Highlights • Pharmacological approaches to induce hyperactivity as a model of human mania have been used for many years. • Environmental manipulations are used to induce manic-like states which mimic ...multiple facets of this complex disorder. • Most recent studies have focused on genetic models. • Certain outbred strains of mice may be useful in modeling the polygenic nature of this disease. • Ultimately, models that cycle through various mood states are needed.
The integration of nanophotonics and atomic physics has been a long-sought goal that would open new frontiers for optical physics, including novel quantum transport and many-body phenomena with ...photon-mediated atomic interactions. Reaching this goal requires surmounting diverse challenges in nanofabrication and atomic manipulation. Here we report the development of a novel integrated optical circuit with a photonic crystal capable of both localizing and interfacing atoms with guided photons. Optical bands of a photonic crystal waveguide are aligned with selected atomic transitions. From reflection spectra measured with average atom number N=1.1+/-0.4, we infer that atoms are localized within the waveguide by optical dipole forces. The fraction of single-atom radiative decay into the waveguide is Γ1D/Γ'≃(0.32±0.08), where Γ1D is the rate of emission into the guided mode and Γ' is the decay rate into all other channels. Γ1D/Γ' is unprecedented in all current atom-photon interfaces.
Experiments and numerical simulations are described that develop quantitative understanding of atomic motion near the surfaces of nanoscopic photonic crystal waveguides (PCWs). Ultracold atoms are ...delivered from a moving optical lattice into the PCW. Synchronous with the moving lattice, transmission spectra for a guided-mode probe field are recorded as functions of lattice transport time and frequency detuning of the probe beam. By way of measurements such as these, we have been able to validate quantitatively our numerical simulations, which are based upon detailed understanding of atomic trajectories that pass around and through nanoscopic regions of the PCW under the influence of optical and surface forces. The resolution for mapping atomic motion is roughly 50 nm in space and 100 ns in time. By introducing auxiliary guided-mode (GM) fields that provide spatially varying AC Stark shifts, we have, to some degree, begun to control atomic trajectories, such as to enhance the flux into the central vacuum gap of the PCW at predetermined times and with known AC Stark shifts. Applications of these capabilities include enabling high fractional filling of optical trap sites within PCWs, calibration of optical fields within PCWs, and utilization of the time-dependent, optically dense atomic medium for novel nonlinear optical experiments.
Summary
Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone ...mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial.
Introduction
Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN.
Methods
The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D
3
(5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg.
Results
Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension.
Conclusions
This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.
Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for ...lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.
Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, ...mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.
Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that ...display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.
An increasingly older population is one of the major social and medical challenges we currently face. Between 2010 and 2050, it is estimated that the proportion of adults over 65 years of age will ...double from 8% to 16% of the global population. A major concern associated with aging is the changes in health that can lead to various diseases such as cancer and neurogenerative diseases, which are major burdens on individuals and societies. Thus, it is imperative to better understand changes in sleep and circadian rhythms that accompany aging to improve the health of an older population and target diseases associated with aging. Circadian rhythms play a role in most physiological processes and can contribute to age-related diseases. Interestingly, there is a relationship between circadian rhythms and aging. For example, many older adults have a shift in chronotype, which is an individual's natural inclination to sleep certain times of the day. As adults age, most people tend to go to sleep earlier while also waking up earlier. Numerous studies also suggest that disrupted circadian rhythms may be indicative of developing age-related diseases, like neurodegenerative disorders and cancer. Better understanding the relationship between circadian rhythms and aging may allow us to improve current treatments or develop novel ones that target diseases commonly associated with aging.
Although there are clear interactions between circadian rhythms and drug addiction, mechanisms for such interactions remain unknown. Here we establish a role for the Clock gene in regulating the ...brain's reward circuit. Mice lacking a functional Clock gene display an increase in cocaine reward and in the excitability of dopamine neurons in the midbrain ventral tegmental area, a key brain reward region. These phenotypes are associated with increased expression and phosphorylation of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis), as well as changes in several genes known to regulate dopamine activity in the ventral tegmental area. These findings demonstrate the involvement of a circadian-associated gene, Clock, in regulating dopamine function and cocaine reward.
PDF
