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.

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.

Posttraumatic stress disorder in the National Comorbidity Survey.

BACKGROUND: Data were obtained on the general population epidemiology of DSM-III-R posttraumatic stress disorder (PTSD), including information on estimated life-time prevalence, the kinds of traumas most often associated with PTSD, sociodemographic correlates, the comorbidity of PTSD with other lifetime psychiatric disorders, and the duration of an index episode. METHODS: Modified versions of the DSM-III-R PTSD module from the Diagnostic Interview Schedule and of the Composite International Diagnostic Interview were administered to a representative national sample of 5877 persons aged 15 to 54 years in the part II subsample of the National Comorbidity Survey. RESULTS: The estimated lifetime prevalence of PTSD is 7.8%. Prevalence is elevated among women and the previously married. The traumas most commonly associated with PTSD are combat exposure and witnessing among men and rape and sexual molestation among women. Posttraumatic stress disorder is strongly comorbid with other lifetime DSM-III-R disorders. Survival analysis shows that more than one third of people with an index episode of PTSD fail to recover even after many years. CONCLUSIONS: Posttraumatic stress disorder is more prevalent than previously believed, and is often persistent. Progress in estimating age-at-onset distributions, cohort effects, and the conditional probabilities of PTSD from different types of trauma will require future epidemiologic studies to assess PTSD for all lifetime traumas rather than for only a small number of retrospectively reported "most serious" traumas.

Prevalence and correlates of drug use and dependence in the United States. Results from the National Comorbidity Survey.

OBJECTIVES: To analyze nationally representative data on the lifetime and 12-month prevalences of use of and dependence on illegal drugs (marijuana/hashish, cocaine/crack, heroin, hallucinogens), nonmedical prescription psychotropic drugs (sedatives, tranquilizers, stimulants, analgesics), and inhalants; and to examine data on the sociodemographic correlates of use and dependence. METHODS: The data come from the National Comorbidity Survey, a structured diagnostic interview administered to persons aged 15 to 54 years that generates reliable diagnoses according to the definitions and criteria of DSM-III-R. RESULTS: Of the respondents, 51.0% used one of the above drugs at some time in their lives, and 15.4% did so in the past 12 months. These estimates are similar to those obtained in the 1991 National Household Survey of Drug Abuse, where lifetime prevalence was 45.2% and 12-month prevalence was 16.7% among respondents in the age range 15 to 54 years. Of National Comorbidity Survey respondents, 7.5% (14.7% of lifetime users) were dependent at some time in their lives and 1.8% were dependent in the past 12 months. The prevalence estimate for lifetime dependence was reduced to 5.3% when calculated the percentage of respondents in the age range of 28 to 54 years who reported an onset of dependence as of 10 years earlier (ie, when they were 18 to 44 years old) was computed. This is similar to the Epidemiologic Catchment Area Study estimate of 5.1% among respondents in the age range 18 to 44 years, a comparison that matches the two studies on year of assessment, age of risk, and cohort. Males were significantly more likely to report both lifetime and 12-month use and dependence. Use and dependence were found to be more common in cohorts born after World War II than those born before the end of the war. The demographic predictors of lifetime use differed from the predictors of lifetime dependence among users, and these, in turn, differed from the predictors of recent dependence among people with a lifetime history of dependence. CONCLUSIONS: Drug use and dependence are highly prevalent in the general population. The fact that there are differences in the correlates of first use, dependence among users, and persistence of dependence means that future research aimed at pinpointing modifiable risk factors must be based on disaggregated analyses of separate stages of progression.

Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.

BACKGROUND: This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States. METHODS: The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview. RESULTS: Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status. CONCLUSIONS: The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.

Synthesis of 1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyrido[3,4-f]- quinoxaline-2,3-dione and related quinoxalinediones: characterization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (and N-methyl-D-aspartate) receptor and anticonvulsant activity.

Four related series of substituted quinoxalinediones containing angular fused-piperidine rings have been synthesized as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists with potential as neuroprotective agents, primarily for acute therapy immediately following a stroke. The compounds were tested for their affinity to the AMPA, kainate, and strychnine-insensitive glycine receptor sites. In AMPA binding, the most potent compound was 27a (PNQX, IC50 = 63 nM), with affinity comparable to the literature standard 1 (NBQX, IC50 = 52 nM). Other 6-nitro analogs from the 9-aza series had comparable affinity at the AMPA receptor, as did 6-nitro-8-aza derivatives such as 13a (iPNQX, IC50 = 290 nM). The receptor binding profile of 27a differed from that of 1 in that 27a possessed significant affinity at the glycine site of the N-methyl-D-aspartate (NMDA) receptor, whereas 1 was essentially inactive. Three compounds, 26c, 26d, and 26e, demonstrated moderate selectivity for kainate relative to AMPA receptors. Selected analogs reported herein as well as in the literature were superimposed to generate an AMPA pharmacophore model, and 6-substituted compounds from the PNQX and iPNQX series were combined and analyzed via quantitative structure-activity relationship techniques. Compounds with high affinity at non-NMDA receptors were further characterized in functional assays in neuronal cell culture and in a cortical wedge preparation. Both 1 and 27a showed comparable effectiveness in an AMPA- and kainate-induced excitoxicity assay. Both inhibited AMPA-induced depolarizations in the cortical wedge. However, 27a also inhibited spontaneous epileptiform discharges in the cortical wedge (reversed by glycine), while 1 was ineffective. The combination of AMPA and NMDA antagonist activity may contribute to the 30-fold difference in potency between 27a and 1 in the maximal electroshock convulsant assay in mice. The significant in vivo potency of 27a suggests that it has potential clinical utility.

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.

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).

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.

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.

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.

Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence.

Basic epidemiologic prevalence data are presented on sex differences in DSM-III-R major depressive episodes (MDE). The data come from the National Comorbidity Survey (NCS), the first survey in the U.S. to administer a structured psychiatric interview to a nationally representative sample of the general population. Consistent with previous research, women are approximately 1.7 times as likely as men to report a lifetime history of MDE. Age of onset analysis shows that this sex difference begins in early adolescence and persists through the mid-50s. Women also have a much higher rate of 12-month depression than men. However, women with a history of depression do not differ from men with a history of depression in either the probability of being chronically depressed in the past year or in the probability of having an acute recurrence in the past year. This means that the higher prevalence of 12-month depression among women than men is largely due to women having a higher risk of first onset. The implications of these results for future research are discussed in a closing section of the paper.

Sex and depression in the National Comorbidity Survey. II: Cohort effects.

Data from a nationally representative sample of the general population are used to study cohort differences in the prevalence of DSM-III-R Major Depressive Episode (MDE). We document increasing lifetime prevalence of MDE among both men and women in more recent cohorts, but no major change in the sex ratio over the 40-year period retrospectively covered in the survey. We find a cohort difference in 12-month MDE, with older women much more likely than older men to have recurrent episodes. This sex difference in recurrence plays an important part in the elevated 12-month prevalence of depression among women compared to men in the 45-54 age range.

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.

An estimation of daily food usage factors for assessing radionuclide intakes in the U.S. population.

We have statistically analyzed data from the 1977-78 USDA Nationwide Food Consumption Survey to estimate the daily average food intakes by individuals in the general population and various subpopulations of the United States. These estimates are intended for use in assessing radionuclide intake by individuals through food consumption. We have also compared our results with those from other studies.

Estimates of radiogenic cancer risks.

A methodology recently developed by the U.S. EPA for estimating the carcinogenic risks from ionizing radiation is described. For most cancer sites, the risk model is one in which age-specific, relative risk coefficients are obtained by taking a geometric mean of the coefficients derived from the atomic bomb survivor data using two different methods for transporting risks from the Japanese to the U.S. population. The risk models are applied to estimate organ-specific risks per unit dose for a stationary population with mortality rates governed by 1980 U.S. vital statistics. With the exception of breast cancer, low-LET radiogenic cancer risk estimates are reduced by a factor of 2 at low doses and dose rates compared to acute high dose exposure conditions. For low dose (or dose rate) conditions, the risk of inducing a premature cancer death from uniform, whole body, low-LET irradiation is calculated to be 5.1 x 10(-2) Gy-1. Neglecting nonfatal skin cancers, the corresponding incidence risk is 7.6 x 10(-2) Gy-1. High-LET (alpha particle) risks are presumed to increase linearly with dose and to be independent of dose rate. High-LET risks are estimated to be 20 times the low-LET risks estimated under low dose rate conditions, except for leukemia and breast cancer where RBEs of 1 and 10 are adopted, respectively.

Bone cancer risk estimates.

Due to confusion between endosteal (bone surface) dose and average skeletal dose, ICRP 60 has substantially overestimated the risk of radiogenic bone cancer. This confusion apparently stems from an incorrect reading of the BEIR IV report, which does not clearly draw this distinction. It should also be noted that what appear to be summary numerical risk estimates for bone sarcoma induction in BEIR IV and BEIR V refer only to average skeletal dose as calculated for 224Ra.

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.