Anhedonia in adolescents at transdiagnostic familial risk for severe mental illness: Clustering by symptoms and mechanisms of association with behavior.

BACKGROUND: Anhedonia is a transdiagnostic symptom of severe mental illness (SMI) and emerges during adolescence. Possible subphenotypes and neural mechanisms of anhedonia in adolescents at risk for SMI are understudied. METHODS: Adolescents at familial risk for SMI (N = 81) completed anhedonia (e.g., consummatory, anticipatory, social), demographic, and clinical measures and one year prior, a subsample (N = 46) completed fMRI scanning during a monetary reward task. Profiles were identified using k-means clustering of anhedonia type and differences in demographics, suicidal ideation, impulsivity, and emotional processes were examined. Moderation analyses were conducted to investigate whether levels of brain activation of reward regions moderated the relationships between anhedonia type and behaviors. RESULTS: Two-clusters emerged: a high anhedonia profile (high-anhedonia), characterized by high levels of all types of anhedonia, (N = 32) and a low anhedonia profile (low-anhedonia), characterized by low levels of anhedonia types (N = 49). Adolescents in the high-anhedonia profile reported more suicidal ideation and negative affect, and less positive affect and desire for emotional closeness than low-anhedonia profile. Furthermore, more suicidal ideation, less positive affect, and less desire for emotional closeness differentiated the familial high-risk, high-anhedonia profile adolescents from the familial high-risk, low-anhedonia profile adolescents. Across anhedonia profiles, moderation analyses revealed that adolescents with high dmPFC neural activation in response to reward had positive relationships between social, anticipatory, and consummatory anhedonia and suicidal ideation. LIMITATIONS: Small subsample with fMRI data. CONCLUSION: Profiles of anhedonia emerge transdiagnostically and vary on clinical features. Anhedonia severity and activation in frontostriatal reward areas have value for clinically important outcomes such as suicidal ideation.

Reaching small scales with low-frequency imaging: applications to the Dark Ages.

The initial conditions for the density perturbations in the early Universe, which dictate the large-scale structure and distribution of galaxies we see today, are set during inflation. Measurements of primordial non-Gaussianity are crucial for distinguishing between different inflationary models. Current measurements of the matter power spectrum from the cosmic microwave background only constrain this on scales up to k ∼ 0.1 Mpc-1. Reaching smaller angular scales (higher values of k) can provide new constraints on non-Gaussianity. A powerful way to do this is by measuring the HI matter power spectrum at [Formula: see text]. In this paper, we investigate what values of k can be reached for the Low-Frequency Array (LOFAR), which can achieve [Formula: see text]1″ resolution at approximately 50 MHz. Combining this with a technique to isolate the spectrally smooth foregrounds to a wedge in [Formula: see text]-k⊥ space, we demonstrate what values of k we can feasibly reach within observational constraints. We find that LOFAR is approximately five orders of magnitude away from the desired sensitivity, for 10 years of integration time. This article is part of a discussion meeting issue 'Astronomy from the Moon: the next decades'.

The Global Landscape of Occupational Exposure Limits--Implementation of Harmonization Principles to Guide Limit Selection.

Occupational exposure limits (OELs) serve as health-based benchmarks against which measured or estimated workplace exposures can be compared. In the years since the introduction of OELs to public health practice, both developed and developing countries have established processes for deriving, setting, and using OELs to protect workers exposed to hazardous chemicals. These processes vary widely, however, and have thus resulted in a confusing international landscape for identifying and applying such limits in workplaces. The occupational hygienist will encounter significant overlap in coverage among organizations for many chemicals, while other important chemicals have OELs developed by few, if any, organizations. Where multiple organizations have published an OEL, the derived value often varies considerably-reflecting differences in both risk policy and risk assessment methodology as well as access to available pertinent data. This article explores the underlying reasons for variability in OELs, and recommends the harmonization of risk-based methods used by OEL-deriving organizations. A framework is also proposed for the identification and systematic evaluation of OEL resources, which occupational hygienists can use to support risk characterization and risk management decisions in situations where multiple potentially relevant OELs exist.

Why do anxious children become depressed teenagers? The role of social evaluative threat and reward processing.

BACKGROUND: Depression is a leading cause of worldwide disability. Adolescence represents a key developmental window in which rates of this disorder increase markedly. Children with an anxiety disorder show a particular risk of developing depression during adolescence. METHOD: We present and review evidence for a developmental model that considers the intersection of two vulnerabilities relevant to the trajectory from anxiety to depression: difficulties in response to potential social evaluation and changes in reward processing at puberty. RESULTS: Evidence suggests that these vulnerabilities (a) have been associated with depression, (b) are likely to be problematic in many, but not all, anxious youth, and (c) may be exacerbated by maturational processes that occur around pubertal development in ways that can create a negative spiral into a depressive disorder. CONCLUSIONS: We discuss the possibility that early intervention strategies targeting key aspects of these vulnerabilities could alter the trajectory away from depression for many anxious youth.

Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141(+)XCR1+ dendritic cells.

Monocyte-derived dendritic cells (moDC) have been widely used in cancer immunotherapy but show significant donor-to-donor variability and low capacity for the cross-presentation of tumour-associated antigens (TAA) to CD8(+) T cells, greatly limiting the success of this approach. Given recent developments in induced pluripotency and the relative ease with which induced pluripotent stem (iPS) cell lines may be generated from individuals, we have succeeded in differentiating dendritic cells (DC) from human leukocyte antigen (HLA)-A(*)0201(+) iPS cells (iPS cell-derived DC (ipDC)), using protocols compliant with their subsequent clinical application. Unlike moDC, a subset of ipDC was found to coexpress CD141 and XCR1 that have been shown previously to define the human equivalent of mouse CD8α(+) DC, in which the capacity for cross-presentation has been shown to reside. Accordingly, ipDC were able to cross-present the TAA, Melan A, to a CD8(+) T-cell clone and stimulate primary Melan A-specific responses among naïve T cells from an HLA-A(*)0201(+) donor. Given that CD141(+)XCR1(+) DC are present in peripheral blood in trace numbers that preclude their clinical application, the ability to generate a potentially unlimited source from iPS cells offers the possibility of harnessing their capacity for cross-priming of cytotoxic T lymphocytes for the induction of tumour-specific immune responses.

Male-immature relationships in multi-male groups of mountain gorillas (Gorilla beringei beringei).

We examined the pattern and possible functions of social interactions between adult males and immatures in three free-ranging, multi-male groups of mountain gorillas (Gorilla beringei beringei). Previous studies conducted during the 1970s when groups contained one to three adult males concluded that male-immature relationships were likely to be a form of low-cost paternal investment [Stewart, Mountain gorillas: three decades of research at Karisoke. Cambridge, UK: Cambridge University Press, 2001]. We evaluated whether this hypothesis still held in groups containing six to nine adult males, or if male-immature relationships might serve other functions (e.g. mating effort, kin selection, or alliance building). Overall, we found that immatures spent the most time near, and interacted most with, the alpha silverback. These behaviors peaked during the period when infants were still quite vulnerable but increasing their independence from their mothers. Such findings suggest that parenting effort remains the primary function of male-immature relationships; however, there is some evidence for the mating effort hypothesis as well.

The role of black holes in galaxy formation and evolution.

Virtually all massive galaxies, including our own, host central black holes ranging in mass from millions to billions of solar masses. The growth of these black holes releases vast amounts of energy that powers quasars and other weaker active galactic nuclei. A tiny fraction of this energy, if absorbed by the host galaxy, could halt star formation by heating and ejecting ambient gas. A central question in galaxy evolution is the degree to which this process has caused the decline of star formation in large elliptical galaxies, which typically have little cold gas and few young stars, unlike spiral galaxies.

Seasonal sexual segregation in two Thalassarche albatross species: competitive exclusion, reproductive role specialization or foraging niche divergence?

Sexual segregation by micro- or macrohabitat is common in birds, and usually attributed to size-mediated dominance and exclusion of females by larger males, trophic niche divergence or reproductive role specialization. Our study of black-browed albatrosses, Thalassarche melanophrys, and grey-headed albatrosses, T. chrysostoma, revealed an exceptional degree of sexual segregation during incubation, with largely mutually exclusive core foraging ranges for each sex in both species. Spatial segregation was not apparent during brood-guard or post-guard chick rearing, when adults are constrained to feed close to colonies, providing no evidence for dominance-related competitive exclusion at the macrohabitat level. A comprehensive morphometric comparison indicated considerable species and sexual dimorphism in wing area and wing loading that corresponded, both within and between species, to broad-scale habitat preferences relating to wind strength. We suggest that seasonal sexual segregation in these two species is attributable to niche divergence mediated by differences in flight performance. Such sexual segregation may also have implications for conservation in relation to sex-specific overlap with commercial fisheries.

Probing large distance higher-dimensional gravity with cosmic microwave background measurements.

Higher-dimensional gravity theories may manifest themselves not only at short microscopic distances but also at large cosmological scales. We study the constraints that cosmic microwave background measurements set on such large distance modifications of the gravitational potential.

A new approach to the management of pretibial lacerations.

This paper describes a technique for the management of pretibial lacerations by deep reinforced suturing through steristrips, which are applied parallel to the wound edges. This is carried out under local anaesthesia and followed by application of gentle localised compression dressing. Typical victims of pretibial lacerations are the elderly and patients on long-term systemic steroid therapy. This suturing technique, which was used on both flap and linear lacerations, obliterates the dead space in the wound and prevents tearing of the thin, fragile skin of these patients. The dressing technique used, has a great advantage over the toes to knee pressure dressing currently used for such lacerations, because it frees the foot of bandaging and allows the patients (especially the elderly with decreased mobility) to wear their normal footwear immediately post-operatively and to maintain their normal mobility. In the total sample of 147 patients treated by this method, the average healing time was 26 days for 112 patients with flap lacerations, and 16 days for the remaining 35 patients with linear lacerations. This is significantly shorter than that reported in the medical literature using both non-operative methods and simple suturing. Moreover, none of these patients required skin grafting or hospitalisation (except for social reasons).

Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux.

Inhibitory gamma-aminobutyric acid (GABA)(A) receptors are subject to modulation at a variety of allosteric sites, with pharmacology dependent on receptor subunit combination. The influence of different alpha subunits in combination with beta3gamma2s was examined in stably expressed human recombinant GABA(A) receptors by measuring (36)Cl influx through the ion channel pore. Muscimol and GABA exhibited similar maximal efficacy at each receptor subtype, although muscimol was more potent, with responses blocked by picrotoxin and bicuculline. Receptors containing the alpha3 subunit exhibited slightly lower potency. The comparative pharmacology of a range of benzodiazepine site ligands was examined, revealing a range of intrinsic efficacies at different receptor subtypes. Of the diazepam-sensitive GABA(A) receptors (alpha1, alpha2, alpha3, alpha5), alpha5 showed the most divergence, being discriminated by zolpidem in terms of very low affinity, and CL218,872 and CGS9895 with different efficacies. Benzodiazepine potentiation at alpha3beta3gamma2s with nonselective agonist chlordiazepoxide was greater than at alpha1, alpha2, or alpha5 (P < 0.001). The presence of an alpha4 subunit conferred a unique pharmacological profile. The partial agonist bretazenil was the most efficacious benzodiazepine, despite lower alpha4 affinity, and FG8205 displayed similar efficacy. Most striking were the lack of affinity/efficacy for classical benzodiazepines and the relatively high efficacy of Ro15-1788 (53 +/- 12%), CGS8216 (56 +/- 6%), CGS9895 (65 +/- 6%), and the weak partial inverse agonist Ro15-4513 (87 +/- 5%). Each receptor subtype was modulated by pentobarbital, loreclezole, and 5alpha-pregnan-3alpha-ol-20-one, but the type of alpha subunit influenced the level of potentiation. The maximal pentobarbital response was significantly greater at alpha4beta3gamma2s (226 +/- 10% increase in the EC(20) response to GABA) than any other modulator. The rank order of potentiation for pregnanolone was alpha5 > alpha2 > alpha3 = alpha4 > alpha1, for loreclezole alpha1 = alpha2 = alpha3 > alpha5 > alpha4, and for pentobarbital alpha4 = alpha5 = alpha2 > alpha1 = alpha3.

Conceptualizing mental disorders in children: where have we been and where are we going?

Conceptions of mental illness in children are bound by cultural and social conventions of what constitutes healthy and unhealthy development. To understand current conceptualizations of disorders in children, we review the history of these conceptualizations from three intertwined perspectives: a sociopolitical history of American children and families, the history of the mental health fields and scientific disciplines involved in diagnosing children, and the evolution of children's role in the Diagnostic and Statistical Manual of Mental Disorders. We review where the field has been in its conception of childhood mental illness throughout the past century, where we believe it is now, and raise questions about the direction in which child diagnosis may be headed as we enter the new millennium. We conclude with social policy recommendations based on theory and research regarding mental disorders in children.

Empirical evaluation of preservation methods for faecal DNA.

We evaluate the relative effectiveness of four methods for preserving faecal samples for DNA analysis. PCR assays of fresh faecal samples collected from free-ranging baboons showed that amplification success was dependent on preservation method, PCR-product size, and whether nuclear or mitochondrial DNA was assayed. Storage in a DMSO/EDTA/Tris/salt solution (DETs) was most effective for preserving nuclear DNA, but storage in 70% ethanol, freezing at -20 degrees C and drying performed approximately equally well for mitochondrial DNA and short (< 200 bp) nuclear DNA fragments. Because faecal DNA is diluted and degraded, repeated extractions from faeces may be necessary and short nuclear markers should be employed for genotyping. A review of molecular scatology studies further suggests that three to six faeces per individual should be collected.

Extracting primordial density fluctuations

The combination of detections of anisotropy in cosmic microwave background radiation and observations of the large-scale distribution of galaxies probes the primordial density fluctuations of the universe on spatial scales varying by three orders of magnitude. These data are found to be inconsistent with the predictions of several popular cosmological models. Agreement between the data and the cold + hot dark matter model, however, suggests that a significant fraction of the matter in the universe may consist of massive neutrinos.

Making amends : Adaptive perspectives on conflict remediation in monkeys, apes, and humans.

Conflict is an integral, and potentially disruptive, element in the lives of humans and other group-living animals. But conflicts are often settled, sometimes within minutes after the altercation has ended. The goal of this paper is to understand why primates, including humans, make amends. Primatologists have gathered an impressive body of evidence which demonstrates that monkeys and apes use a variety of behavioral mechanisms to resolve conflicts. Peaceful post-conflict interactions in nonhuman primates, sometimes labeled "reconciliation," have clear and immediate effects upon former adversaries, relieving uncertainty about whether aggression will continue, reducing stress, increasing tolerance, and reducing anxiety about whether aggressors will resume aggression toward former victims. However, the long-term effects of these interactions are less clearly established, leaving room to debate the adaptive function of conflict resolution strategies among primates. It is possible that reconciliatory behavior enhances the quality of valued, long-term social relationships or that reconciliatory interactions are signals that the conflict has ended and the actor's intentions are now benign. Both of these hypotheses may help us to understand how and why monkeys, apes, and humans make amends.