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The recent observations of gravitational waves during the coalescence of black holes has confirmed various predictions of general relativity. However, some concerns have been raised that these putative waves are artifacts. We have analyzed the ten confident gravitational waves detected in Observation Run 1 (O1) and Observation Run 2 (O2) and the gravitational wave emitted by the single known example of a neutron star coalescence, all of which have been verified by the Advanced Laser Interferometer Gravitational Wave Observatory and/or the Advanced Virgo Collaboration. On three occasions both Advanced LIGO and Advanced Virgo detected the same event ( Abbott et al., 2019 ). Whitening of the Hanford data (Gravitational Wave Open Science Center) was employed in this study to reduce colored non-transient noise, but template matching was not employed. In each of the ten events mentioned above we verified the presence of such waves by the application of non-stationary data analysis via the Morlet wavelet. We examined the strain data before, during and after each wave. In each case we employed seven measures of complexity or information before, and during each wave and analyzed these data using doubly multivariate MANOVA, the appropriate statistical test for repeated measures (pre-wave vs wave). In addition we compared the strain data before and after the putative event to see if there was persistence of any effect of the event. In each case the information content was significantly elevated during the wave compared to similar time samples taken before the wave. No persistent effects on the strain data were noted after the event. We conclude our analysis is consistent with the actual detection of gravitational waves by the LIGO and Virgo Collaboration. Our results suggest black hole coalescence generates mathematically complex gravitational waves which may elucidate aspects of such coalescence.

Interactions between turbulent structures (eddies) and premixed flame fronts were characterized with simultaneous CH2O-/OH-PLIF and stereo-PIV at high framing rate (20 kHz). The high temporal resolution of these measurements permitted the tracking and subsequent characterization of the evolution of turbulence–flame interactions. Common events were identified and their effects on the flame structure were assessed, the first of these being that the flame front was locally broadened by large eddies (i.e. those larger than twice the laminar flame thickness). The results suggest that large eddies likely have a two-fold effect on the overall propagation rate, one linked to the increase in burning area (consistent with classical theories) and the other stemming from an enhancement in the local diffusivity experienced by the flame. While this latter point has not been predicted, it has been postulated that large eddies could convect preheated fluid upstream of the flame. To our knowledge the results presented here provide the first conclusive experimental evidence of this phenomenon. The second common event was the persistence of locally thin preheat layers through extremely turbulent flow fields (i.e. those possessing scales much smaller than the laminar flame thickness). Comparisons between sequences of such events and those where broadening occurred indicate that the latter is typically associated with elevated turbulent diffusivity, which supports arguments in favor of using a criterion based on a ratio of diffusivities rather than length scales to predict the onset of preheat-zone broadening.

Understanding of ignition processes is central to design for reliable and safe aerospace combustor systems. Ignition is influenced by many factors including combustor geometry, flow conditions, fuel composition, turbulence intensity, ignition source, and energy deposition method. A toroidal jet-stirred reactor (TJSR) utilizes bulk fluid motion, presence of recirculation zones, a bulk residence time, and turbulence intensities which emulate characteristics relevant to cavity stabilized and swirl stabilized combustors. In this work, a TJSR was used to quantify ignitability and time-to-ignition of premixed ethylene and air. The effects of inlet temperature, residence time, and reactivity were studied on forced ignition processes. Experimental conditions ranged from residence times of 15–35 ms, mixture temperatures of 340–450 K, and equivalence ratios of 0.5–1 using capacitive spark-discharge ignition. The minimum equivalence ratio for ignition (MER), or the equivalence ratio at 50% probability, shows an inverse relationship with mixture temperature and residence time. Prior theory of real engine combustor performance for lean light off, proposed by Ballal and Lefebvre, was compared to the MER and displayed similar trends to the model. Spatially integrated OH* chemiluminescence was used to measure time to ignition within the reactor. Reduction in ignitibility was experienced as the time-to-ignition approached the residence time stressing the importance of device flow time scales in relation to kernel growth dynamics and ignition probability.

Ignition processes in scramjet pilot cavities are highly transient events that are influenced by factors including freestream Mach number and inlet geometry, turbulence intensity, cavity geometry, ignition source, and fueling composition and flow rate. In particular, the location of the flame kernel and associated propagation rate of the flame front throughout the cavity can significantly influence the end state of the ignition process. In this work formaldehyde (CH2O) was used as a flame marker to track ignition progress in a plane throughout the span-wise width of the cavity, while chemiluminescence imaging provided path-integrated flame location along the span-wise and axial directions. Planar laser-induced fluorescence (PLIF) excitation utilized the 355 nm frequency-tripled output of an Nd:YAG burst-mode laser operating at 50–100 kHz over 10 ms with available pulse energy up to 80 mJ. Simultaneous CH* chemiluminescence imaging from the top of the cavity was obtained with a high-speed complementary metal-oxide semiconductor camera. A freestream Mach number of 2 with ethylene fuel rates from 55–90 standard liters per minute were examined along with two different ignition sources: a spark discharge and pulse detonator. The resulting formaldehyde PLIF and chemiluminescence images indicate a strong correlation between fueling rate and the delay between the onset of ignition and stable combustion. More importantly, the span-wise propagation rate and structure of the flame front is highly dependent on the fueling rate, burning region, and ignition source.

Objective The aim of this study is to describe the clinical phenotype of alcohol use disorder (AUD) treatment-seeking patients with Roux-en-Y Gastric Bypass Surgery (RYGB) history; and to compare it to AUD obese non-RYGB controls. Methods Retrospective study of electronic medical records for all patients 30–60 years treated at the Mayo Clinic Addiction Treatment Program, between June, 2004 and July, 2012. Comparisons were performed with consumption patterns pre-RYGB and at time of treatment; excluding patients with AUD treatments pre-RYGB. Results Forty-one out of 823 patients had a RYGB history (4.9%); 122 controls were selected. Compared to controls, the RYGB group had significantly more females [ n = 29 (70.7%) vs. n = 35 (28.7%) p p = 0.002). On average, RYGB patients reported resuming alcohol consumption 1.4 ± 0.2 years post-surgery, meeting criteria for AUD at 3.1 ± 0.5 years and seeking treatment at 5.4 ± 0.3 years postoperatively. Pre-surgical drinks per day were significantly fewer compared to post-surgical consumption [2.5 ± 0.4 vs. 8.1 ± 1.3, p = 0.009]. Prior to admission, RYGB patients reported fewer drinking days per week vs. controls (4.7 ± 0.3 vs. 5.5 ± 1.8 days, p = 0.02). Neither RYGB, gender, age nor BMI was associated with differential drinking patterns. Conclusion The results of this study suggest that some patients develop progressive AUD several years following RYGB. This observation has important clinical implications, calling for AUD-preventive measures following RYGB. Further large-scale longitudinal studies are needed to clarify the association between RYGB and AUD onset.

Methane, a potential biosignature, has recently been detected in the martian atmosphere. This Note focuses on field investigations/operational simulations and laboratory studies which resulted in successful detection of methane within arid terrestrial soils, as distinct from the usual methanogen environment, but in at least partial analogy to martian conditions.

In mammals, the suprachiasmatic nucleus (SCN) contains a biological clock that drives circadian rhythms in vivo and in vitro. Primary dissociated neuronal culture is a useful research tool, which allows cell-by-cell morphological and physiological study of the SCN. A long-term primary dissociated SCN neuron culture is the prerequisite to understanding how neural activity and morphology interact in the SCN. The essential details of recent effective SCN culture methods are reviewed, including preparation of cells, medium and substrate, maintenance of cultures, and characterization of cultured SCN neurons. This technique is growing in importance, especially with the advent of multi-electrode array (MEA) recording.

CD8 serves both as an adhesion molecule for class I MHC molecules and as a coreceptor with the TCR for T cell activation. Here we study the developmental regulation of CD8-mediated binding to noncognate peptide/MHC ligands (i.e., those not bound by the TCR). We show that CD8's ability to bind soluble class I MHC tetramers and to mediate T cell adhesion under shear flow conditions diminishes as double-positive thymocytes mature into CD8+ T cells. Furthermore, we provide evidence that this decreased CD8 binding results from increased T cell sialylation upon T cell maturation. These data suggest that CD8's ability to interact with class I MHC is not fixed and is developmentally regulated through the T cell's glycosylation state.

Mouse NK cells express at least seven inhibitory Ly49 receptors. Here we employ a semiquantitative cell–cell adhesion assay as well as class I/peptide tetramers to provide a comprehensive analysis of specificities of Ly49 receptors for class I MHC molecules in eight MHC haplotypes. Different Ly49 receptors exhibited diverse binding properties. The degree of class I binding was related to the extent of functional inhibition. The tetramer studies demonstrated that neither glycosylation nor coreceptors were necessary for class I binding to Ly49 receptors and uncovered peptide-specific recognition by a Ly49 receptor. The results provide a foundation for interpreting and integrating many existing functional studies as well as for designing tests of NK cell development and self-tolerance.

Our previous studies demonstrated that nicotine induces c-fos expression in the suprachiasmatic nucleus (SCN) of the rat during a narrow developmental window occurring in the perinatal period. We have extended these observations by showing that c-fos cannot be induced in the adult SCN by nicotine even during the subjective night, when phase shifts do occur. In contrast to the SCN, significant induction of c-fos and NGFI-A was observed in the medial habenula and paraventricular nucleus at all circadian times. In the fetal rat SCN we show that NGFI-A and junB are also induced by nicotine, but not c-jun. To investigate whether changes in nicotinic acetylcholine receptor (nAChR) expression in the SCN may underlie this change in sensitivity during the perinatal period, we examined nAChR mRNAs across this developmental period. By Northern analyses, alpha2, alpha3 and alpha4 subunit mRNAs are relatively abundant in the fetal SCN but decline substantially in the adult. alpha7 mRNA increases substantially while beta2 mRNA is relatively abundant throughout development. We also examine expression in the whole mouse brain beginning at embryonic day 11. Many mRNA sizes for nAChR subunits in both the rat and mouse are characterized here for the first time by Northern analyses and some show very large changes in expression across development. In particular, a small 1.4 kb alpha2-related mRNA is highly expressed during early development, perhaps indicating an important novel function for this subunit.

Considerable data support a role for cholinergic influences on the circadian system. The extent to which these influences are mediated by nicotinic acetylcholine receptors (nAChRs) has been controversial, as have the specific actions of nicotine and acetylcholine in the suprachiasmatic nucleus (SCN) of the hypothalamus. In this article we review the existing literature and present new data supporting an important role for nAChRs in both the developing and adult SCN. Specifically, we present data showing that nicotine is capable of causing phase shifts in the circadian rhythms of rats. Like light and carbachol, nicotine appears to cause phase delays in the early subjective night and phase advances in the late subjective night. In the isolated SCN slice, however, only phase advances are seen, and, surprisingly, nicotine appears to cause the inhibition rather than the excitation of neurons. Among nAChR subunit mRNAs, alpha 7 appears to be the most abundant subunit in the adult SCN, whereas in the perinatal period, the more typical nAChRs with higher affinity for nicotine predominate in the SCN. This developmental change in subunit expression may explain the dramatic sensitivity of the perinatal SCN to nicotine that we have previously observed. The effects of nicotine on the SCN may contribute to alterations caused by nicotine in other physiological systems. These effects might also contribute to the dependence properties of nicotine through influences on arousal.

The cyclic adenosine monophosphate (cAMP) analog, 8-bromo-cAMP, phase advanced circadian neuronal rhythms in both aged and adult rat suprachiasmatic nuclei (SCN) by approximately 2 h in vitro. Rhythm amplitude was 20% lower in aged compared to adult SCN. The diminished efficacy of serotonergic agonists to phase shift behavioral rhythms of aged animals may be due to decrements in signal transduction mechanisms proximal to cAMP.

Prostate cancer can be detected using assays for blood-borne prostate-specific antigen (PSA), which is the clinically most useful diagnostic marker of malignant disease. This paper characterizes the 5 -flanking prostate-specific enhancer which controls expression of the human PSA gene This enhancer, located between -5824 and -3738, is androgen-responsive and requires a promoter for activity. Inductions of 12-100-fold activity occur at 1 nM concentrations of the testosterone analog R1881. The enhancer demonstrated tissue specificity as judged by transfections of several human cell lines. Electrophoretic mobility shift assays comparing nuclear extracts from breast cancer cells MCF-7, and prostate cancer cells LNCaP, showed three regions of prostate-specific binding. These three regions are -4168 to -4797 (region I), -4710 to 4479 (region II), and -4168 to -3801 (region III). Region III contained a putative androgen response element at -4136 that markedly affected activity if mutated. These data suggest that prostate-specific gene expression may involve interaction of prostate-specific proteins or protein complexes with the enhancer in addition to binding of the androgen receptor to androgen response elements.

The primary mammalian circadian clock is located within the suprachiasmatic nuclei (SCN), but the cellular organization of the clock is not yet known. We investigated the potential role of glial cells in the clock mechanism by determining whether disrupting glial activity affects the in vitro circadian rhythm of neuronal activity and the in vivo circadian activity rhythm in rats. We used two agents (octanol and halothane) that block gap junctions, and one (fluorocitrate) that inhibits glial metabolism. All three agents disrupted the circadian pattern of neuronal activity. Octanol flattened the rhythm at the highest concentration (200 microM) and induced a small phase delay at a lower concentration (66 microM). Halothane and fluorocitrate induced ultradian rhythmicity. Fluorocitrate injected into the SCN of an intact rat induced arrhythmicity for about 1 week, after which the rhythm reappeared with a 1.6 h delay. These results suggest that glia play an important role in the SCN circadian clock.

The mammalian circadian clock located in the suprachiasmatic nuclei (SCN) continues to oscillate when isolated in a brain slice preparation, and can be phase shifted in vitro by a variety of serotonergic (5-HTergic) agents. We have previously shown that 5-HT and a 5-HT agonist, quipazine, induce phase advances in the daytime and phase delays at night; the phase advances are mimicked by the 5-HT1A-selective agonist 8-OH-DPAT, by analogs of cyclic AMP, and by treatments that increase endogenous levels of cyclic AMP. Here we investigated the intracellular pathway through which these daytime phase advances occur. We find that quipazine- and 8-OH-DPAT-induced phase advances are blocked by two inhibitors of the cyclic AMP-dependent protein kinase, PK-A (H8 and Rp-cAMPS) as well as by a variety of K+ channel blockers (BaCl2, apamin, and charybdotoxin). Furthermore, we confirm previous work showing that a cyclic AMP analog induces phase advances in the daytime, and show that these phase advances are also blocked by BaCl2 and apamin. Finally, we show that a K+ ionophore induces similar phase advances in the subjective day, and these phase advances are blocked by Rp-cAMPS. These results indicate that both activation of PK-A and opening of K+ channels are necessary for 5-HT-induced phase advances of the SCN circadian clock. We propose a model that can account for our results.

We report the cloning and characterization of a novel serotonin receptor, designated as 5-HT 7 , which is coupled to the stimulation of adenylyl cyclase. 5-HT 7 mRNA is expressed discretely throughout the CNS, predominantly in the thalamus and hypothalamus. 5-HT 7 has a unique pharmacological profile that redefines agonist and antagonist classification of Iigands previously thought to be "selective." The circadian phase of spontaneous neuronal activity of the rat suprachiasmatic nucleus of the hypothalamus advances in response to serotonin ligands with a pharmacological profile consistent exclusively with that of 5-HT 7 . These findings suggest a physiological role in the regulation of circadian rhythms for one subtype of serotonin receptor, 5-HT 7 , and provide a pharmacological test to evaluate its role in other neuronal systems.

The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) receives a large serotonergic (5-HTergic) projection from the raphe nuclei. Whether the SCN pacemaker can be modulated by this afferent projection is a question of considerable theoretical and practical interest. In this study we investigated whether the 5-HT agonist, quipazine, can reset the phase of the SCN clock when it is isolated in vitro. Our results show that 1 h treatments with quipazine induce robust phase shifts in vitro, and that this effect depends upon the circadian time of treatment. We further show that the ability of quipazine to induce phase shifts is dose-dependent. These results suggest that the SCN circadian pacemaker is sensitive to 5-HTergic stimulation, and therefore that the 5-HTergic projection to the SCN may play a role in modulating the phase of the SCN clock in the intact animal.

Single-unit activity of the rat suprachiasmatic nucleus and surrounding regions was recorded in vivo. Photically responsive neurons were typically inhibited by low intravenous doses of the serotonin (5-HT) agonist quipazine. The 5-HT antagonist, metergoline, administered in a low intravenous dose, reversed the effects of quipazine. The subsequent response to photic stimulation was essentially identical to the initial photic response. Thus the photic response of neurons in the suprachiasmatic nucleus (SCN) and adjacent regions is relatively uninfluenced by 5-HT blockade.

In two separate studies a significantly greater concentration of DA (dopamine) and its metabolite, DOPAC (3,4-dihydroxyphenylacetic acid), was observed in the amygdala of narcoleptic canines. DOPAC was also significantly elevated in the reticularis parvicellularis, whereas NE (norepinephrine) was significantly elevated in the reticularis oralis, but depressed in the preoptic hypothalamus. No changes were observed in concentrations of serotonin or its metabolite, 5-HIAA (5-hydroxyindoleauric acid) in any region in the narcoleptic canine brain. Results of the two studies were similar, except that previously observed differences between narcoleptic and control canines in DOPAC levels in the caudate and reticularis oralis failed to replicate. Thus, steady state measures of neurotransmitter/metabolite tissue concentrations suggest region-specific alterations in DA and NE metabolism, rather than a global deficit in catecholamine neurotransmission in canine narcolepsy.

Single unit activity of dopamine and non-dopamine neurons in the substantia nigra and ventral tegmental area was recorded across stages of sleep and waking in the rat. These stages consisted of slow wave sleep (SWS), rapid eye movement (REM) sleep, awake-quiet (AQ) and awake-moving (AM). The dopamine neurons showed no change in mean firing rate across the stages of sleep or waking. During REM sleep, however, the dopamine cells fired with a more variable interspike interval than during SWS. In contrast, non-dopamine neurons in the substantia nigra and ventral tegmental area showed large increases in firing rate in REM compared to SWS, and in AM compared to AQ, without showing changes in interspike interval variability. In conclusion, whereas other monoaminergic neurons and various cortical and subcortical neurons exhibit marked changes in firing rate across the stages of sleep and waking, the dopamine neurons are unique in their lack of change in firing rate across stages.

L-sulpiride, at a dose of 4 mg/kg, essentially abolished motion-induced emesis in a group of 6 squirrel monkeys undergoing horizontal rotation at 25 rpm, a terrestrial model of space motion sickness (SMS). Extrapyramidal side effects were not observed. In the absence of the drug, the usual emetic response returned. In comparison while typical neuroleptics were also strongly anti-emetic, they produced a considerable degree of rigidity and akinesia.

Neurotransmitter receptor binding and Na + ,K + -ATPase activity were examined in the brains of six rats exposed to 7 days of microgravity during the flight of Spacelab 3. The same variables were examined in a group of six ground control rats. 5-HT 1 receptor number in the hippocampus was significantly elevated by exposure to the microgravity environment, and cortical sodium-potassium pump activity was significantly depressed. A marginal depression in dopamine D-2 binding in the striatum was noted. Dopamine and 5-HT binding in a wide variety of other central regions, in addition to GABA A , muscarine acetylcholine, adenosine A 1 , and opiate receptor binding, and adrenoceptor binding, was unaffected by microgravity exposure.

The pattern of retinal projection to the hypothalamus and the morphological properties of the retinal ganglion cells that comprise the retinohypothalamic tract have been examined in the cat. Intraocular injections of horseradish peroxidase revealed a dense retinal projection to the ventral suprachiasmatic nucleus; however, lighter projections were seen in the dorsal suprachiasmatic nucleus, and in hypothalamic regions both dorsal and lateral to the suprachiasmatic nucleus. Intrasuprachiasmatic nucleus injections of horseradish peroxidase retrogradely labelled retinal ganglion cells that were small to medium in soma size. The labelled ganglion cells exhibited long thin dendrites that were sparsely branched. The labelled retinal ganglion cells exhibited a significant change in soma size associated with retinal eccentricity. The morphological characteristics of the ganglion cells that project to the suprachiasmatic nucleus are similar to those of gamma cells.

A microelectrode positioner system and restraint apparatus are described for chronic single-unit recording in the behaving rat. This system allows recordings of single cells with a high signal-to-noise ratio, a capacity for running multiple electrode tracks in the same animal over numerous testing sessions, a capacity for remote and precise automatic driving of the microelectrode with stereotaxic accuracy, and ease in surgical implantation.

Different dopaminergic mechanisms that could explain behavioral supersensitivity to amphetamine or apomorphine in REM-deprived rats were examined. Four days of REM sleep deprivation induced a highly significant elevation in striatal DOPAC relative to normal controls, but not to stress controls. DOPAC levels in frontal cortex were not affected in any of the groups. Post synaptic D2 receptor number (Bmax) and affinity (Kd) were unchanged in both terminal regions. Similarly, no changes in pre-synaptic receptor sensitivity (apomorphine-induced inhibition of tyrosine hydroxylase) occurred in striatum. A stress control group exhibited no changes in any of the biochemical measures in comparison with either the REM deprived group or unstressed controls. Thus, the enhanced response to dopamine agonists reported previously is not due to altered dopamine receptor sensitivity. Alternative hypotheses to explain enhanced responses to direct and indirect acting dopamine agonists are discussed.