Health and development of gay and lesbian youths: implications for HIV/AIDS

Health and behavioral issues of gay and lesbian adolescents have recently become a focus of research and interest. A well conceived framework within which to consider thoughtfully the uniqueness of problems faced by homosexual youths and the role of health-care providers is needed. The prevalence, sociocultural history, and theories of origin of the homosexual orientation (biologic, psychoanalytic, and social processes) as well as general issues in adolescent development (biologic, cognitive, and emotional) all contribute to the development of a comprehensive perspective through which better health care and education can be provided. Responsible sexual behavior, depression, and suicide are health-care issues that physicians must be sensitive to and address openly. Up to 50% of gay youths have seriously contemplated, suicide and 25% are estimated to have attempted suicide, according to the literature. In one study, up to 38% of pediatricians were uncomfortable in caring for homosexual adolescents within their practice. Practical suggestions include reviewing the language in office information forms and brochures providing appropriate literature that demonstrates acceptance of homosexual and bisexual orientations, and avoiding heterosexist bias in questions inquiring about sexuality. Physicians have an opportunity to modify the health and psychosocial risks faced by gay and lesbian youths by restructuring professional settings and accepting broader responsibilities for raising community awareness

Truncated nonsmooth Newton multigrid methods for convex minimization problems

We present a new inexact nonsmooth Newton method for the solution of convex minimization problems with piecewise smooth, pointwise nonlinearities. The algorithm consists of a nonlinear smoothing step on the fine level and a linear coarse correction. Suitable postprocessing guarantees global convergence even in the case of a single multigrid step for each linear subproblem. Numerical examples show that the overall efficiency is comparable to multigrid for similar linear problems

Numerical simulation of coarsening in binary solder alloys

Coarsening in solder alloys is a widely accepted indicator for possible failure of joints in electronic devices. Based on the well-established Cahn–Larché model with logarithmic chemical energy density (Dreyer and Müller, 2001) [20], we present a computational framework for the efficient and reliable simulation of coarsening in binary alloys. Main features are adaptive mesh refinement based on hierarchical error estimates, fast and reliable algebraic solution by multigrid and Schur–Newton multigrid methods, and the quantification of the coarsening speed by the temporal growth of mean phase radii. We provide a detailed description and a numerical assessment of the algorithm and its different components, together with a practical application to a eutectic AgCu brazing alloy

Nonsmooth Schur-Newton methods for multicomponent Cahn-Hilliard systems

We present globally convergent nonsmooth Schur–Newton methods for the solution of discrete multicomponent Cahn–Hilliard systems with logarithmic and obstacle potentials. The method solves the nonlinear set-valued saddle-point problems arising from discretization by implicit Euler methods in time and first-order finite elements in space without regularization. Efficiency and robustness of the convergence speed for vanishing temperature is illustrated by numerical experiments

FMRI Effective Connectivity and TMS Chronometry: Complementary Accounts of Causality in the Visuospatial Judgment Network

BACKGROUND: While traditionally quite distinct, functional neuroimaging (e.g. functional magnetic resonance imaging: fMRI) and functional interference techniques (e.g. transcranial magnetic stimulation: TMS) increasingly address similar questions of functional brain organization, including connectivity, interactions, and causality in the brain. Time-resolved TMS over multiple brain network nodes can elucidate the relative timings of functional relevance for behavior ("TMS chronometry"), while fMRI functional or effective connectivity (fMRI EC) can map task-specific interactions between brain regions based on the interrelation of measured signals. The current study empirically assessed the relation between these different methods. METHODOLOGY/PRINCIPAL FINDINGS: One group of 15 participants took part in two experiments: one fMRI EC study, and one TMS chronometry study, both of which used an established cognitive paradigm involving one visuospatial judgment task and one color judgment control task. Granger causality mapping (GCM), a data-driven variant of fMRI EC analysis, revealed a frontal-to-parietal flow of information, from inferior/middle frontal gyrus (MFG) to posterior parietal cortex (PPC). FMRI EC-guided Neuronavigated TMS had behavioral effects when applied to both PPC and to MFG, but the temporal pattern of these effects was similar for both stimulation sites. At first glance, this would seem in contradiction to the fMRI EC results. However, we discuss how TMS chronometry and fMRI EC are conceptually different and show how they can be complementary and mutually constraining, rather than contradictory, on the basis of our data. CONCLUSIONS/SIGNIFICANCE: The findings that fMRI EC could successfully localize functionally relevant TMS target regions on the single subject level, and conversely, that TMS confirmed an fMRI EC identified functional network to be behaviorally relevant, have important methodological and theoretical implications. Our results, in combination with data from earlier studies by our group (Sack et al., 2007, Cerebral Cortex), lead to informed speculations on complex brain mechanisms, and TMS disruption thereof, underlying visuospatial judgment. This first in-depth empirical and conceptual comparison of fMRI EC and TMS chronometry thereby shows the complementary insights offered by the two methods

The effects of maternal social phobia on mother-infant interactions and infant social responsiveness

Background: Social phobia aggregates in families. The genetic contribution to intergenerational transmission is modest, and parenting is considered important. Research on the effects of social phobia on parenting has been subject to problems of small sample size, heterogeneity of samples and lack of specificity of observational frameworks. We addressed these problems in the current study.Methods: We assessed mothers with social phobia (N = 84) and control mothers (N = 89) at 10 weeks in face-to-face interactions with their infants, and during a social challenge, namely, engaging with a stranger. We also assessed mothers with generalised anxiety disorder (GAD) (N = 50). We examined the contribution to infant social responsiveness of early infant characteristics (neonatal irritability), as well as maternal behaviour. Results: Mothers with social phobia were no less sensitive to their infants during face-to-face interactions than control mothers, but when interacting with the stranger they appeared more anxious, engaged less with the stranger themselves, and were less encouraging of the infant's interaction with the stranger; infants of index mothers also showed reduced social responsiveness to the stranger. These differences did not apply to mothers with GAD and their infants. Regression analyses showed that the reduction in social responsiveness in infants of mothers with social phobia was predicted by neonatal irritability and the degree to which the mother encouraged the infant to interact with the stranger.Conclusions: Mothers with social phobia show specific parenting difficulties, and their infants show early signs of reduced social responsiveness that are related to both individual infant differences and a lack of maternal encouragement to engage in social interactions

The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation.

Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+-conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+-conductance as the unbound channel. Further, activation kinetics are more sigmoidal, indicating that multiple conformational changes coupled to opening are modulated. Single-channel current amplitudes reveal that each channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1 channels by GxTx results from decreased open probability due to increased occurrence of long-lived closed states; the time constant of the final pore opening step itself is not impacted by GxTx. When intracellular potential is less than 0 mV, GxTx traps the gating charges on Kv2.1's voltage sensors in their most intracellular position. Gating charges translocate at positive voltages, however, indicating that GxTx stabilizes the most intracellular conformation of the voltage sensors (their resting conformation). Kinetic modeling suggests a modulatory mechanism: GxTx reduces the probability of voltage sensors activating, giving the pore opening step less frequent opportunities to occur. This mechanism results in K+-conductance activation kinetics that are voltage-dependent, even if pore opening (the rate-limiting step) has no inherent voltage dependence. We conclude that GxTx stabilizes voltage sensors in a resting conformation, and inhibits K+ currents by limiting opportunities for the channel pore to open, but has little, if any, direct effect on the microscopic kinetics of pore opening. The impact of GxTx on channel gating suggests that Kv2.1's pore opening step does not involve movement of its voltage sensors

Regulating repression : roles for the Sir4 N-terminus in linker DNA protection and stabilization of epigenetic states

The Gasser laboratory is supported by the Novartis Research Foundation and the EU training network Nucleosome 4D. SK was supported by an EMBO long-term fellowship, a Schrodinger fellowship from the FWF, and the Swiss SystemsX.ch initiative/C-CINA; HCF by an EMBO long-term fellowship.Silent information regulator proteins Sir2, Sir3, and Sir4 form a heterotrimeric complex that represses transcription at subtelomeric regions and homothallic mating type (HM) loci in budding yeast. We have performed a detailed biochemical and genetic analysis of the largest Sir protein, Sir4. The N-terminal half of Sir4 is dispensable for SIR-mediated repression of HM loci in vivo, except in strains that lack Yku70 or have weak silencer elements. For HM silencing in these cells, the C-terminal domain (Sir4C, residues 747-1,358) must be complemented with an N-terminal domain (Sir4N; residues 1-270), expressed either independently or as a fusion with Sir4C. Nonetheless, recombinant Sir4C can form a complex with Sir2 and Sir3 in vitro, is catalytically active, and has sedimentation properties similar to a full-length Sir4-containing SIR complex. Sir4C-containing SIR complexes bind nucleosomal arrays and protect linker DNA from nucleolytic digestion, but less effectively than wild-type SIR complexes. Consistently, full-length Sir4 is required for the complete repression of subtelomeric genes. Supporting the notion that the Sir4 N-terminus is a regulatory domain, we find it extensively phosphorylated on cyclin-dependent kinase consensus sites, some being hyperphosphorylated during mitosis. Mutation of two major phosphoacceptor sites (S63 and S84) derepresses natural subtelomeric genes when combined with a serendipitous mutation (P2A), which alone can enhance the stability of either the repressed or active state. The triple mutation confers resistance to rapamycin-induced stress and a loss of subtelomeric repression. We conclude that the Sir4 N-terminus plays two roles in SIR-mediated silencing: it contributes to epigenetic repression by stabilizing the SIR-mediated protection of linker DNA; and, as a target of phosphorylation, it can destabilize silencing in a regulated manner.Publisher PDFPeer reviewe