Sensitivity-bandwidth limit in a multi-mode opto-electro-mechanical transducer

An opto--electro--mechanical system formed by a nanomembrane capacitively coupled to an LC resonator and to an optical interferometer has been recently employed for the high--sensitive optical readout of radio frequency (RF) signals [T. Bagci, \emph{et~al.}, Nature {\bf 507}, 81 (2013)]. Here we propose and experimentally demonstrate how the bandwidth of such kind of transducer can be increased by controlling the interference between two--electromechanical interaction pathways of a two--mode mechanical system. With a proof--of--principle device \new{operating at room temperature, we achieve a sensitivity of 300 nV/Hz^(1/2) over a bandwidth of 15 kHz in the presence of radiofrequency noise, and an optimal shot-noise limited sensitivity of 10 nV/Hz^(1/2) over a bandwidth of 5 kHz. We discuss strategies for improving the performance of the device, showing that, for the same given sensitivity, a mechanical multi--mode transducer can achieve a bandwidth} significantly larger than that of a single-mode one

Generation and detection of large and robust entanglement between two different mechanical resonators in cavity optomechanics

We investigate a general scheme for generating, either dynamically or in the steady state, continuous variable entanglement between two mechanical resonators with different frequencies. We employ an optomechanical system in which a single optical cavity mode driven by a suitably chosen two-tone field is coupled to the two resonators. Significantly large mechanical entanglement can be achieved, which is extremely robust with respect to temperature.Comment: To appear in New J. Phys. Small extensions in response to the points raised by the referee and Refs adde

Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward

Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nM menthol alone also increased nAChR number and favored the formation of (α4)_3(β2)_2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)_2(β2)_3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway

Interactions of (2S,6S;2R,6R)-Hydroxynorketamine, a Secondary Metabolite of (R,S)-Ketamine, with Morphine

Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-d-aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of 7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6-hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high-performance liquid chromatography-tandem mass spectrometry. Ketamine (10 mg/kg), but not 6-hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6-hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6-hydroxynorketamine were doubled by morphine pre-treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co-administration of 6-hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6-hydroxynorketamine brain concentrations were increased after co-administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6-hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.Peer reviewe

Religious Fundamentalism in Eight Muslim‐Majority Countries: Reconceptualization and Assessment

To capture the common features of diverse fundamentalist movements, overcome etymological variability, and assess predictors, religious fundamentalism is conceptualized as a set of beliefs about and attitudes toward religion, expressed in a disciplinarian deity, literalism, exclusivity, and intolerance. Evidence from representative samples of over 23,000 adults in Egypt, Iraq, Jordan, Lebanon, Pakistan, Saudi Arabia, Tunisia, and Turkey supports the conclusion that fundamentalism is stronger in countries where religious liberty is lower, religion less fractionalized, state structure less fragmented, regulation of religion greater, and the national context less globalized. Among individuals within countries, fundamentalism is linked to religiosity, confidence in religious institutions, belief in religious modernity, belief in conspiracies, xenophobia, fatalism, weaker liberal values, trust in family and friends, reliance on less diverse information sources, lower socioeconomic status, and membership in an ethnic majority or dominant religion/sect. We discuss implications of these findings for understanding fundamentalism and the need for further research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146946/1/jssr12549.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146946/2/jssr12549_am.pd

Cannabinoids Inhibit Insulin Receptor Signaling in Pancreatic β\beta-Cells

Objective: Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting $\beta$-cells in the islets of Langerhans. Insulin itself positively regulates $\beta$-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CB1R) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CB1Rs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate $\beta$-cell proliferation and if they influence insulin action. Research Design and Methods: We measured EC production in isolated human and mouse islets and $\beta$-cell line in response to glucose and KCl. We evaluated human and mouse islets, several $\beta$-cell lines, and CB1R-null (CB1R$^{−/−}$) mice for the presence of a fully functioning EC system. We investigated if ECs influence $\beta$-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice. Results: ECs are generated within $\beta$-cells, which also express CB1Rs that are fully functioning when activated by ligands. Genetic and pharmacologic blockade of CB1R results in enhanced IR signaling through the insulin receptor substrate 2-AKT pathway in $\beta$-cells and leads to increased $\beta$-cell proliferation and mass. CB1R antagonism in db/db mice results in reduced blood glucose and increased $\beta$-cell proliferation and mass, coupled with enhanced IR signaling in $\beta$-cells. Furthermore, CB1R activation impedes insulin-stimulated IR autophosphorylation on $\beta$-cells in a G$\alpha_i$-dependent manner. Conclusions: These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of $\beta$-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance $\beta$-cell function and proliferation in diabetes

In Vitro Ketamine CYP3A Mediated Metabolism Study using Mammalian Liver S9 Fractions, cDNA Expressed Enzymes and Liquid Chromatography Tandem Mass Spectrometry

Ketamine is widely used in medicine in combination with several benzodiazepines including midazolam. The objectives of this study were to develop a novel HPLC-MS/SRM method capable of quantifying ketamine and norketamine using an isotopic dilution strategy in biological matrices and study the formation of norketamine, the principal metabolite of ketamine with and without the presence of midazolam, a well-known CYP3A substrate. The chromatographic separation was achieved using a Thermo Betasil Phenyl 100 x 2 mm column combined with an isocratic mobile phase composed of acetonitrile, methanol, water and formic acid (60:20:20:0.4) at a flow rate of 300 μL/min. The mass spectrometer was operating in selected reaction monitoring mode and the analytical range was set at 0.05–50 μM. The precision (%CV) and accuracy (%NOM) observed were ranging from 3.9–7.8 and 95.9.2–111.1% respectively. The initial rate of formation of norketamine was determined using various ketamine concentration and Km values of 18.4 μM, 13.8 μM and 30.8 μM for rat, dog and human liver S9 fractions were observed respectively. The metabolic stability of ketamine on liver S9 fractions was significantly higher in human (T1/2 = 159.4 min) compared with rat (T1/2 = 12.6 min) and dog (T1/2 = 7.3 min) liver S9 fractions. Moreover significantly lower IC50 and Ki values observed in human compared with rat and dog liver S9 fractions. Experiments with cDNA expressed CYP3A enzymes showed the formation of norketamine is mediated by CYP3A but results suggest an important contribution from others isoenzymes, most likely CYP2C particularly in rat

High-potency ligands for DREADD imaging and activation in rodents and monkeys.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping

Middle Eastern Beliefs about the Causal Linkages of Development to Freedom, Democracy, and Human Rights

This paper investigates the extent to which people in five Middle Eastern countries endorse key beliefs of developmental idealism that associate development with freedom, democracy, and human rights. Developmental idealismis a set of beliefs concerning the desirability of development, the methods for achieving it, and its consequences. The literature suggests that these beliefs have diffused worldwide among elites and lay citizens and posits that when such beliefs are disseminated they become forces for social and economic changes. Although developmental idealism research has primarily examined family and demographic issues, developmental idealism has tremendous potential to influence other aspects of society. This paper extends knowledge by considering societal aspects not addressed previously in the developmental idealism literature: personal freedom, democracy, and human rights. Using survey data from Egypt, Iraq, Lebanon, Saudi Arabia, and Turkey, we investigate how publics of these countries associate development with these elements. We find that majorities believe development brings greater personal freedom, democracy, and human rights. Conversely, the data show that in four of the countries majorities believe more personal freedom contributes to development. These findings provide support for the idea that developmental idealism beliefs concerning freedom, democracy, and human rights have diffused to lay publics in these five Middle Eastern countries. We also find evidence of uniquely Islamic developmental models; a significant proportion of people in these countries believe that more religion will bring more development

Recent progress in genetics of aging, senescence and longevity: focusing on cancer-related genes

It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the “hyperfunction theory�, which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin). These pathways consist of different enzymes, mostly kinases, but also phosphatases, deacetylases, GTPases, and some other molecules that cause overactivation of normal cellular functions. Overactivation of these sensory signal transduction pathways can cause cellular senescence, age-related diseases, including cancer, and shorten life span. Here we review some of the numerous very recent publications on the role of signal transduction molecules in aging and age-related diseases. As was emphasized by the author of the “hyperfunction model�, many (or actually all) of them also play roles in cancer. So these “participants� in pro-aging signaling pathways are actually very well acquainted to cancer researchers. A cancer-related journal such as Oncotarget is the perfect place for publication of such experimental studies, reviews and perspectives, as it can bridge the gap between cancer and aging researchers