Investigation of the Tribological Behaviour of Various AMC Surfaces against Brake Lining Material.

AlSi7Mg/SiCp aluminium matrix composites (AMCs) with a high ceramic content (35 vol.%) that were produced by using the field-assisted sintering technique (FAST) were subjected to tribological preconditioning and evaluated as a potential lightweight material to substitute grey cast iron brake discs. However, since an uncontrolled running-in process of the AMC surface can lead to severe wear and thus to failure of the friction system, AMC surfaces cannot be used directly after finishing and have to be preconditioned. A defined generation of a tribologically conditioned surface (tribosurface) is necessary, as was the aim in this study. To simulate tribological conditions in automotive brake systems, the prepared AMC samples were tested in a pin-on-disc configuration against conventional brake lining material under dry sliding conditions. The influence of the surface topography generated by face turning using different indexable inserts and feeds or an additional plasma electrolytic treatment was investigated at varied test pressures and sliding distances. The results showed that the coefficient of friction remained nearly constant when the set pressure was reached, whereas the initial topography of the samples studied by SEM varied substantially. A novel approach based on analysing the material ratio determined by 3D surface measurement was developed in order to obtain quantitative findings for industrial application.

Heat Treatment Influencing Porosity and Tensile Properties of Field Assisted Sintered AlSi7Mg0.6.

In this study, an attempt was made to improve the mechanical properties and in particular the strength of a precipitation-hardenable aluminum alloy while still maintaining high ductility. For this purpose, AlSi7Mg0.6 (A357) powder with an average particle diameter of d50 = 40 µm was consolidated using field assisted sintering technique (FAST), and two material conditions were compared: an as-sintered and an underaging heat treated condition (T61). Mechanical properties were determined using tensile tests and hardness measurements. In addition, the microstructure was investigated by optical microscopy. Further, porosity and density were analyzed after the different heat treatments. By the underaging heat treatment, the surface hardness was increased by 100% and the yield strength was increased by 80% compared to the as-sintered material. However, the elongation to failure dropped to one third of that of the as-sintered material. Presumably, this effect was a result of an increased porosity due to the heat treatment. It is assumed that the observed pores were generated by artefacts from the FAST process used to manufacture the samples. The internal gas pressure and equilibrium diffusion supported by heat treatment temperature, and the reduction in surface energy caused by coalescent micropores, led to the enlargement of previously undetectable inhomogeneities in the as-sintered material that resulted in pores in the heat-treated sintered alloy.

Chemogenetic activation of oxytocin neurons: Temporal dynamics, hormonal release, and behavioral consequences.

Chemogenetics provides cell type-specific remote control of neuronal activity. Here, we describe the application of chemogenetics used to specifically activate oxytocin (OT) neurons as representatives of a unique class of neuroendocrine cells. We injected recombinant adeno-associated vectors, driving the stimulatory subunit hM3Dq of a modified human muscarinic receptor into the rat hypothalamus to achieve cell type-specific expression in OT neurons. As chemogenetic activation of OT neurons has not been reported, we provide systematic analysis of the temporal dynamics of OT neuronal responses in vivo by monitoring calcium fluctuations in OT neurons, and intracerebral as well as peripheral release of OT. We further provide evidence for the efficiency of chemogenetic manipulation at behavioral levels, demonstrating that evoked activation of OT neurons leads to social motivation and anxiolysis. Altogether, our results will be profitable for researchers working on the physiology of neuroendocrine systems, peptidergic modulation of behaviors and translational psychiatry.

Brain neuropeptide S: via GPCR activation to a powerful neuromodulator of socio-emotional behaviors.

Neuropeptide S (NPS) has attracted the attention of the scientific community due to its potent anxiolytic-like and fear-attenuating effects studied in rodents. Therefore, NPS might represent a treatment option for neuropsychiatric disorders, such as anxiety disorders, even more so as single nucleotide polymorphisms in the human NPS receptor gene have been associated with increased anxiety traits that contribute to the pathogenesis of fear- and anxiety-related disorders. However, the signaling mechanisms underlying the behavioral effects of NPS and the interaction with other brain neuropeptides are still rather unknown. To illuminate how NPS modulates the expression of selected emotional and social behaviors, the present review focuses on neuroanatomical and electrophysiological studies, as well as intracellular signaling mechanisms following NPS receptor stimulation in rodents. We will also discuss interactions of the NPS system with two well-described neuropeptides, namely corticotropin-releasing factor and oxytocin, which may contribute to the fear- and anxiety-reducing effects.

Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation.

Oxytocin (OXT)-mediated behavioral responses to social and stressful cues have extensively been studied in male rodents. Here, we investigated the capacity of brain OXT receptor (OXTR) signaling in the lateral septum (LS) to prevent social fear expression in female mice using the social-fear-conditioning paradigm. Utilizing the activated OXT system during lactation, we show that lactating mice did not express fear 24 hr after social fear conditioning. Supporting the role of OXTR signaling in the LS in attenuation of social fear, synthetic OXT infusion or overexpression of OXTR in the LS diminished social fear expression, whereas constitutive OXTR knockout severely impaired social fear extinction in virgin mice. Subsequently, both pharmacological blockade of local OXTRs in the LS and chemogenetic silencing of supraoptic nucleus OXTergic afferents to the LS increased social fear expression in lactating mice. Hence, LS-projecting OXT neurons suppress social fear in female mice.

Neuropeptide S Induces Acute Anxiolysis by Phospholipase C-Dependent Signaling within the Medial Amygdala.

Neuropeptide S (NPS) is an important anxiolytic substance of the brain. However, the signaling pathways downstream of NPS receptor (NPSR) activation, underlying the behavioral effect of NPS, remain largely unknown. Here, we show that bilateral microinfusion of NPS (0.2 nmol/0.5 µl) into the medial amygdala (MeA) of male adult Wistar rats reduced anxiety-related behavior on both the elevated plus-maze and the open field. Moreover, as shown in amygdala tissue micropunches intracerebroventricular infusion of NPS (1 nmol/5 µl) (1) evoked phosphorylation and synthesis of CaMKIIα in relation to reference protein ß-tubulin representing Ca2+ influx, and (2) induced phosphorylation of mitogen-activated protein kinase ERK1/2. The NPS-induced anxiolysis was prevented by local inhibition of phospholipase C signaling using U73122 (0.5 nmol/0.5 µl) in the MeA, indicating the behavioral relevance of this pathway. Conversely, local pharmacological blockade of adenylyl cyclase signaling using 2',5'-dideoxyadenosine (12.5 nmol/0.5 µl) failed to inhibit the anxiolytic effect of NPS infused into the MeA. Hence, NPS promotes acute anxiolysis within the MeA dependent on NPSR-mediated phospholipase C signaling. Taken together, our study extends the knowledge about the intracellular signaling mechanisms underlying the potent anxiolytic profile of NPS.

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis.

Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.

Salivary oxytocin concentrations in response to running, sexual self-stimulation, breastfeeding and the TSST: The Regensburg Oxytocin Challenge (ROC) study.

Intranasal oxytocin (OXT) application is emerging as a potential treatment for socio-emotional disorders associated with abnormalities in OXT system (re-) activity. The crucial identification of patients with such abnormalities could be streamlined by the assessment of basal and stimulus-induced OXT concentrations in saliva, using a simple, stress-free sampling procedure (i.e. an OXT challenge test). We therefore established the Regensburg Oxytocin Challenge (ROC) test to further validate salivary OXT concentrations as a practical, reliable and sensitive biomarker. OXT concentrations were quantified by radioimmunoassay in samples collected at home by healthy adult male and female volunteers before and after running ("Run") or sexual self-stimulation ("Sex"). In lactating women, salivary OXT concentrations were quantified before, during and after breastfeeding. Salivary OXT along with salivary cortisol and heart rate were monitored in healthy adult participants undergoing the Trier Social Stress Test (TSST). The home-based "Run" and "Sex" challenges as well as the laboratory-based TSST caused quantifiable, rapid, and consistent increases in salivary OXT (approximately 2.5-fold after 10-15min), which were similar for men and women. Breastfeeding did not result in measurably increased salivary OXT levels, probably because the short pulses of OXT release characteristic for lactation were missed. Taken together, ROC tests reliably assess the responsiveness of the OXT system (i.e., the increase in salivary OXT concentrations as compared to basal levels) to challenges such as "Run" and "Sex" at home or psychosocial stress (TSST) in the laboratory. Further studies with larger sample numbers are essentially needed in order to reveal individual differences in ROC test outcomes depending on, for example, genetic or environmental factors.

Oxytocin Stimulates Extracellular Ca2+ Influx Through TRPV2 Channels in Hypothalamic Neurons to Exert Its Anxiolytic Effects.

There is growing interest in anxiolytic and pro-social effects of the neuropeptide oxytocin (OXT), but the underlying intraneuronal mechanisms are largely unknown. Here we examined OXT-mediated anxiolysis in the hypothalamic paraventricular nucleus (PVN) of rats and effects of OXT administration on signaling events in hypothalamic primary and immortalized cells. In vivo, the application of SKF96365 prevented the anxiolytic activity of OXT in the PVN, suggesting that changes in intracellular Ca(2+) mediate the acute OXT behavioral effects. In vitro, mainly in the neurons with autonomous Ca(2+) oscillations, OXT increased intracellular Ca(2+) concentration and oscillation amplitude. Pharmacological intervention revealed OXT-dependent changes in Ca(2+) signaling that required activation of transient receptor potential vanilloid type-2 channel (TRPV2), mediated by phosphoinositide 3-kinase. TRPV2 induced the activation of the anxiolytic mitogen-activated protein kinase kinase (MEK1/2). In situ, immunohistochemistry revealed co-localization of TRPV2 and OXT in the PVN. Thus, functional and pharmacological analyses identified TRPV2 as a mediator of anxiolytic effects of OXT, conveying the OXT signal to MEK1/2 via modulation of intracellular Ca(2+).

Selective breeding for high anxiety introduces a synonymous SNP that increases neuropeptide S receptor activity.

Neuropeptide S (NPS) has generated substantial interest due to its anxiolytic and fear-attenuating effects in rodents, while a corresponding receptor polymorphism associated with increased NPS receptor (NPSR1) surface expression and efficacy has been implicated in an increased risk of panic disorder in humans. To gain insight into this paradox, we examined the NPS system in rats and mice bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior, and, thereafter, determined the effect of central NPS administration on anxiety- and fear-related behavior. The HAB phenotype was accompanied by lower basal NPS receptor (Npsr1) expression, which we could confirm via in vitro dual luciferase promoter assays. Assessment of shorter Npsr1 promoter constructs containing a sequence mutation that introduces a glucocorticoid receptor transcription factor binding site, confirmed via oligonucleotide pull-down assays, revealed increased HAB promoter activity-an effect that was prevented by dexamethasone. Analogous to the human NPSR1 risk isoform, functional analysis of a synonymous single nucleotide polymorphism in the coding region of HAB rodents revealed that it caused a higher cAMP response to NPS stimulation. Assessment of the behavioral consequence of these differences revealed that intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as well as the impaired cued-fear extinction in HAB rats and the enhanced fear expression in HAB mice, respectively. These results suggest that alterations in the NPS system, conserved across rodents and humans, contribute to innate anxiety and fear, and that HAB rodents are particularly suited to resolve the apparent discrepancy between the preclinical and clinical findings to date.

Multidimensional Homophily in Friendship Networks.

Homophily - the tendency for individuals to associate with similar others - is one of the most persistent findings in social network analysis. Its importance is established along the lines of a multitude of sociologically relevant dimensions, e.g. sex, ethnicity and social class. Existing research, however, mostly focuses on one dimension at a time. But people are inherently multidimensional, have many attributes and are members of multiple groups. In this article, we explore such multidimensionality further in the context of network dynamics. Are friendship ties increasingly likely to emerge and persist when individuals have an increasing number of attributes in common? We analyze eleven friendship networks of adolescents, draw on stochastic actor-oriented network models and focus on the interaction of established homophily effects. Our results indicate that main effects for homophily on various dimensions are positive. At the same time, the interaction of these homophily effects is negative. There seems to be a diminishing effect for having more than one attribute in common. We conclude that studies of homophily and friendship formation need to address such multidimensionality further.

How natural selection can create both self- and other-regarding preferences, and networked minds.

Biological competition is widely believed to result in the evolution of selfish preferences. The related concept of the 'homo economicus' is at the core of mainstream economics. However, there is also experimental and empirical evidence for other-regarding preferences. Here we present a theory that explains both, self-regarding and other-regarding preferences. Assuming conditions promoting non-cooperative behaviour, we demonstrate that intergenerational migration determines whether evolutionary competition results in a 'homo economicus' (showing self-regarding preferences) or a 'homo socialis' (having other-regarding preferences). Our model assumes spatially interacting agents playing prisoner's dilemmas, who inherit a trait determining 'friendliness', but mutations tend to undermine it. Reproduction is ruled by fitness-based selection without a cultural modification of reproduction rates. Our model calls for a complementary economic theory for 'networked minds' (the 'homo socialis') and lays the foundations for an evolutionarily grounded theory of other-regarding agents, explaining individually different utility functions as well as conditional cooperation.

Modeling the impact of supra-structural network nodes: The case of anonymous syringe sharing and HIV among people who inject drugs.

Networks are well understood as crucial to the diffusion of HIV among injection drug users (IDUs), but quasi-anonymous risk nodes - such as shooting galleries - resist measurement and incorporation into empirical analyses of disease diffusion. Drawing on network data from 767 IDUs in Bushwick, Brooklyn, we illustrate the use of calibrated agent-based models (CABMs) to account for network structure, injection practices, and quasi-anonymous transmission in shooting galleries. Results confirm the importance of network structure and actor heterogeneity to the magnitude and speed of HIV transmission. Models further demonstrate that quasi-anonymous injections in shooting galleries increase the speed of HIV diffusion across the whole network and have the greatest impact on HIV seroconversion levels for IDUs at the network periphery. Shooting galleries are shown to be transmission hubs that operate independently of traceable structural ties, linking otherwise unconnected network components. CABMs potentially increase understandings of HIV diffusion dynamics by infusing computer simulations with empirical data.