistic combination of tight binding (TB) theory and optical SHG spectroscopy to determine the surface second order susceptibilities of nearly spherical 33 ± 13 nm crystalline ZnO NPs dispersed in acetonitrile. The corresponding χ and χ were determined to be 0.86 × 10-8 esu and 1.72 × 10-8 esu for the O-terminated surface and 3.28 × 10-8 esu and 6.64 × 10-8 esu for the Zn-terminated surface. A further application of the TB-SHG approach revealed that adsorption of coumarin based dye, which forms a bidentate attachment between the carboxyl and Zn-terminated surface, does not restructure the NP surface significantly to manifest a change in the SHG polarization profile. However, if the dye acts as an independent source of SHG, its orientation on the surface dictates the overall change in the observed SHG. The results highlighted here bear a strong potential to further our knowledge of molecular interactions at the solid-liquid interface of crystalline nanostructures.

Design and synthesis of novel quinoxaline-2,3-dione AMPA/GlyN receptor antagonists: amino acid derivatives.

PNQX (1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3, 4-f]quinoxaline-2,3-dione) is a potent AMPA (IC50 = 0.063 microM) and GlyN (IC50 = 0.37 microM) receptor antagonist that was developed in our laboratories. While possessing a desirable in vitro and in vivo activity profile, this compound suffers from low aqueous solubility. In an effort to improve its potency and physical properties, we have designed and synthesized novel ring-opened analogues 4, 6, 9, and 11. Modeling analyses demonstrated that, while the 5-substituent in these analogues was forced to adopt an out-of-plane conformation due to steric contacts with neighboring substituents, the overall structure retained a good fit to a previously described AMPA pharmacophore model. This nonplanar orientation may lessen efficient packing in the solid state, compared to PNQX, leading to increased water solubility. Indeed, several nonplanar analogues containing appropriate functionalities, for example, the sarcosine analogue 9, were found to retain AMPA (IC50 = 0.14 microM) and GlyN (IC50 = 0.47 microM) receptor affinity and possess improved aqueous solubility compared to PNQX. The synthesis and the SAR of these compounds are discussed.

Identification and characterization of m1 selective muscarinic receptor antagonists1.

A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential m1 selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtypes (Hm1-Hm5) was determined by the displacement of [3H]-NMS binding using membranes from transfected Chinese hamster ovarian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R1 = (CH2)5CH3], which has an IC50 value of 27.3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this analogue appears to be more selective on the basis of binding than the prototypical m1 antagonist, pirenzepine. Functional data, such as the inhibition of carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogues confirmed the muscarinic antagonistic properties of this chemical series.

Factor structures for DSM-IV substance disorder criteria endorsed by alcohol, cannabis, cocaine and opiate users: results from the WHO reliability and validity study.

AIMS: The factor structure of DSM-IV substance disorder criteria is examined among alcohol, cannabis, cocaine and opiate users to determine the dimensionality of abuse and dependence criteria within each of these drug classes and whether a common construct can be generalized across drug classes. DESIGN: 12-month criterion prevalence was assessed as part of the World Health Organization's Study on the Reliability and Validity of the Alcohol and Drug Use Disorder Instruments in various settings at eight sites around the world using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). A majority of respondents were recruited from non-treatment settings. In addition to exploratory factor analysis, confirmatory factor analysis was used to analyse factor structures using weighted least square methods and tetrachoric correlation matrices. Multi-sample analysis techniques were used to model differences between drug-classes. FINDINGS: In the full data analyses identified a single factor solution for each user population and across user populations. However, analyses of data from users reporting low to moderate symptomatology identified a two-dimensional construct among alcohol, cannabis and opiate users consisting of a major "dependence" factor and a lesser "abuse" factor. In addition, results showed that neither the abuse criterion "(A2) use in physical hazardous situations" or the dependence criterion "(D7) use despite knowledge of psychological/physical problems" were central to the latent construct in any of the user populations, except for D7 among alcohol users. CONCLUSIONS: The multi-dimensional results found among users with low to moderate symptomatology indicate that: (1) previous results from relatively homogeneous populations may have been biased towards lesser order solutions, and that (2) the DSM-IV substance disorder criteria describe at least two distinct phenomena, supporting the current DSM-IV organization of substance disorder criteria. Further work needs to evaluate whether prevalent symptoms are present in random or predictable combinations, whether combinations reflecting a specific hierarchy of severity can be identified, and whether incident symptoms are accumulated in a predictable pattern, within specific user populations and across user populations.

DSM-IV alcohol disorders in a general population sample of adolescents and young adults.

UNLABELLED: AIMS/DESIGNS: As part of the Early Developmental Stages of Psychopathology (EDSP) study, results from the baseline cross-sectional assessment of DSM-IV alcohol disorders are presented for a sample of 14-24-year-olds residents in Munich, Germany (N = 3021; 71% response rate). FINDINGS: Life-time prevalence of DSM-IV alcohol abuse (men: 15.1%; women; 4.5%) was found to be considerably more prevalent than dependence (men: 10.0%; women 2.5%) with few cases among respondents younger than 16 years of age; 12-month prevalence of abuse was 8.4% among men and 2.7% among women and of dependence was 7.3% among men and 2.2% among women. Results show that peak incidence of alcohol disorders occurs at 16-17 years of age and that early initiation into alcohol use is associated with an increasing odds of disorder onset, especially for dependence among women. Exploratory analysis of retrospectively assessed diagnostic stability show: a temporal progression to abuse and then dependence, that nearly half of past abuse diagnoses are in remission, abuse remission is more common than progression to dependence, and dependence is highly persistent, especially among women. CONCLUSIONS: Alcohol disorders are frequent in adolescent and young adults being characterized by transient abuse and less prevalent but persistent dependence syndromes. The relatively high prevalence of dependence diagnoses in this young population wit few years of alcohol use is discussed with regard to the clinical validity of DSM-IV criteria in adolescents and young adults.

Early developmental stages of psychopathology study (EDSP): objectives and design.

The primary and secondary objectives of the Early Developmental Stages of Substance Abuse Study (EDSP) are described along with a detailed description of the overall design, special design features and instruments used. The EDSP is a 5-year prospective study with three waves of assessments. Special design features are the linkages with family genetic investigations as well as neuroendocrinological stress tests in high-risk subjects. Overall, 3,021 adolescents and young adults aged 14-24 years are included. The response rate for the baseline investigation was 71%. Diagnostic assessments were made by using a modified lifetime (baseline) and 12-month change version of the WHO-CIDI, adjusted for DSM-IV. Modifications refer to a more detailed quantitative assessment of symptoms and substance use variables as well as the inclusion of questions to assess course of disorders and subthreshold diagnostic conditions.

Smoking and nicotine dependence. Results from a sample of 14- to 24-year-olds in Germany.

Ths paper describes the distribution of dependence criteria and diagnoses in a sample of 14- to 24-year-olds from Munich, Germany (n = 3,021; 71% response rate), evaluates differences between nondependent and dependent smokers and examines associations of smoking with other substances, affective and anxiety disorders. Assessment was made using the M-CIDI. The lifetime prevalence of DSM-IV nicotine dependence in the total sample is 19%, rising to 52% among regular smokers. No gender differences were seen in the progression from regular smoking to nicotine dependence, although men were more likely than women to initiate regular use. Analysis of daily cigarette use identified a significant dose-response relationship with the number of endorsed DSM-IV dependence criteria with unsuccessful cut-backs being the most prevalent criterion. As compared to nondependent smokers, dependent smokers were more likely to associate negative health effects with smoking and to have a desire to change and attempt a change in their pattern of use. Regular use of nicotine was found to be significantly associated with other substance and nonsubstance disorders, although dependent regular use was more strongly associated with these disorders than nondependent regular use. These results indicate that daily smoking is a behavior which is resistant to change despite an expressed desire and repeated cut-back attempts. Although initiation of regular smoking among nonsmokers does not occur frequently after the early twenties, the risk for dependent smoking among regular users persists into adulthood and is associated with a range of mental disorders.

Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist.

The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).

Temporal progression of alcohol dependence symptoms in the U.S. household population: results from the National Comorbidity Survey.

General population data are presented on patterns and predictors of temporal progression of alcohol dependence symptoms in the general population. The data come from the National Comorbidity Survey, a nationally representative general population survey of respondents ages 15-54. Lifetime symptom classes were estimated with latent class analysis (LCA). A 4-class LCA solution, including a 1st asymptomatic class and 3 progressively more serious symptomatic classes, was found to fit the data. Probability of initial symptom onset among drinkers was found to be highest in the 10-24 age range, to be higher among men than women, and to have increased dramatically in the past 4 decades. Age, gender, and cohort effects were less powerful in predicting symptom progression. A narrowing of the gender difference over time was due largely to a convergence in initial symptom onset among men and women ages 10-24. These results suggest that a rise in initial problems was more important than an increase in the transition from problems to dependence in accounting for the growing prevalence of alcohol dependence during the post-World War II years in the United States.

Prevalence of mental disorders and psychosocial impairments in adolescents and young adults.

BACKGROUND: As part of a longitudinal study, prevalence findings of DSM-IV disorders are presented for a random sample of 3021 respondents aged 14 to 24, with response rate 71%. METHOD: Assessment included various subtypes of disorders, subthreshold conditions and disorders that have only rarely been studied in other epidemiological surveys. The computer-assisted Munich-Composite International Diagnostic Interview (M-CIDI) was used to derive DSM-IV diagnoses. RESULTS: Substance disorders were the most frequent (lifetime 17.7%; 12-month 11.4%), with abuse being considerably more frequent than dependence. Other mental disorders had a lifetime prevalence of 27.5% (12-month, 17.5%) with depressive disorders (16.8%) being more frequent than anxiety disorders (14.4%). Eating disorders (3.0%) and threshold somatoform disorders (1.2%) were rare disorders. Subthreshold anxiety and somatoform disorders, however, were more frequent than threshold disorders. Prevalence of disorders was equally high for males and females, although specific disorder prevalence varied significantly by gender. The co-occurrence of disorders (co-morbidity) was substantial and was significantly related to greater reductions in work productivity and increased rates of professional helpseeking behaviour. CONCLUSIONS: Findings underline that mental disorders in young adults are frequent and impairing, limiting work and education ability and social interaction. Given the fact that adolescents and young adults are in a key phase of socialization in terms of professional career and interpersonal relationships, our findings indicate a considerable risk potential for an accumulation of complicating factors and future chronicity. This paper is the first report of this ongoing longitudinal study about early developmental conditions of mental disorders.

Pharmacological characterization of PD 152255, a novel dimeric benzimidazole dopamine D3 antagonist.

152255 (E-1,1'-(2-butene-1,4-diyl)bis[2-[4-[3-(1-piperidinyl)propoxy]-phe nyl]-1H-benzimidazole]) exhibited high affinity (Ki = 12.7 nM) for human dopamine (DA) D3 receptors expressed in CHO K1 cells but not for DA D2L receptors (Ki = 565 nM), DA D42 or DA D1 receptors (Ki > 3 microM) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D3 receptors was demonstrated by blockade of quinpirole-stimulated [3H]-thymidine uptake in D3 transfected cells, an effect that was 28-fold more potent than in D2-transfected cells. Unlike classical DA D2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D3 antagonist that may have antipsychotic activity.

Identification and characterization of m4 selective muscarinic antagonists.

Our interest in the area of m4 muscarinic antagonists had led us to study a series of benzoxazine isoquinolines. One of the most potent and selective compounds of this series is example 1 with an IC50 value of 90.7 nM at m4 receptors, and 72-fold (m1), 38-fold (m2), 10-fold (m3), and 82-fold (m5) more selective compared to the other receptors. The synthesis and receptor binding affinity of analogs of 1 are reported.

Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey.

OBJECTIVE: To study patterns of co-occurrence of lifetime DSM-III-R alcohol disorders in a household sample. METHODS: Data came from the National Comorbidity Survey (NCS), a nationally representative household survey. Diagnoses were based on a modified version of the Composite International Diagnostic Interview. RESULTS: Respondents with lifetime NCS/DSM-III-R alcohol abuse or dependence had a high probability of carrying at least 1 other lifetime NCS/DSM-III-R diagnosis. Retrospective reports have suggested that most lifetime co-occurring alcohol disorders begin at a later age than at least 1 other NCS/DSM-III-R disorder. Earlier disorders are generally stronger predictors of alcohol dependence than alcohol abuse and stronger among women than men. Lifetime co-occurrence is positively, but weakly, associated with the persistence of alcohol abuse among men and of alcohol dependence among both men and women. CONCLUSIONS: Caution is needed in interpreting the results due to the fact that diagnoses were made by nonclinicians and results are based on retrospective reports of the age at onset. Within the context of these limitations, though, these results show that alcohol abuse and dependence are often associated with other lifetime DSM-III-R disorders and suggest that, at least in recent cohorts, the alcohol use disorders are usually temporally secondary. Prospective data and data based on clinically confirmed diagnoses are needed to verify these findings.

Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey.

General population data are presented on the prevalence and correlates of comorbidity between DSM-III-R major depressive disorder (MDD) and other DSM-III-R disorders. The data come from the US National Comorbidity Survey, a large general population survey of persons aged 15-54 years in the non-institutionalised civilian population. Diagnoses are based on a modified version of the Composite International Diagnostic Interview (CIDI). The analysis shows that most cases of lifetime MDD are secondary. In the sense that they occur in people with a prior history of another DSM-III-R disorder. Anxiety disorders are the most common primary disorders. The time-lagged effects of most primary disorders on the risk of subsequent MDD continue for many years without change in magnitude. Secondary MDD is, in general, more persistent and severe than pure or primary MDD. This has special public health significance because lifetime prevalence of secondary MDD has increased in recent cohorts, while the prevalence of pure and primary depression has remained unchanged.

Patterns of DSM-III-R alcohol dependence symptom progression in a general population survey.

Age of onset reports obtained retrospectively for each symptom of DSM-III-R alcohol dependence (AD) are used to study patterns of lifetime symptom progression in a large general-population survey of people in the United States. It is shown that symptom progression among a substantial majority of respondents can be summarized as movement across three clusters. Cluster A is defined by symptoms of role impairment/hazardous use (A4), use despite social, psychological or physical problems (A6), and drinking larger amounts or over a longer period of time than intended (A1). Cluster B is defined by tolerance (A7) and impaired control (A2, A3). Cluster C is defined by withdrawal (A8, A9) and giving up activities in order to drink (A5). Clusters are shown to follow a time sequence, with at least one symptom in Cluster A usually occurring first, followed by symptoms in Clusters B and C. In all, 83.4% of the symptom cluster transitions estimated from retrospective age of onset reports are consistent with this progression. Progression to AD is differentially predicted by symptom profiles reported at the age of first symptom onset, with persons reporting Cluster C symptoms most likely to progress subsequently to AD. Furthermore, profiles of AD defined by the highest symptom cluster present at AD onset are differentially predicted by prior personal and parental histories of psychopathology and, among men, are predictive of diagnosis persistence.

The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization.

General population data from the National Comorbidity Survey are presented on co-occurring DSM-III-R addictive and mental disorders. Co-occurrence is highly prevalent in the general population and usually due to the association of a primary mental disorder with a secondary addictive disorder. It is associated with a significantly increased probability of treatment, although the finding that fewer than half of cases with 12-month co-occurrence received any treatment in the year prior to interview suggests the need for greater outreach efforts.