text:
Hiroshi Yamamoto1, Charlotte E. Lee1, Jacob N. Marcus1, Todd D. Williams2, J. Michael Overton2, Marisol E. Lopez1, Anthony N. Hollenberg1, Laurie Baggio3, Clifford B. Saper4, Daniel J. Drucker3 and Joel K. Elmquist1,4
1Department of Medicine and Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA2 Department of Nutrition, Food, and Exercise Science, Program in Neuroscience, Florida State University, Tallahassee, Florida, USA3 Department of Medicine, Toronto General Hospital, and the Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada4 Department of Neurology, Beth Israel Deaconess Medical Center, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA
Address correspondence to: Joel K. Elmquist, Division of Endocrinology, Beth Israel Deaconess Medical Center, 347 Research North, 99 Brookline Avenue, Boston, Massachusetts 02215, USA. Phone: (617) 667-3218; Fax: (617) 667-2927; E-mail: email@example.com.
Published July 1, 2002Submitted: April 3, 2002; Accepted: May 28, 2002.
Glucagon-like peptide-1 (GLP-1) released from the gut functions as an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that controls feeding and drinking behavior and gastric emptying and elicits neuroendocrine responses including development of conditioned taste aversion. Although GLP-1 receptor (GLP-1R) agonists are under development for the treatment of diabetes, GLP-1 administration may increase blood pressure and heart rate in vivo. We report here that centrally and peripherally administered GLP-1R agonists dose-dependently increased blood pressure and heart rate. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in brainstem catecholamine neurons. These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in vivo.
Glucagon-like peptide-1 (GLP-1) acts as a nutrient-stimulated incretin secreted from enteroendocrine L cells in the intestine (1). GLP-1 promotes nutrient assimilation via stimulation of glucose-dependent insulin release and inhibition of glucagon secretion. Native GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) in the bloodstream. In contrast, modified peptidase-resistant GLP-1 analogues and lizard exendin-4 (EXN-4) are highly resistant to degradation by DPP-IV, exhibit longer half-lives, and are substantially more potent than native GLP-1 (2, 3). Accordingly, GLP-1 analogues and EXN-4 are currently being assessed in clinical trials for the treatment of subjects with type 2 diabetes (4, 5).
GLP-1 is also a neuropeptide synthesized by neurons in the caudal regions of the nucleus of the solitary tract (NTS) (6). In contrast to the limited sites of GLP-1 synthesis in the CNS, GLP-1–immunoreactive fibers and GLP-1 receptors (GLP-1Rs) are quite widespread throughout the brain (6–8). Not surprisingly, GLP-1 exerts diverse actions in the CNS, including inhibition of food and water intake. Intracerebroventricular (i.c.v.) administration of GLP-1 induces Fos-like immunoreactivity (Fos-IR) in the paraventricular nucleus of the hypothalamus (PVH) (9, 10). Peripheral administration of EXN-4 reduces fasting and postprandial glucose and energy intake in humans (11). Whether GLP-1 acts specifically on inhibitory feeding centers to produce satiety or acts as a mediator of aversive stimuli remains uncertain, as several experiments demonstrate development of taste aversion (12, 13) and activation of signaling pathways mediating interoceptive stress responses (14–16) following GLP-1 administration. Consistent with the involvement of GLP-1 signaling in stress responses, central administration of GLP-1 activates neurons containing corticotropin-releasing hormone (CRH) in the PVH and elevates plasma corticosterone (17). Furthermore, both GLP-1 and EXN-4 produce chronotropic and pressor responses in anesthetized animals (18–21); however, whether these effects are direct, due to activation of cardiac GLP-1Rs, or indirect remains unclear. Despite the accumulating data linking GLP-1R signaling to autonomic and neuroendocrine responses, the neural pathways underlying these actions of central GLP-1 are not fully understood. To determine the mechanisms and potential physiological significance of central GLP-1 pathways impinging on sympathetic outflow systems, we investigated the distribution of GLP-1–activated neurons that innervate sympathetic preganglionic neurons and assessed GLP-1 effects on cardiovascular parameters.
Animals and surgical procedures. Adult male pathogen-free Sprague-Dawley rats (250–350 g; Taconic, Germantown, New York, USA) were housed in a light-controlled (12 hours on, 12 hours off) and temperature-controlled (21.5–22.5°C) environment. The animals and procedures used were approved by the Harvard Medical School and Beth Israel Deaconess Medical Center institutional animal care and use committees.
Rats were anesthetized with isoflurane (induction 5%, maintenance 2%) and were implanted in the abdominal aorta with a catheter coupled with a sensor and transmitter (TA11PA-C40; Data Sciences International, St. Paul, Minnesota, USA) (22). Telemetry signals were received by an antenna below the rat's cage that relays the signals to a signal processor (DataQuest A.R.T. Gold version 2.1 system; Data Sciences International) connected to a Compaq Deskpro PC (Compaq Computer Corp., Houston, Texas). These transmitters allow remote monitoring of blood pressure (BP) and heart rate (HR) in unanesthetized and unrestrained animals. In the same surgical session, rats were implanted intravenously (i.v.) with a silastic catheter into the femoral vein (23) or i.c.v. with a guide cannula into the lateral ventricle (24). In a subset of the animals, the retrograde tracer Fluorogold (FG) (2.5% in pyrogen-free saline) (Fluorochrome, Denver, Colorado, USA) was injected with a glass micropipette and air pressure injection system (25, 26). The injections included the intermediolateral cell column (IML) and consisted of two injections of 50 nl in the rostral (T1–T4) or caudal (T6–T10) thoracic spinal cord.
Ten to fourteen days after surgery, base-line mean arterial blood pressure (MAP) and HR were recorded for the preceding day and night, and rats were injected with EXN-4 (30, 300, or 3000 ng per rat i.v. or 3, 30, or 300 ng per rat i.c.v.; n = 4–6 for each group) or pyrogen-free saline (PFS) (0.25 ml i.v. or 5 μl i.c.v., total volume per rat; n = 4–6 for each group). In our initial experiments, we observed that both i.v. and i.c.v. injections of PFS induced a transient increase in MAP and HR. Thus, we used a long line to avoid a handling stress during injection in a subsequent experiment. The long line was connected 2 hours before i.c.v. injection of GLP-1(7–36) (300 ng per rat; n = 3) or PFS (5 μl total volume per rat; n = 3). The action of [des-His1,Glu9]exendin-4 of the GLP-1R antagonist (13) was investigated by i.c.v. administration of 1 μg of the peptide 30 minutes before i.c.v. administration of 30 ng of EXN-4. All drugs were given to unrestrained rats between 2 and 5 hours after lights on. The cardiovascular data were collected and stored in 1-minute bins, and, before further analysis, the data were averaged into 10-minute bins. Results are expressed as means ± SEM from groups of four to six rats. Statistical comparisons between animals were performed at each time. ANOVA for repeated measurement was used to estimate dose-dependent effects within each group, and the differences between groups in each time were assessed by Fisher's protected least significant difference (PLSD).
Animal perfusion and histology. Two hours after administration of peptides or PFS, rats were deeply anesthetized with isoflurane and perfused transcardially with diethyl pyrocarbonate–treated 0.9% saline followed by 10% neutral formalin (Sigma-Aldrich, St. Louis, Missouri, USA). For tyrosine hydroxylase (TH) heteronuclearRNA (hnRNA) in situ hybridization studies, rats were perfused 0, 15, or 30 minutes or 1, 2, 6, or 24 hours after administration of EXN-4 or PFS (n = 3 for each group). Before perfusion, blood was collected from the heart, and blood glucose was measured using a glucose oxidase–based method (LifeScan OneTouch; Johnson & Johnson, Milpitas, California, USA). Tissues were removed and postfixed in the same fixative for 4 hours, submerged in 20% sucrose, and cut at 30 μm (1:5 series).
Immunohistochemistry. The procedures for immunohistochemistry were performed as reported previously (23, 26, 27). For single-label immunohistochemistry, sections were pretreated with 0.3% hydrogen peroxide in PBS for 30 minutes, and then in 3% normal donkey serum (Jackson ImmunoResearch Laboratories Inc., West Grove, Pennsylvania, USA) with 0.25% Triton X-100 in PBS (PDT), followed by overnight incubation in Fos rabbit primary antisera (Ab5; Oncogene Research Products, Cambridge, Massachusetts, USA; 1:100,000 dilution in PDT) at room temperature. After washing in PBS, sections were incubated in biotinylated donkey anti-rabbit IgG (Jackson ImmunoResearch Laboratories Inc.; 1:1,000) and then incubated with avidin-biotin complex (Vector Elite ABC Kit; Vector Laboratories Inc., Burlingame, California, USA; 1:500 in PBS). A combination of 0.04% diaminobenzidine tetrahydrochloride (DAB; Sigma-Aldrich), 0.01% nickel ammonium sulfate (Fisher Scientific Co., Pittsburgh, Pennsylvania, USA), 0.01% cobalt chloride (Fisher Scientific Co.), and 0.01% hydrogen peroxide dissolved in PBS was used for the chromogen reaction with two successive rinses in PBS. The tissue sections were mounted onto subbed slides, air-dried, dehydrated in alcohol, cleared in xylene, and then coverslipped with Permaslip (Alban Scientific, St. Louis, Missouri, USA).
For double-label immunohistochemistry, the sections stained with Fos were blocked and then incubated overnight in FG rabbit primary antisera (Chemicon International, Temecula, California, USA; 1:20,000 in PDT) or mouse anti-TH (Chemicon International; 1:20,000 in PDT). The sections were processed as described above using DAB as a chromogen.
For triple-label immunohistochemistry, the tissue sections were incubated in Fos antisera and were processed as described above but incubated in the DAB solution without nickel sulfate and cobalt chloride, resulting in a brown nuclear reaction product. Sections were then incubated in FG rabbit primary antisera and mouse anti-TH overnight at room temperature. After washing in PBS, sections were incubated in FITC-conjugated donkey anti-rabbit IgG (Jackson ImmunoResearch Laboratories Inc.; 1:200 in PDT) and Cy3-conjugated donkey anti-mouse IgG (Jackson ImmunoResearch Laboratories Inc.; 1:200 in PDT). The Fos-IR was observed with brightfield optics, the TH-immunoreactivity (TH-IR) with a rhodamine filter system, and the retrograde label with a FITC filter system.
In situ hybridization histochemistry. A fragment of the rat TH gene (28) including intron 2 was amplified by PCR with rat genomic DNA (BD Biosciences Clontech, Palo Alto, California, USA) as a template. The following primers were used for amplification: primer 1, 5′-TGTCTCGGGCTGTAAAAGTATTTGA-3′; and primer 2, 5′-AGTGGTGAATTTTGGCTTCAAATGT-3′. The insert was cloned into the pGEM-T Easy Vector (Promega Corp., Madison, Wisconsin, USA). The PCR product was cloned and the identity of the insert as TH intron was confirmed by sequence analysis and comparison to the GenBank database (accession number AF014956). For generation of 550 bp of antisense 35S-labeled cRNA, the plasmid was linearized by digestion with NcoI and subjected to in vitro transcription with SP6 polymerase. The protocol for in situ hybridization histochemistry was a modification of that previously reported by our laboratory (29) and several other laboratories (30). Control procedures to confirm the specificity of our in situ hybridization histochemistry procedures included hybridization with antisense probes after tissue pretreatment with RNase A (200 μg/ml).
Estimates of cell counts. In all procedures, the estimates of cell counts (Fos, TH, and FG) were done with a grid reticule and a 10× objective by an observer blinded to the treatment groups (23, 26). The data were not corrected for double counting and a stereological technique was not used, because the objects we were counting (nuclei and retrogradely labeled cells) did not change in size, and section thickness did not vary between groups. Hence, as all double-label studies are inherently qualitative, our results are meant to provide relative data but are not meant to be accurate estimates of absolute cell counts. Data were analyzed by ANOVA and differences between groups by Fischer's PLSD.
Production of photomicrographs. Photomicrographs were captured with a digital camera (Spot3.0; Diagnostic Instruments, Sterling Heights, Michigan, USA) mounted directly on the microscope (Axioskop 2; Carl Zeiss Inc., Thornwood, New York, USA) and an Apple Macintosh G3 (Apple Computer Inc., Cupertino, California, USA) computer. Image editing software (Adobe Photoshop; Adobe Systems Inc., Mountain View, California, USA) was used to combine photomicrographs into plates. Only the sharpness, contrast, and brightness were adjusted. All figures were printed on a dye-sublimation printer (Kodak 8670; Eastman Kodak Co. Scientific Imaging Systems, New Haven, Connecticut, USA). For drawings (see Figure 4), cytoarchitectonic details were added using a camera lucida.
EXN-4–activated neurons projecting to the spinal cord. A series of line drawings demonstrates the distribution of Fos-IR (black circles), FG-IR (blue circles), and double-labeled (red stars) neurons in three rostral-to-caudal levels of the PVH (a–c), the Arc/RCA (d–f), and the LHA (g–i) of the hypothalamus after i.c.v. injection of EXN-4, in animals with FG injection into the spinal cord. Scale bar = 250 μm in a–c and 1,000 μm in d–i. Divisions of the PVH: dp, dorsal parvocellular; mp, medial parvocellular; pm, posterior magnocellular; vp, ventral parvocellular; lp, lateral parvicellular; ic, internal capsule. VMH, ventromedial nucleus of the hypothalamus; DMH, dorsomedial nucleus of the hypothalamus; ME, median eminence.
GLP-1 agonists increase BP and HR. To ascertain the effects of GLP-1R activation on cardiovascular responses in non-anesthetized rats, we assessed BP and HR in freely moving rats using telemetric monitoring. MAP and HR transiently increased after handling and after i.v. or i.c.v. administration of PFS. Both parameters returned to basal levels within 40–50 minutes (Figure 1, a–d). In contrast, i.v. administration of EXN-4 produced a dose-dependent increase in MAP and HR (Figure 1, a and b). Similarly, i.c.v. administration of EXN-4 dose-dependently increased MAP and HR (Figure 1, c and d). MAP and HR remained significantly increased for up to 2 hours after both i.v. (300 and 3000 ng) and i.c.v. (30 and 300 ng) administration of EXN-4.
Effects of i.c.v. or i.v. administration of EXN-4 on MAP and HR. Both i.v. EXN-4 (a and b) and i.c.v. EXN-4 (c and d) dose-dependently increase MAP (a and c) and HR (b and d). EXN-4 was injected at "0." *P < 0.05, **P < 0.01.
As EXN-4 is a protease-resistant long-acting lizard GLP-1R agonist, we also examined MAP and HR after i.c.v. administration of native mammalian GLP-1(7-36amide). Intracerebroventricular GLP-1 (300 ng) also produced a robust increase in MAP and HR that remained significantly increased up to 60 minutes after administration. The MAP and HR responses were shorter in duration than that induced by EXN-4 and returned to base line by 60 minutes. The specificity of the responses for the GLP-1R was confirmed by the demonstration that pretreatment with i.c.v. administration of 1 μg of [des-His1,Glu9]exendin-4 (13) completely blocked the effects of 30 ng of i.c.v. EXN-4 on MAP and HR.
As peripheral GLP-1 increases insulin secretion in a glucose-dependent fashion, we assessed whether the observed cardiovascular responses were secondary to GLP-1 agonist–induced hypoglycemia. Blood glucose levels increased modestly after i.c.v. administrations of both EXN-4 (basal, 96 ± 1.6; 15 minutes, 105 ± 3.9; 30 minutes, 109 ± 2.4; 60 minutes, 110 ± 3.0; 120 minutes, 110 ± 1.4; mean ± SEM) and PFS (basal, 98 ± 2.0; 15 minutes, 106 ± 4.9; 30 minutes, 104 ± 2.4; 60 minutes, 108 ± 5.6; 120 minutes, 106 ± 4.3; mean ± SEM). Importantly, i.c.v. administration of EXN-4 did not lower blood glucose at any time points after the injection.
Distribution of EXN-4–induced Fos-IR. To determine potential downstream mediators of GLP-1R activation leading to an increase in MAP and HR, we investigated the distribution of Fos-IR 2 hours after i.v. or i.c.v. EXN-4 administration at doses that increase MAP and HR (i.v., 300 ng; i.c.v., 30 ng). Intravenous administration induced Fos-IR in several autonomic control sites (31) that showed little or no Fos-IR after PFS injection (Figure 2, a–t). These regions included the PVH, the lateral hypothalamic area (LHA), the arcuate nucleus (Arc) and the retrochiasmatic area (RCA), the external lateral parabrachial nucleus (PBel), the locus coeruleus (LC), the A5 catecholamine cell group (A5), the area postrema (AP), the NTS, the rostral ventrolateral medulla (RVLM), the caudal ventrolateral medulla (CVLM), and the IML of the spinal cord. The distribution of Fos-immunoreactive neurons induced by i.c.v. EXN-4 was similar to that induced by i.v. EXN-4 (Figure 3, a–t).
Distribution of i.v. EXN-4–induced Fos-IR in the brain. A series of photomicrographs demonstrates Fos-IR in neurons 2 hours after i.v. administration of EXN-4 (first and third columns) or PFS (second and fourth columns) in several brain regions. These regions include (a and b) the paraventricular nucleus of the hypothalamus (PVH); (c and d) the lateral hypothalamic area (LHA); (e and f) the arcuate nucleus (Arc) and the retrochiasmatic area (RCA); (g and h) the external lateral subdivision of the parabrachial nucleus (PBel); (i and j) the locus coeruleus (LC); (k and l) the A5 cell group (A5); (m and n) the area postrema (AP) and the NTS; (o and p) the rostral ventrolateral medulla (RVML); (q and r) the caudal ventrolateral medulla (CVLM); and (s and t) the IML in the spinal cord. 3v, third ventricle; f, fornix; 4v, fourth ventricle; VII, facial nerve. Scale bar = 250 μm in a–d, g, and h, and 100 μm in e, f, and i–t.
Distribution of i.c.v. EXN-4–induced Fos-IR in the brain and the adrenal gland. A series of photomicrographs demonstrates Fos-IR in neurons 2 hours after i.c.v. administration of EXN-4 (a–t, first and third columns; v–x) or PFS (a–t, second and fourth columns; u) in several brain regions and the adrenal gland. The brain regions include (a and b) the PVH; (c and d) the LHA; (e and f) the Arc/RCA; (g and h) the PBel; (i and j) the LC; (k and l) the A5; (m and n) the AP and the NTS; (o and p) the RVML; (q and r) the CVLM; and (s and t) the IML in the spinal cord. In the adrenal gland, after administration of PFS, little Fos-IR is visible (u). After i.c.v. EXN-4 at subthreshold dose (v; 3 μg), a little Fos-IR is visible. In contrast, i.c.v. EXN-4 at threshold dose (w; 30 μg) or a higher dose (x; 300 μg) induces Fos-IR in the adrenal medulla. Note that at the higher dose (x), Fos-IR is also visible in the cortex. Scale bar = 500 μm in a–d, g, and h; 200 μm in e, f, and i–t; and 50 μm in u–x.
Distribution of EXN-4–activated neurons projecting to the spinal cord. To ascertain whether the observed increase in MAP and HR was due to activation of GLP-1–sensitive cell groups that also innervate sympathetic preganglionic neurons, we injected the retrograde tracer FG) into the spinal thoracic cord centered on the IML (26, 27), with or without concomitant i.c.v. EXN-4 administration. The distribution of retrogradely labeled (FG-immunoreactive) neurons in the hypothalamus and the brainstem was similar to that in previous reports (26, 27, 32, 33). Following administration of EXN-4, we observed many double-labeled cells (Fos + FG) in the hindbrain, including the LC, the A5, and the RVLM (see Figure 5, n and p; Table 1). In the NTS, despite the existence of separate groups of neurons expressing either Fos-IR or FG-IR, we did not observe any double-labeled neurons. Many double-labeled neurons were observed in the hypothalamus, including the PVH, the Arc/RCA, and the LHA (Figure 4; Figure 5, a–c; Table 1).
EXN-4 activates medullary catecholamine neurons projecting to the spinal cord. (a–c) Double-label immunohistochemistry demonstrates that neurons that innervate sympathetic preganglionic neurons (brown cytoplasm) also contain i.c.v. EXN-4–induced Fos-IR (black nuclei) in (a) the PVH, (b) the Arc/RCA, and (c) the LHA of the hypothalamus. (d–f) Higher-magnification view of the boxed areas in a–c, respectively. (g–i) Double-label immunohistochemistry demonstrates that TH-immunoreactive neurons (brown cytoplasm) also contain i.c.v. EXN-4–induced Fos-IR (black nuclei) in (g) the NTS, (h) the LC, and (i) the CVLM. (j–l) Higher-magnification view of the boxed areas in g–i, respectively. (m–p) Triple-label immunohistochemistry reveals that many medullary catecholamine neurons (red cytoplasm in m and o) that project to the IML in the spinal cord (green neurons in n and p) also contain i.c.v. EXN-4–induced Fos-IR (black nuclei) in the RVLM (m and n) and the A5 (o and p). Scale bar = 100 μm in a–c and g–i, 25 μm in d–f and j–l, and 50 μm in m–p.
Intracerebroventricular EXN-4 activates hypothalamic and brainstem neurons projecting to the spinal cord
GLP-1R agonists activate catecholamine neurons. As the topographical distribution of neurons displaying EXN-4–induced Fos-IR in the brainstem resembles the distribution of catecholamine neurons that are known to play essential roles in regulating the sympathetic nervous system (34–36), we assessed whether medullary catecholamine neurons were activated by doses of EXN-4 that increase MAP and HR. We found double-labeled (TH + Fos) neurons following i.c.v. EXN-4 administration in the LC, the A5, the AP, the NTS, the RVLM, and the CVLM (Figure 5, g–i, m, and o).
Using triple labeling, we observed that approximately 25% of TH-immunoreactive neurons in the RVLM contain Fos-IR following i.c.v. EXN-4 and also project to the IML (Figure 5, m and n). Similarly, approximately 30% of the TH-immunoreactive neurons in the A5 group contained both Fos and FG (Figure 5, o and p). In contrast, although we observed many double-labeled neurons (Fos + TH) in the NTS, we did not observe any triple-labeled neurons in this region. In the LC, nearly all retrogradely labeled neurons activated by EXN-4 contained TH.
Previous studies have demonstrated that stimuli that induce sympathoadrenal response also display Fos-IR in the adrenal gland (37). To determine whether a dose of i.c.v. EXN-4 that increases MAP and HR is associated with activation of both central and peripheral catecholaminergic pathways, we investigated the distribution of Fos-IR in the adrenal gland 2 hours after EXN-4 administration. Intracerebroventricular administration of EXN-4 at doses that increase MAP and HR also markedly induced Fos-IR in the adrenal medulla (Figure 3, w and x). PFS injection or EXN-4 injection at subthreshold doses (3 ng) induced little or no Fos (Figure 3, u and v). The higher dose of i.c.v. EXN-4 (300 ng) also induced Fos-IR in the adrenal cortex (Figure 3x).
GLP-1R agonists activate TH gene transcription. TH catalyzes the rate-limiting step in catecholamine biosynthesis, and the concentration and activity of TH correlate with neuronal activity (38). Both pharmacological stimulation and electrical stimulation increase TH transcription (36, 39). However, basal expression of TH mRNA in the brainstem is relatively high, making quantitative assessments of mRNA levels difficult. To combat this problem, we constructed an intron-specific (hnRNA) probe using PCR.
hnRNA probes have been widely used as indices of in vivo transcriptional activity (40, 41). hnRNA probes hybridize to intron-specific RNA sequences prior to processing to mature mRNA. The short half-life of hnRNA makes them useful tools to study recent transcriptional activation in individual neurons following specific stimuli (40, 41). We found that the relative levels of TH hnRNA were comparatively high in the LC (Figure 6b) even after PFS administration. In addition, a few neurons in the A5, the NTS, the RVLM, and the CVLM displayed a nuclear hybridization signal (Figure 6, d, f, h, and j). In these regions, neither i.v. nor i.c.v. administration of PFS further induced TH hnRNA expression at any time points examined. In contrast, both i.v. and i.c.v. administration of EXN-4 (i.v., 300 ng; i.c.v., 30 ng) provoked a robust and rapid increase in TH hnRNA expression in the A5, the NTS, the RVLM, and the CVLM (Figure 6, c, e, g, and i). Specifically, TH hnRNA expression was induced 15 minutes to 6 hours after i.c.v. injection, and the TH hnRNA expression returned to base line by 24 hours.
Intracerebroventricular EXN-4 activates TH transcription in the medullary catecholamine neurons. All sections were hybridized with a specific TH intronic RNA probe 15 minutes after administration of i.c.v. EXN-4 (left column) or PFS (right column) in several brainstem regions, including (a and b) the LC, (c and d) the A5, (e and f) the RVLM, (g and h) the CVLM, and (i and j) the caudal part of the NTS. CC, central canal. Scale bar = 100 μm.
Using telemetric methods, we found that central GLP-1R agonists dose-dependently increased MAP and HR in unrestrained, conscious rats. In addition, we found that doses of EXN-4 that increase MAP and HR also induced Fos-IR in several autonomic control sites in the brain regions and in the adrenal medulla. In the hypothalamus and the brainstem, we also observed Fos-IR in neurons (including catecholamine neurons) that innervate sympathetic preganglionic neurons. Furthermore, EXN-4 increased TH transcription in medullary catecholamine neurons. These findings suggest that CNS pathways known to be critical regulators of sympathetic outflow are engaged by central GLP-1 neurons to regulate physiological processes including BP and HR responses.
GLP-1 neurons are expressed predominantly in the caudal medulla. However, the GLP-1R is widely expressed in the CNS. Available data suggest that central GLP-1 action produces taste aversion (13) and that GLP-1R signaling systems are activated following exposure to agents that serve visceral illness such as lithium chloride (LiCl) or LPS (12, 15). These models are internal stressors and induced responses defined as interoceptive stress (16). Interestingly, GLP-1R antagonists attenuate the increase in Fos-IR induced by the administration of LiCl or LPS. Notably, several interoceptive stress models also activate sympathetic outflow (27, 42). Taken together, these data suggest that the autonomic alterations characteristic of interoceptive stress may be mediated by central GLP-1 systems.
Our current findings extend previous reports linking GLP-1 or EXN-4 to increases in MAP and HR in anesthetized rats (18–21) and provide a mechanism invoking catecholaminergic neurons as downstream mediators of GLP-1 action. In anesthetized animals, bilateral vagotomy blocks the stimulatory effects of i.c.v. GLP-1 on BP and HR (20), suggesting that the cardiovascular effects of central GLP-1 systems may be due to mechanisms including inhibition of vagal tone to the cardiovascular system. However, the inherent confounding effects of anesthesia on cardiovascular physiology must be considered (43, 44). Difference in potential mechanisms of GLP-1 action on the cardiovascular system between various studies may be due in part to experimental differences in the preparation and handling of the animals and the doses of the agonists used in each study. In our system, the threshold dose of i.c.v. EXN-4 to increase MAP is approximately one-tenth to one-hundredth the threshold dose of i.v. EXN-4, and i.c.v. administration of GLP-1R antagonist blocked the effect of i.c.v. EXN-4 on MAP and HR. As GLP-1 is well known to be a potent stimulator of glucose-dependent insulin secretion, we excluded the possibility that changes in blood glucose following GLP-1 administration might be responsible for induction of Fos activation and counter-regulatory responses leading to sympathetic nervous system activation (3). The demonstration that GLP-1 agonists activate Fos, TH gene transcription, and cardiovascular responses at doses that do not lower blood glucose strongly suggests that central GLP-1 systems are capable of regulating BP and HR independent of the established peripheral actions of GLP-1 on glucoregulation.
Based on our findings, we propose that two possible effector pathways downstream of central GLP-1 neurons regulate sympathetic outflow. These two pathways include monosynaptic hypothalamo-spinal and bulbo-spinal projections to sympathetic preganglionic neurons (32, 45). Several studies have demonstrated that neurons in the RVLM and A5 provide descending input to sympathetic preganglionic neurons. Additionally, the RVLM provides tonic excitatory input to the cardiovascular system (34, 46–48). Therefore, we suggest that central GLP-1 systems are involved in regulating cardiovascular function in part by engaging catecholamine neurons that project to the IML to activate the adrenal medulla. The PVH is composed of functionally distinct subnuclei that regulate endocrine and autonomic responses (31). Within the PVH, EXN-4 induced Fos-IR in the medial parvicellular neurons and in the ventral, dorsal, and lateral subdivisions, suggesting that central GLP-1 systems may regulate the hypothalamo-pituitary-adrenocortical (HPA) axis and autonomic outflow. Indeed, neurons in the caudal NTS that project to the PVH contain GLP-1 (17). GLP-1 also activates the HPA axis, presumably through stimulation of CRH neurons (17). With respect to autonomic responses, the transneuronal tracing has identified the PVH as one of a few brain sites that regulate the entire sympathetic outflow (49). Our current study suggests that GLP-1 acts in the PVH to mediate neuroendocrine responses and to modulate sympathetic outflow.
In our current study, both peripheral and central administration of GLP-1 agonists rapidly increased BP and HR and induced similar patterns of Fos-IR throughout the brain, including several key autonomic regulatory sites. The induction of Fos-IR in these sites is consistent with the concept that the increased activity of these neurons contributes to the increases in BP and HR. However, we cannot rule out the possibility that the expression of Fos in some of these sites may simply be secondary to the increased BP and HR and may not represent activation of neurons inducing the observed responses. Still, the Fos patterns induced by GLP-1 agonists in the brainstem are distinct from patterns induced by phenylephrine-induced hypertension, which does not induce Fos-IR in catecholamine neurons (50). Indeed, the patterns of GLP-1–induced Fos are more similar to those of stimuli that increase HR and BP, increase Fos-IR in TH neurons, and activate TH mRNA (36, 50). Thus, we suggest that Fos induction in central autonomic control sites by GLP-1 agonists is not likely to be a secondary consequence of increased BP and HR.
One interesting difference in the patterns of i.v. and i.c.v. injections was that in the AP. Specifically, i.v. EXN-4 induced much more Fos-IR than did i.c.v. EXN-4 in the AP. GLP-1Rs are prominently expressed in the AP, a circumventricular organ that lacks a blood-brain barrier. Therefore, it is likely that neurons in the AP have access to circulating GLP-1. Indeed, recent studies using 125I-GLP-1 have demonstrated that GLP-1Rs are accessible to peripheral GLP-1 in the subfornical organ and the AP in the rat (51). Furthermore, in our preliminary study, we found that i.v. EXN-4 induced Fos-IR in GLP-1 neurons, suggesting that peripheral EXN-4 activates the central GLP-1 system, which may contribute to the effects we observed. Consistent with this hypothesis, Barragan et al. (20) showed that i.c.v. administration of a GLP-1 antagonist blocked cardiovascular responses to systemically injected GLP-1. Therefore, it is plausible that circulating GLP-1 activates GLP-1–responsive neurons in the AP and also activates GLP-1 neurons in the underlying NTS. This model would predict that GLP-1 neurons in turn activate neurons expressing GLP-1Rs in the hypothalamus and the brainstem, leading to coordinated endocrine and autonomic effects (Figure 7).
A neuroanatomical model of GLP-1's actions in the rat brain. Circulating GLP-1 engages GLP-1Rs on the hypothalamic neurons in the PVH, Arc, and LHA, and medullary catecholamine neurons in the A5, RVLM, and CVLM, probably through the AP and NTS where GLP-1 neurons are located. These GLP-1–activated neurons in the hypothalamus and brainstem have monosynaptic descending projections to the sympathetic preganglionic neurons in the IML, which innervate the adrenal medulla and heart to increase BP and HR (autonomic responses). This model predicts that some of the medullary catecholamine neurons project to the hypothalamic neurons. GLP-1–activated neurons in the PVH also act on the pituitary to engage neuroendocrine responses.
The data reported here suggest that the central GLP-1 system can regulate sympathetic outflow. In normal humans and rodents, circulating levels of GLP-1 are low in the fasting state, rise following nutrient ingestion, and fall within minutes due to rapid enzymatic inactivation by DPP-IV. Indeed, continuous infusion of GLP-1 does not increase BP and HR in human subjects with type 2 diabetes (52). In contrast, more potent degradation-resistant long-acting GLP-1 analogues, including EXN-4, are being considered as therapeutic agents for the treatment of type 2 diabetes. Our current results demonstrate a dose-dependent increase in BP and HR following both central and peripheral administration of EXN-4. However, the pathophysiological significance of our findings in rodents must be assessed in further studies that carefully examine dose response relationships in both acute and chronic paradigms, especially in diabetic subjects. Nonetheless, our results suggest that the central GLP-1 system is a regulator of sympathetic outflow and raise questions about the potential consequences of sustained GLP-1R activation for the treatment of patients with type 2 diabetes.
The authors thank Quan Ha, Toshiro Kishi, Im Jihee, Brian J. Choi, Hiromichi Kashihara, Takuma Kishimoto, and Hiroshi Muraki for technical assistance. This work was supported by NIH grants DK-59751 and DK-56116 and Juvenile Diabetes Research Foundation grant 2000-559.
Conflict of interest: D.J. Drucker is a consultant to Amylin Pharmaceuticals Inc. and Conjuchem Inc.
Nonstandard abbreviations used: glucagon-like peptide-1 (GLP-1); GLP-1 receptor (GLP-1R); dipeptidyl peptidase-4 (DPP-IV); exendin-4 (EXN-4); nucleus of the solitary tract (NTS); intracerebroventricular(ly) (i.c.v.); intravenous(ly) (i.v.); immunoreactivity (IR); Fos-like immunoreactivity (Fos-IR); paraventricular hypothalamus (PVH); corticotropin-releasing hormone (CRH); blood pressure (BP); heart rate (HR); Fluorogold (FG); intermediolateral cell column (IML); mean arterial blood pressure (MAP); pyrogen-free saline (PFS); tyrosine hydroxylase (TH); protected least significant difference (PLSD); heteronuclearRNA (hnRNA); avidin-biotin complex (ABC); diaminobenzidine tetrahydrochloride (DAB); lateral hypothalamic area (LHA); external lateral parabrachial nucleus (PBel); locus coeruleus (LC); A5 catecholamine cell group (A5); area postrema (AP); rostral ventrolateral medulla (RVLM); causal ventrolateral medulla (CVLM); hypothalamo-pituitary-adrenocortical (HPA).


text:
App Description
Meet the cutest dogs of the Smartphone games history!From now on, Playbean gives you the cutest puppies running in your arms.
★ PLAY Hint!! ★
Right / Left hand – Drag up a hand you want
Sit – Drag the head down
Lie flat – Drag the head down when your dog sitting
Bang! – Drag the head a side when your dog sitting
Lie - Drag the head a side when Bang!
Roll - Drag the head a side when your dog lies
* Detail tips of tricks are referred below the link of video.
★ Expected UPDATE ★
A lot of new puppies like Pug, Chihuahua, Miniature Pinsche..etc.
Various rewards when you level up!
Many things you can do with your friends together... Talk with your friends about the episodes when growing your dog. And share rewards visiting friends' house and helping them.
★ About 'My First Dog' ★
â– Live and breathe dogs in your Smartphone.
- The dogs express their emotions like joy, sadness and they'll do cute actions.
- Enjoying all the things when you bring up your puppy like dressing, feeding
and taking a walk.
â– Hundreds of various costume items.
- Dressing your puppy using enormous costume items
- Finding hidden items when taking a walk or going out with your dog!
â– Puppy will get new talent as your love.
- Getting along with your dog more, your puppy gets a new talent.
- Boast your talents and try to win the championship! It gives you Wealth and Fame!
★ Play Tip! ★
- Touch your dog and move it ways. According to action, your dog does a new thing.
- When you find a gift box during taking a walk, lead your dog to it.
- Your dog often play outside so don't be panic if your dog is not in house. Sometimes your dog bring an amazing item.
Play awesome games of PlayBean!
* Homerun Superstars – Extreme homerun derby with immersive hit effect!
* The Heroes of Three Kingdoms – Spectacular Full 3D action RPG!
* Master of Dungeon – Feel the pleasure of annihilation! Gather mobs and wipe 'em out!
* Fantasy Defense – A tower defense game based on fantasy!
* AstroWings2 : SPACE ODYSSEY – Exciting shooting game with highly-enhanced graphics!
* Second World War –WW2 is on your hand. Bring victory from famous battles and rewrite history!
â"'TheAppsGames : You develop it, We'll publish it
App Changes
November 30, -0001 Initial Release

subset: commoncrawl


text:
When I was approached with the prospect of exchanging information about the Suns and our upcoming opponent, the Portland Trail Blazers, I jumped at the opportunity. No time like the present to get an inside perspective on a Western Conference adversary that has undergone wholesale changes. No better person to provide that perspective than someone who is eminently qualified as an authoritative source on all things Blazers, but since I couldn't track that person down I settled for Dave from Blazer's Edge. I jest, I jest.
We may not share the most cordial relationship with Portland fans and we may take a special satisfaction in plotting the team's demise, but everyone loves Dave. We each answered the same set of questions, with Dave's thoughtful responses listed below. My astute analysis blithering flummery can be viewed over at Blazer's Edge. Thanks again for investing the time in this collaborated effort, Dave. Enjoy Brightsiders.
What were the major moves for Portland this off-season?
There's been plenty of turnover in the Valley of the Rain this year, a situation familiar to Phoenix fans. You guys picked up Goran Dragic, Luis Scola, Michael Beasley, Jermaine O'Neal...solid to semi-solid middle class acquisitions. General Manager Lance Blanks was like a nice dad to you. It's not like you got a Lamborghini but, you know, he outfitted the family with iPods over the summer and you'll have fun with them.
Facing similar circumstances, Portland General Manager Neil Olshey played cheap dad. When the two teams meet tonight Phoenix fans are going to show off your nice Apple products while Blazers fans sport their barely-functional, off-brand tablets. Adam Morrison, Sasha Pavlovic, Victor Claver, a used Jarred Jeffries, a used Ronnie Price...say hello to our Magnavorx SuperTab. Ooooh! 320x200 resolution! Wait, I didn't know you could have dial-up on a tablet. Where do you plug in the...oh. Right there. I see. As long as we stay within 20 feet of a phone jack, we're good. Thanks, dad!
To be fair, there's something to be said for not chasing the 8th seed. If you're not ready to contend, disposable guys on $1-2 million contracts are the way to go. Check that...a way to go. And that's the way the Blazers went.
On the bright side, Portland also got a couple of potentially-nifty pieces on rookie contracts through the draft. Damian Lillard is as poised as I've seen an expectation-laden rookie point guard. He's light years ahead of where he should be, especially since he has a reputation as a scorer first. He can do that, but he sees and runs the floor well. His shot is confident and well-timed. Aside from defense, Blazers fans will love everything about this kid.
Illinois center Meyers Leonard has incredible lateral and vertical floor quickness. This guy can scoot. He needs work on fundamentals on both ends, especially in the paint. But he's going to be a versatile 5 someday...not earth-shaking but nice.
Import Brit Joel Freeland is Portland's other new big man. The jury is out on his skill set but he's mobile and active at least.
It'll be fun watching these guys develop...mostly. Portland fans aren't expecting wins as much as a new start.
How do the early returns look after the first preseason game?
As much as one can judge from a single pre-season outing, good. Coach Terry Stotts' new schemes suit his players. The Blazers want to spread the floor with distance shooting (the one area in which most of these players excel) and use the extra real estate to free LaMarcus Aldridge in single coverage or some combination of wings working off screens, diving, and receiving passes. Portland's bigs will also take advantage of their speed to finish on the break. In the first game we saw a fair number of layups, dunks, and made threes...a far cry from the Brandon-Roy-heavy matchup-based offense of the past.
Defensively the Blazers have changed how they deal with screens, long a sore spot. Those mobile forward and centers show and assist their guards in slowing the dribbler instead of just switching.
As far as individuals, Lillard and Meyers looked impressive in Game 1. Jeffries, Price, and Morrison also shone. It was a positive outing.
What are you looking for from the team and/or specific players during the remainder of the preseason?
Execution, mostly. When your offense depends on fast breaks, cuts away from the ball, and three-pointers you have to stay committed and run it right. The Blazers no longer have the luxury of unstoppable matchups on either side of the floor. Aldridge is still money but he can't score 100. If the Blazers hustle, keep moving, and make sure the ball goes inside before it's kicked back out for the long shot they will succeed. As soon as they get lazy and start holding the ball those long jumpers after 0-1 passes become awful shots.
Realistically a skilled, motivated defense will still be able to take away what the Blazers want to do, so there will be plenty of ugly games this season. But we all need to see the Blazers keep their heads instead of just driving straight into the inevitable potholes. Make other teams take the game from you. Don't just give it to them.
What are the goals for this year and the long term direction?
Survive with confidence intact and positive momentum as a team. Also develop the young players, particularly those first-round picks. That's the agenda for 2012-13.
After that look for the Blazers to add talent via the draft and eventually free agency. Their eventual starting lineup would look decent in a couple years even without any changes. It could look great if the right move came along at shooting guard, small forward, or center. But Portland's bench is a stinky-awful eyesore right now. That's not meant to disrespect the players involved. Any of them could be a contributor in the right circumstances. But realistically you're looking at a huge swath of 10th-15th men populating Portland's pines. Having one 11th man with the potential to step up is great. Fielding 7 11th men and needed 5 of them to step up is not going to work. Adding talent will be high on Portland's priority list once this season closes.
Dave -- Blazer'sEdge
The Phoenix Suns played their first preseason game on Wednesday, Oct 10, to mixed results. That they won or lost the game was immaterial.
Preseason is all about evaluating players, and Alvin Gentry has to choose three to five guys from a pool of 12 to supplement the Suns returning rotation. From last season, only Marcin Gortat, Jared Dudley, Markieff Morris, Shannon Brown and Sebastian Telfair return. Each will get a rotation spot, at least at the beginning of the season. Alvin Gentry needs some kind of continuity while the new guys learn the system.
Certainly, if any or all of them get beaten out by new guys, that's the way it goes. But Gentry won't be able to see that and make that decision if the new guys are just languishing on the bench all preseason.
So he has to play the new guys as much as possible while also getting everyone into game shape.
"We're just going to take a look at see how players fit together," said Gentry to arizonasports.com. "We had a pretty good gauge in the past about who played well with who and the matchups and the rotations. But, with this group right here it's practically brand new."
I was not surprised when Shannon Brown and Sebastian Telfair were held out of last night's game. Sure they had minor injuries (Brown got stitches on his forehead, Telfair had a sore wrist). But it was also convenient to rest them for the same reasons that Luke Zeller and Ike Diogu didn't play.
"I want guys out there long enough so they can get a feel," he said in that same interview. "We'll give guys some extended minutes. Most of the guys that go in are going to play seven or eight minutes straight so they can at least get a feel of the game."
By not playing Telfair, Gentry had a chance to see more of Kendall Marshall and Diante Garrett.
By not playing Zeller and Diogu, Gentry got to see more of Solomon Jones and Jermaine O'Neal.
By not playing Brown, Gentry got to see more of Othyus Jeffers, Wesley Johnson and P.J. Tucker.
So, what did Gentry glean from these guys last night? To be honest, I have no idea. I only had a tiny stream on my computer running while listening to the out-of-synch radio call by McCoy and keeping up on twitter and game stats, not to mention writing the recap and popping into the game thread.
And even if I did have all the video and time in the world, I'm not a basketball coach. I rarely notice the little things beyond the basketball. I don't even know what offensive plays they were running each time, unless it was a pick-and-roll.
I can guess that Gentry can see Johnson in a "shooter" role, and Beasley in a jack-of-all-trades role on the wing. And I can guess that Gentry didn't like the flow of the offense when Marshall or Garrett were running the team.
But those suppositions can change from game to game. Expect Gentry to keep playing roulette all the way through the preseason (and even into the season for a month or two). There's no all-star on this team, no sure-fire winning lineup. It's all about mixing and matching guys who have never played together as a group before. And then figuring out which "good" and "bad" is repeatable to the point of consistency.
Not only does he need to figure out if these guys can play NBA-level basketball, he needs to see who plays best with whom.
And that's a tall order.
The Phoenix Suns have been bitten a bit by the injury bug early in training camp. The first issue is with Shannon Brown, who, according to Arizona Republic's Paul Coro, will miss his second preseason game after suffering what some are calling "Halloween eye." As this photo from reporter Craig Grialou shows, Brown suffered a sizable laceration above his left eye after a collision with forward P.J. Tucker during practice.
The area is pretty swollen and would certainly make it hard for the young guard to play.
The other injury issue the Suns are dealing with is Sebastian Telfair's wrist. He managed to practice on Thursday, but he was held out of Wednesday's preseason game with the Kings as a precaution. Here is the latest from Phoenix:
#Suns Telfair practiced w/his left wrist taped; he was held out of last night's gm as a precaution, should play Friday vs. Blazers
— Craig Grialou (@Craig620) October 11, 2012


text:
Visit our other Wisconsin Historical Society websites!
Refine or narrow your results by clicking any term in the gray boxes below.
Expand your results by removing any breadcrumb in a gray outlined box above. Click on the blue "X" to remove the term.
Narrow your results by entering a keyword into the search box above. Then click the "Search Within" checkbox, then click on the orange "Search" button.
If you did not find what you are looking for or you did not get any results, try changing your search term(s). See our Search Help page for more tips.
Date: 1947
Description: Members of the Arms family (and a friend?) pose on Bernard Arms's farm. From left to right are Nellie Arms, Bernard Arms, unidentified man with eyes rolled...
Date: 1918
Description: View of the Ringling Brothers Circus winter quarters from across the Baraboo River, looking due north. The brick building, center, was one of the two "Cat...
Date: date unknown
Description: A group of men and women sit outdoors, playing a card game around a table at Devil's Lake.
Date: 1956-06-14
Description: Interior view of St. Joseph's Catholic Church, Baraboo, decorated by Clemens Rath.
Date: 1925 ca.
Description: View across road of a two-story home located on a corner lot at 330 5th Avenue. There are signs on the lawn advertising rooms for tourists. A man is standi...
Date: 1927
Description: Exterior view of a two-story house with a front porch and an enclosed porch on the side. In the background is a barn or outbuilding.
Date: 1930 ca.
Description: A young woman sits on the floor, one arm resting on an open dresser drawer, gazing into the distance and holding a letter. She is wearing an old-fashioned...
Description: Lewis Arms and friends perch on a bluff overlooking Devil's Lake. From left to right are Arms, Eddie Elvord (Alvord?), Mary Rogers, and George Green (Green...
Date: 1877 ca.
Description: ,Well-dressed young couples sit in the foreground while in the background is a picket fence running along a busy road with horse and buggy traffic. Further...
Description: A view of high water on a river, possibly the Baraboo River, in a rural setting.
Date: 1940 ca.
Description: A group of 14 hunters poses in front of seven field dressed deer which hang from a rack made of metal pipe. There is a barn in the far background, left, an...
Date: 1931
Description: Two employees standing along the storefront of an International Harvester dealership owned by the Schwartz Bros. The dealership sold McCormick-Deering farm...
Date: 1876-07 ca.
Description: A camping party rests at the top of a bluff at Devil's Lake State Park.
Description: A night view of the window display in the Hansch and Hill Electrical Store, 121 Fourth Avenue. Floor lamps and wall sconces are featured, as are displays o...
Description: Front entrance of the Trimpey house.
Description: A model posed as an angel sits on the ground in front of a sylvan backdrop, warming her hands over a fire. She wears wings and a dress of diaphanous materi...
Date: 1920 ca.
Description: A woman in an old style dress stands in profile by a keyboard instrument with her left knee resting on a Gothic Revival chair. A candle burns in a brass ca...
Description: A studio portrait of a child as Cupid wearing wings and holding a bow and arrow, posed leaning against an owl and sitting on a tree stump.
Description: An old oil lamp with a cut cased glass font and a cast metal base in the form of a cavalier.
Description: A young woman poses with a basket of flowers over one arm. She wears an old-fashioned costume and stands in front of a painted backdrop which mimics a ston...
If you didn't find the material you searched for, our Library Reference Staff can help.
Call our reference desk at 608-264-6535 or email us at:


text:
If I Walked Away
Helen D'Aguiar (aka Hot Heels) - 22/03/2002
Being a massive fan of "Razor Sharp" I couldn't resist this dance, especially after seeing it danced at Caleys/Buffalo Boyz workshop last month. I have now taught it to my class and they seem to love it (those that like waltzes, that is!). Great dance, Stephen! Keep them coming!!
Singapore Swing
Helen D'Aguiar (aka Hot Heels) - 22/03/2002
I taught this to my class as a warm up dance this week and they had a lot of fun with it! We had a few different styles coming out of the walk at the end and the music is such fun. Nice little dance, Bill!
What Do You Say
Sally Clarke - 22/03/2002
Although this is an easy dance to learn I found it a very pleasent dance and a good choice of music I will be telling my instructor about this one for our class
What Do You Say
Brian Davis - 22/03/2002
Interesting dance for only 32 steps I,ll be teaching this dance at our club
trisha conroy - 21/03/2002
Just learnt the dance last night. Think a lot of people are put off by the intro to the music but percieve its sound.
Feel Like Leaving
Anne from England - 21/03/2002
Nice track, easy dance does loose it slightly with music later on but gets back on course, even so nice effort and well done Mike !neverthless well done Mike !
Would You Dance (If I Asked You To Dance)
ChrissieB - 21/03/2002
Have been taught this and Michaels' dance but I feel this fits the music so much better, flows beautifully. Hazel has obviously felt the music as it feels so good and a lovely intro! Like it very much!
Would You Dance (If I Asked You To Dance)
Trisha Conroy - 21/03/2002
Hazel Your mate Kate Potts taught me your dance Tuesday night really sound dance.Watch out Maggie G.
Mean 2 Me
Trisha Conroy - 21/03/2002
This has got to be a No 1. It took a while to master but well worth it.Well done Chrissie.
Mamma Afrika
Trisha Conroy - 21/03/2002
I was taught this at one of the classes I go to but at the other 3 classes the instructers wont do it ,I dont know why I think its superb.
Hero (We All Have One)
Marie - 21/03/2002
The Dance everyone should be dancing to this piece of music is 'Would you Dance' by Hazel Pace. Michael's dance does not fit this music correctly and you would realise this if you were to see Hazel's dance. It's a shame that because Hazel isn't as well known as Michael that she can't get her dance made known as easily.
Mean 2 Me
Marie - 21/03/2002
Like the first half of this dance but find that the 2nd half of the dance is awkward, which means I get fed up with dancing 'Whenever' after about the second wall. Not a patch on some of Chris's other dances.
Bump In The Dark
Susie G - 20/03/2002
Great fun dance that goes well to the track. Not difficult but not boring.


text:
Consistency is the name of the Sepang weather game. The humidity will again be around 94 per cent on Saturday and Sunday, and the ambient temperature on both days is expected to reach between 32 and 34 degrees Celsius.
Everyone knows it is going to be very tough, but at least they should be able to plan their strategies around consistent conditions.
There is still a high probability of rain in the region on both days, but any thunderstorms tend to come late in the afternoon/early evening.
The 5.543 kilometre Sepang International Circuit is unchanged since Fernando Alonso put his Renault on pole and won last year. The race will run over 56 laps (310.408 kilometres) and will start at 1500 hours local time (0700 GMT).


text:
Keb Mo Tickets
Latest Keb Mo Tickets | ||
Keb Mo tickets at Scottish Rite Auditorium - Collingswood,Collingswood,NJ on 3/11 7:30PM | Wed Mar 11 2015 | View Tickets |
Keb Mo tickets at B.B. King Blues Club & Grill - New York,New York,NY on 3/13 8:00PM | Fri Mar 13 2015 | View Tickets |
Keb Mo tickets at Georgia Theatre,Athens,GA on 5/2 8:30PM | Sat May 2 2015 | View Tickets |
Keb Mo tickets at The Kessler,Dallas,TX on 5/23 8:00PM | Sat May 23 2015 | View Tickets |
Keb Mo tickets at Atwood Concert Hall,Anchorage,AK on 6/6 7:30PM | Sat Jun 6 2015 | View Tickets |
Keb Mo Cities |
Details of Keb Mo and the Ticket Luck value
If you want to enjoy the perfect musical night that can make you forget about your worries and help you enjoy heartwarming music, getting Keb Mo tickets is the way to go. As this sensational music icon is soon to hit the stage and entertain music buffs in your city this season, you must act fast and get your hands on tickets for this show. Shows by Mo are always sold out so if you do not get a ticket now, other music enthusiasts will take the lead and you will miss out on this must see performance. So do not think twice and grab a ticket to be a part of a live concert by this award winning music artist now!
This blues musician is well recognized for his great vocal quality. He is also a wonderful guitarist, and songwriter who has won a number of awards for his outstanding contribution in the world of music. His post-modern blues style is influenced by several genres of music. His music has traces of pop, jazz, folk and more, making him stand apart from other conventional music artists. Live gigs by Mo are packed with energy, fun and entertainment. Being a part of his show can be your best chance to enjoy an extravaganza where you can dance, sing and have the time of your life.
Keb Mo was interested in blues and gospel music from the start. This is why he started playing guitar when he was still a kid. He began his career by playing the steel drums and upright bass in a calypso band. He also performed with various blues and backup bands and started recording in the early 1970s with Jefferson Airplane violinist Papa John Creach. During this time, he also served as a staff writer for A&M Records, and arranged demos for Almo - Irving music. Rainmaker was his debut work that was highly appreciated by fans around the country. His self title album was made public in 1994 which included a number of hit numbers. Just Like You was his second work that was a huge hit as well. He got his first Grammy Award for this compilation of music and became a heartthrob of millions of music enthusiasts around the world. As he has huge fan following, his concerts are always packed. So if you do not want to miss out on his upcoming gig, get your hands on a ticket without wasting any time.
Mo's other works include "Slow Down", "The Door" and "Peace... Back by Popular Demand". His music is one of its kind owing to the equipment that he uses as well as due to his creative and innovative approach. Keb Mo employs various types of guitars such as electric guitars, acoustic guitars and more. This is why he is able to give a unique feel to his music that touches your heart and soul.
Live gigs by this talented artist is a feast for music lovers. This is why you must not let go of this once in a lifetime opportunity to attend his concert and discover him up close. Though you can listen to him on your laptop or ipod, nothing can help you discover him better than his live performances. The overall feel of his shows are great. You will come across fans from all age groups and all walks of life. So wait no more and grab a ticket for this event soon to be held in a theater near you. Getting Keb Mo tickets now can also help you find the best deals so act fast and experience an unforgettable musical performance that you would cherish for years.
Frequently Asked Questions
Q:Is there a keb mo concert nashville great seats would be helpful.
A:Our Keb Mo collection is up for grab ,take your pick now!


text:
Studio Luma™. A brand new way to learn cosmetology. Only available at Regency. Watch to learn more.
Let your talent shine. Learn the techniques you need to get started in cosmetology at Regency Beauty Institute's Peoria beauty school.
Express your creativity in an inspired industry. Learn the salon skills you need as a student at Regency's Peoria, Illinois cosmetology school.
Plus, only Regency offers the Studio Luma™ program. It's learning without lectures and a new way of teaching cosmetology that is as creative as you are.
Enroll and experience the Studio Luma™ program at no risk with our Simply Start™ option. Find out more.
The Studio Luma™ program is designed to teach in the way you learn best. Engaging video. Interactive study guides. Self-paced tutorials. Interactive questions instead of final exams. And skilled teachers who don't lecture, but are free to focus on you. Working together, hands-in-hair, guiding you on your path to a successful career in cosmetology.
We designed a convenient class schedule to fit your life. You'll also have four weeks of vacation during the year and time off around major holidays. You'll have time to focus on school and the people in your life you care about.
You'll even gain experience practicing more than just technical skills. You'll learn to develop relationships with clients, increase your client base and recommend products through the STAR program® (Student Training and Rewards). Knowing how to build your business matters when you're turning your creativity into a paying career. You can earn rewards like a STAR diploma when you meet milestones throughout the program.
Our beauty school in Peoria, Illinois is located off Hwy 8 in the Westlake Shopping Center on the northwest corner of Sterling Avenue and I-74. It is accredited by the National Accrediting Commission of Career Arts and Sciences (NACCAS) and able to offer federal financial aid to those who qualify.
Classes start monthly. Full and part-time programs are available. Contact us today to get started!


text:
In addition to Elantra GT, Hyundai has also introduced a sport coupe variant of the Elantra. The Elantra Coupe features a wedge-like sport coupe silhouette with deeply sculpted surfaces. The fast A- and C-pillar angles frame a sharply tapered greenhouse, further accentuating the wedge profile. Just below the belt line, a prominent character line carries [...]
read more
The Chicago Auto Show is in full swing, and Hyundai is busy adding new variants to its hot-selling Elantra lineup. In just a few years Hyundai has gone from joke, to also ran and now, one of the segment's leaders. The Elantra is wel... Read Post
The new 2013 Hyundai Elantra GT hatchback Hyundai Motor America introduced the all-new 2013 Elantra GT in a North American debut at the Chicago Auto Show. Elantra GT brings five-door functionality and European driving dynamics to th... Read Post
The new 2013 Hyundai Elantra Coupe Hyundai introduced a new sport coupe variant to its industry-leading Elantra line-up at the 2012 Chicago Auto Show. This two-door coupe model of the Elantra sedan, available this spring, will attra... Read Post


text:
Get LISNews via email! Enter Your Email Address:
The unexpected reader
"Open access serves all of these unexpected readers of scholarly works. As Carroll summed up his point, every time we create an open environment, we get unexpected developments and innovations. We have come far enough down this road now that the burden of proof is no longer on open access advocates, it is on those who would claim that the traditional models of publishing and distribution are still workable."


text:
Two years into her business, Kushboo Lalwani has lots of people craving for her homemade chocolates and chocolate bouquets… UTHRA NAGARAJAN
A B.Com graduate, 20-something Kushboo Lalwani wanted to do something different that would tap her artistic potential after she got her undergraduate degree. And that led her to the business of homemade chocolates. As the proud owner of Chocobraze, her three-year-old business, has become a known name in this business and has some of the top brass in her clientele. In fact, her first customer for homemade chocolates was the editor of Outlook (who?). "Every occasion, be it a birthday or marriage, is a special one and I like to make it more special with my chocolates," expresses Kushboo.
A starry beginning
She also tried her hand at making chocolate bouquets soon after and they became hugely successful and has a growing demand. "I gave my first chocolate bouquet to actor Kushboo, whom I met at the opening of a pharmaceutical factory," smiles Kushboo.
While she did face some initial hiccups when she started out, once people started recognising the quality of her chocolates, they kept coming back and became her regular customers. She caters to weddings, birthday parties and other functions as well. "For weddings, I make choco nutty cups and for birthdays, I make something along the lines of colourful lollipops," says the young entrepreneur. Priced between Rs.200- 4000, Kushboo says that she must have made around 250 chocolate bouquets till now. Her homemade chocolates are priced at Rs.650 per kilogram.
However, Kushboo has not had any formal training in making chocolates. She learnt chocolate making ten years ago in Pune but hasn't had any other training since then. "My mother is my backbone," she says. "She helps me in the production process as well as managing the company." Quizzed about why she hasn't commercialised her chocolates, Kushboo says that most people prefer international and national chocolate brands available in supermarkets, while she builds her clientele with people who come to her after tasting her chocolates at parties and private functions.
More on the plate
Her latest addition is muffins, which she started making just a month ago. And her first order? "The editor of India Today (who?)," grins Kushboo. She guarantees that everything is fresh, homemade and has a personal touch to them. Not just in Chennai, people from other states also vie for her chocolates. She has an enviable clientele from Delhi, Rajasthan, Pune and Bangalore as well.
Contact: www.facebook.com/Chocobraze


text:
Enter your name and email to receive alerts when new vacation deals are added to any property in this region.
By clicking "Submit" you are agreeing to the
Terms of Service.
Alert successfully created!
Showing 1-1 of 1 Nature Resorts
Tullymore Golf Resort
Tullymore Resort makes it easy to explore the natural beauty of Michigan. You will find 30 lakes and two rivers within seven miles of the resort perfect for plenty of exciting outdoor adventures. Whether you choose to enjoy a refreshing hike along the shores, cast your line for a day of fishing, or just take out a canoe for quiet exploration, this... more
- Wifi
- Restaurant Onsite
- Pets Allowed
- Property Size 36 units
- Conference Facility
- Kids Allowed
- Nearby City Grand Rapids
- Nearby Water Canadian Lakes
- Open Dates All Year
- Meetings
- Family
- Reunions
- Golf
- Honeymoon
- Luxury
- Nature
- Romantic
- Wedding
- Villas and Condos
Showing 1-1 of 1 Nature Resorts


text:
'What I love about his work is how absolutely unexpected it is'
Sean McKeown-Young, creative director for the Gannett Design Studio in Des Moines, Iowa, writes to tip us off about some great work being done there.
He tells us:
I wanted to make sure that you noticed Dave Lafata's work. He has rapidly become an 'uber-designer.'
Aside from being a really great guy with some really exciting ideas about what newspapers can look like, he has a stunning talent. These first two examples are just from [Wednesday]. I am blown away.
He's originally from Warren, Michigan – so he's another Detroit-metro dude. He graduated from Central Michigan University with a degree in Fine Arts in 2012. He started in the studio in 2012 designing Wausau/Wisconsin Rapids/Stevens Point/Marshfield Sports. It's amazing how fast he grew.
He is now the lead designer for Green Bay. That is huge for a young designer.
We've been so lucky to have some tremendously forward-thinking editors that have really collaborated to let his vision shine. Dave is also really lucky to work with Bill Wambeke, the Wisconsin Team Leader. Bill has been a huge influence on Dave's career, allowing him the room to grow and the coaching to hone his statement.
What I love about his work is how absolutely unexpected it is. It feels relevant and relatable but totally fresh. I think that's rare. He is a tremendous artist and his work increasingly has elements of his fine arts work; he's blending hand drawn work with digital.
I get really excited when I see new talent and designers coming into 'their voice.'
Sean has bragged on Dave before — when Dave built a series of covers about a huge air show in Oshkosh. I posted a batch of these covers in 2013 and again in 2014.
A few samples:
Gannett's Dave is not the David Lafata who is an internationally known soccer star. As far as I know.


text:
Contamination close CFA training site
The Victorian Counrty Fire Authorities training facility has been shut down after a dangerous...
15 minutes ago
The Victorian Counrty Fire Authorities training facility has been shut down after a dangerous...
15 minutes ago
Prime Minister Tony Abbott is officially to announce an expansion of Australia's military...
54 minutes ago
Homicide detectives will return to the new search site for missing toddler William Tyrell.
55 minutes ago
Three people including a young child have been found shot dead in a home west of Toowoomba in...
57 minutes ago
Kochie's Angels look at reasons people are claiming more problems getting to sleep.
March 2, 12:42 pm
Nelson Aspen reports on the feud as Taylor Swift refuses to discuss the issue any further.
March 2, 12:40 pm
Gretel Killeen, Zoe Marshall, and Angela Mollard discuss the possibility of school terror...
March 2, 12:36 pm
Alana MacInnes talks about her photo, which broke the internet as the world tried to decide what...
March 2, 12:30 pm
Angela Mollard talks about her work raising money for the Fred Hollows Foundation.
March 2, 12:27 pm
Eddy is on Kangaroo Island and gets a closer look at some of the local inhabitants.
March 2, 12:22 pm
Deputy PM Warren Truss talks about the leadership question, school terror threats, and the...
March 2, 12:16 pm


text: Police Products Mobile Computers Email Comment Inside Access to the 2012 Chevy Caprice Demo Vehicle from Havis Copy and paste the code below to embed this video. Close The Havis Caprice demo is fully loaded with dash mounted touchscreen, K9 transport unit and much more. Tags Products Chevy Vehicles Join the discussion Be the first to comment PoliceOne comments can only be accessed by verified law enforcement professionals. Please sign in or register to view or write your own comments below. Sign In Register


text:
Hey guys! Guess what??? That's right! I'm going to have a mini contest!
To join, just fav the journal! I will choose on random.org
First place:10
Second place: 5
Third place: a free request from me!
Fav: one number
Watch: two numbers
Remember, just fav!
Forgot to say this but comment on this journal too!
I hope you guys join!
One more thing, donate a few points to get more numbers!
1 point= 2 more numbers, 2 points= 4 points and so on.
Ending date: May 1st
please join! I'm willing to give away points.
Since not a lot of people joined, I extended the the ending date
signing off!


text:
Sunday, December 18th, 2005
Join Pastor Wayne as he shares on the house-centric community and the importance of hospitality of the early church.
The Notes area is simply a place where you can type out your notes while listening to this sermon. Currently, these notes are not stored anywhere online, so if you want to save them, please remember to copy them into a document on your computer before you close this window.


text:
So I want to know what the most dependable firearm is in your opinion. I think you can guess the one I pick lol. Who has put their favorite models to the test and how did they perform
Join FirearmsTalk.com Today - It's Free!
Are you a firearms enthusiast? Then we hope you will join the community. You will gain access to post, create threads, private message, upload images, join groups and more. Firearms Talk is owned and operated by fellow firearms enthusiasts. We strive to offer a non-commercial community to learn and share information.
Join FirearmsTalk.com Today! - Click Here
I've owned two guns that never experienced a single failure, no matter what ammo they were loaded with. One was a Springfield XD9, which I no longer own (too bulky and heavy) and my current Bersa Thunder 9 Ultra Compact Pro. Never owned a Glock.
I've seen glocks fail, despite the hype. My 92, never ever. Rain and snow no problems. Humid summers and bitter cold winters. I shot everything out of it from hallow points. To cheap ball and even frangibles. I carried it everyday as my service sidearm and never thought twice about it's capabilities in defending my life. Now I own a Px4, same story... Never a ftf never a hiccup love her dearly. However, I don't regularly throw my sidearm into a puddle of mud... and marketing is lost on me so what a magazine is paid to depict about a gun is useless in my eyes. I like the tried and true method...and a beretta has never let me down
A single shot shotgun
In life, strive to take the high road....It offers a better field of fire. "Robo is right" Fuzzball
Posted by cddbrowns All you young whipper snappers and your new fangled doo dads have no clue what real construction is.......GET OFF MY LAWN! The police cannot protect the citizen at this stage of our development, and they cannot even protect themselves in many cases. It is up to the private citizen to protect himself and his family, and this is not only acceptable, but mandatory. Jeff Cooper
How about a g17 OD? (That's slick on the sly) My Steyr M40A1 has never hiccupped. My Taurus 92 and G34s have only hiccupped due to ammo issues.
I could make a list of a bunch of guns i have, or "have", or wish I had. Why would one feel compelled to provide that infornation freely? Do you feel the need to show off? Is it some immature game of oneupsmanship? Why do you feel it necessary to list your guns?
If I may have a little liberty... The most UNreliable firearm I've seen was one that came from someone attempting to do mods and not knowing what they were doing.
Amendment II: "A well regulated Militia, being necessary to the security of a free State, the right of the people to keep and bear Arms, shall not be infringed." Life Member NRA Life Member NAHC Former President of the ECPT (Eifel Combat Pistol Team)
I see this for shooters a lot. We all have our favorite brands and models. I do like berreta a lot. I had an m9 and it was sweet. I will get a 92 fs ASAP trust that. But my GLOCK did what was told was a factory jam twice and then never again. So all firearms are only as good as the person holding them. But one brand I will never buy again is jimenez arms. I bought one of their JA-22 for jogging and it had FTF almost ever other round. I also hate the sigma series by S&W. I had one and the slide almost came of whilst firing it. Talk about scary.


text:
Home Needs A Spring Cleaning? Do It In Just 10 Minutes A Day!
Messy Microwave
Put a large (4-cup) microwave-safe bowl inside. Fill it with 1 cup of water, chopped up lemon, lime, orange, or several tablespoons of vinegar. Turn the microwave on HIGH for a couple of minutes or until the solution bubbles and the window is steamy. Allow it to cool for 15 minutes BEFORE you open the door. Remove bowl and wipe out inside.


text:
Sold Out
As an international spy and woman of mystery, accuracy and speed are essential to you as well as the primary reasons you opted for Rossignol Temptation 78 Skis w/ Saphir 110L Bindings. These sleek and compact beauties are designed with Power Turn Rocker, making them the perfect choice when you're escaping from former Soviet assassins or making a break to cut off the double agent who stole your country's Intel�and your heart. Power Turn Rocker technology allows for enhanced power and grip. Don't get caught short with cheap skis that let you down and get you sent to the gulag, or worse, let that lying thief get away; choose Rossignol's best and live to spy another day!


text:
Idea of the Day: Baucus Tax Reform Cuts Billions of Dollars in Oil Breaks
On November 21, Sen. Max Baucus (D-MT), chair of the Senate Finance Committee, unveiled adiscussion draft of tax reform legislation that focuses on cost recovery and accounting rules as part of a comprehensive overhaul of the U.S. tax code. This draft package includes the elimination of some longstanding tax breaks for Big Oil companies. The discussion draft proposes to eliminate as much as an estimated $46 billion in unnecessary tax breaks for hugely profitable Big Oil companies over the next decade.
The White House just announced that Sen. Baucus will be nominated to become the next U.S. ambassador to China. If he is confirmed, Sen. Ron Wyden (D-OR) is expected to replace Sen. Baucus as chair of the Senate Finance Committee. Sen. Wyden introduced legislation in previous Congresses that would have eliminated several big oil tax breaks. As chair, Sen. Wyden would have an opportunity to build on Sen. Baucus's proposal to make the tax code fairer by proposing to repeal additional special oil tax breaks, as proposed by Sen. Bernie Sanders (D-VT) and Rep. Keith Ellison (D-MN).
For more on this topic, please see:
- Baucus Tax Reform Cuts $46 Billion in Oil Breaks by Daniel J. Weiss and Miranda Peterson
To speak with our experts on this topic, please contact:
Print: Allison Preiss (economy, education, poverty)
202.478.6331 or firstname.lastname@example.com
Print: Tom Caiazza (foreign policy, health care, energy and environment, LGBT issues, gun-violence prevention)
202.481.7141 or firstname.lastname@example.com
Print: Chelsea Kiene (women's issues, Legal Progress, Half in Ten Education Fund)
202.478.5328 or email@example.com
Spanish-language and ethnic media: Tanya Arditi (immigration, race and ethnicity)
202.741.6258 or firstname.lastname@example.com
TV: Rachel Rosen
202.483.2675 or firstname.lastname@example.com
Radio: Chelsea Kiene
202.478.5328 or firstname.lastname@example.com


text:
166 posts · 55,614 views
Comments on neurobiology, neuroimaging, and psychiatry from a skeptical neuroscientist.
166 posts
Sort by: Latest Post, Most Popular
View by: Condensed, Full
by Neuroskeptic in Neuroskeptic_Discover
According to a new paper, one of neuroscience's most famous case-studies came about as a result of a serious medical blunder.
Henry Molaison (1926 - 2008), better known as HM, was an American man who developed a dramatic form of amnesia after receiving surgery that removed part of the temporal lobes of his brain. The 1953 operation was intended to treat HM's epilepsy, but it had the side effect of leaving him unable to form new memories.
The consequences of HM's surgery are well known ... Read more »
Mauguière F, & Corkin S. (2015) H.M. never again! An analysis of H.M.'s epilepsy and treatment. Revue neurologique. PMID: 25726355
by Neuroskeptic in Neuroskeptic_Discover
Multi-voxel pattern analysis (MVPA) is an increasingly popular approach for analyzing the results of fMRI scanning experiments that measure brain activity. MVPA searches for patterns of activation that correlate with a particular mental state. This is called 'decoding' neural activity.
Now a new paper in the Journal of Neuroscience from Caltech neuroscientists Julien Dubois et al. reports that MVPA is unable to decode certain kinds of information, even though single-unit recordings confirm th... Read more »
Dubois J, de Berker AO, & Tsao DY. (2015) Single-Unit Recordings in the Macaque Face Patch System Reveal Limitations of fMRI MVPA. The Journal of neuroscience : the official journal of the Society for Neuroscience, 35(6), 2791-802. PMID: 25673866
by Neuroskeptic in Neuroskeptic_Discover
In an interesting short paper just published in Trends in Cognitive Science, Caltech neuroscientist Ralph Adolphs offers his thoughts on The Unsolved Problems of Neuroscience.
Here's Adolphs' list of the top 23 questions (including 3 "meta" issues), which, he says, was inspired by Hilbert's famous set of 23 mathematical problems:
Problems that are solved, or soon will be:
I. How do single neurons compute?
II. What is the connectome of a small nervous system, like that of Caenorhabi... Read more »
Adolphs R. (2015) The unsolved problems of neuroscience. Trends in cognitive sciences. PMID: 25703689
by Neuroskeptic in Neuroskeptic_Discover
In a new paper, a group of MIT researchers argue that science is producing PhDs in far greater numbers than there are available tenured jobs for them to fill.
The authors, engineers Richard C. Larson, Navid Ghaffarzadegan, and Yi Xue, start out by noting that
The academic job market has become more and more competitive... nowadays, less than 17% of new PhDs in science, engineering and health-related fields find tenure-track positions within 3 years after graduation.
But why? Are we simp... Read more »
Larson RC, Ghaffarzadegan N, & Xue Y. (2014) Too Many PhD Graduates or Too Few Academic Job Openings: The Basic Reproductive Number R 0 in Academia. Systems research and behavioral science, 31(6), 745-750. PMID: 25642132
by Neuroskeptic in Neuroskeptic_Discover
How do people in different cultures view history? Around the globe, who are regarded as the best and worst historical figures? A new survey out now in PLoS ONE reveals the patterns of world opinion: "Heroes" and "Villains" of World History across Cultures.
The researchers, led by Katja Hanke of Germany and James H. Liu of New Zealand, polled 6,902 university students from 37 different countries. In an anonymous survey, the participants rated 40 historical figures on a seven point scale f... Read more »
Hanke K, Liu JH, Sibley CG, Paez D, Gaines SO Jr, Moloney G, Leong CH, Wagner W, Licata L, Klein O.... (2015) "Heroes" and "Villains" of World History across Cultures. PloS one, 10(2). PMID: 25651504
by Neuroskeptic in Neuroskeptic_Discover
What do Hennessy, Jack Daniels, and Everclear have in common? According to a rather fascinating new study, these three brands are especially popular with those teenage drinkers who get into booze-related fights.
In the new paper, researchers Sarah P. Roberts and colleagues of Boston say that some brands of alcohol are correlated with self-reported involvement in "alcohol related fights and injuries", in a national sample of American underage drinkers (i.e. drinkers under the age of 21).
... Read more »
Roberts SP, Siegel MB, DeJong W, Naimi TS, & Jernigan DH. (2015) Brand Preferences of Underage Drinkers Who Report Alcohol-Related Fights and Injuries. Substance use . PMID: 25612075
by Neuroskeptic in Neuroskeptic_Discover
When scientists disagree about something, what often happens is that the two sides of the argument form separate communities, with scientists collaborating with others on their "team" while avoiding working with their "opponents". But is there a better way?
A paper just published today presents the results of an experiment that was conducted as an 'adversarial collaboration'. This is where some researchers sit down with some members of the "other side" and agree upon a plan for a study to... Read more »
Matzke D, Nieuwenhuis S, van Rijn H, Slagter HA, van der Molen MW, & Wagenmakers EJ. (2015) The effect of horizontal eye movements on free recall: A preregistered adversarial collaboration. Journal of Experimental Psychology: General, 144(1). PMID: 25621378
by Neuroskeptic in Neuroskeptic_Discover
Ethnographer Jill A. Fisher offers a fascinating look at the rumors and urban legends that circulate among the volunteers who get paid to take part in medical research: Stopped hearts, amputated toes and NASA
Fisher visited six clinical trial facilities across the USA. All of these facilities were exclusively devoted to running phase I trials, testing new drugs to see if they are safe in humans. She spent a total of 450 hours in the field, getting to know the 'guinea pigs', and the staf... Read more »
Fisher JA. (2015) Stopped hearts, amputated toes and NASA: contemporary legends among healthy volunteers in US phase I clinical trials. Sociology of health , 37(1), 127-42. PMID: 25601069
by Neuroskeptic in Neuroskeptic_Discover
A simple statistical misunderstanding is leading many neuroscientists astray in their use of machine learning tools, according to a new paper in the Journal of Neuroscience Methods: Exceeding chance level by chance.
As the authors, French neuroscientists Etienne Combrisson and Karim Jerbi, describe the issue:
Machine learning techniques are increasingly used in neuroscience to classify brain signals. Decoding performance is reflected by how much the classification results depart from the... Read more »
Combrisson E, & Jerbi K. (2015) Exceeding chance level by chance: The caveat of theoretical chance levels in brain signal classification and statistical assessment of decoding accuracy. Journal of Neuroscience Methods. PMID: 25596422
by Neuroskeptic in Neuroskeptic_Discover
A compelling article in the Journal of Medical Biography recounts the story of Bayard Holmes and Henry Cotton, two American "surgeon-psychiatrists" who believed that they could cure schizophrenia by removing parts of their patients' intestines (and other organs). Both men tested their theories on their own children - with tragic results. The article is by Jonathan Davidson of Duke University.
Holmes and Cotton had a theory to justify these extreme treatments: autointoxication - the id... Read more »
Davidson J. (2014) Bayard Holmes (1852-1924) and Henry Cotton (1869-1933): Surgeon-psychiatrists and their tragic quest to cure schizophrenia. Journal of medical biography. PMID: 25504547
by Neuroskeptic in Neuroskeptic_Discover
A new study offers two reasons to be cautious about some of the claims made for the role of the hormone oxytocin in human behavior.
The paper's out now in PLoS ONE from researchers James C. Christensen and colleagues, who are based at the US Air Force Research Laboratory in Ohio. That the military are interested in oxytocin at all is perhaps a testament to the huge amount of interest that this molecule has attracted in recent years. Oxytocin has been called the "hug hormone", and is said to b... Read more »
Christensen, J., Shiyanov, P., Estepp, J., & Schlager, J. (2014) Lack of Association between Human Plasma Oxytocin and Interpersonal Trust in a Prisoner's Dilemma Paradigm. PLoS ONE, 9(12). DOI: 10.1371/journal.pone.0116172
by Neuroskeptic in Neuroskeptic_Discover
Subliminal perception has long been a hot topic. The idea that something (generally an image) could appear and disappear before us so quickly that it escapes conscious perception, and yet affect us subconsciously, is a fascinating (and scary) one.
Psychologists and neuroscientists are fairly skeptical of any grand or sinister claims for the power of subliminal advertising or propaganda, but on the other hand, many of them use the technique as a research tool.
So what's the absolute speed l... Read more »
Sperdin HF, Spierer L, Becker R, Michel CM, & Landis T. (2014) Submillisecond unmasked subliminal visual stimuli evoke electrical brain responses. Human brain mapping. PMID: 25487054
by Neuroskeptic in Neuroskeptic_Discover
Back in April, I blogged about a paper published in the Journal of Nervous and Mental Disease (JNMD) claiming that a little-known technique called 'quantum resonance spectrometry' (QRS) was able to diagnose mental health problems. I expressed surprise that the paper didn't explain what QRS actually is, how it works, or what it measures.
Now, eight months later, a Letter to the Editor has been published in the JNMD: Methodological Queries Regarding "Exploratory Quantum Resonance Spectr... Read more »
Baguley T, Moriarty P, Nestler S, & Ritchie SJ. (2015) Methodological Queries Regarding "Exploratory Quantum Resonance Spectrometry" (Zhang et al., 2014). The Journal of nervous and mental disease, 203(1), 71. PMID: 25536102
by Neuroskeptic in Neuroskeptic_Discover
In a provocative new paper, a group of UCLA biologists say that the leading theory for how memory is stored in the brain needs a rethink. But is it really time to throw out the textbooks?
In their study, published in Elife, authors Shanping Chen, Diancai Cai, and colleagues examined the formation of synapses, connections between neurons. They used neurons from Aplysia, a sea slug whose rather simple nervous system is popular among learning and memory neuroscientists.
Chen, Cai et al. t... Read more »
Chen S, Cai D, Pearce K, Sun PY, Roberts AC, & Glanzman DL. (2014) Reinstatement of long-term memory following erasure of its behavioral and synaptic expression in Aplysia. eLife. PMID: 25402831
by Neuroskeptic in Neuroskeptic_Discover
What happens when scientists publish papers that aren't meant to be taken seriously? Is ironic, satirical and joke science all in good fun, or can it be dangerous?
This is the question asked by Drexel University researchers Maryam Ronagh and Lawrence Souder in a new paper is called The Ethics of Ironic Science in Its Search for Spoof.
The British BMJ journal is known for an annual Christmas special issue filled with unusual articles. For example, two years ago they explored the questio... Read more »
Ronagh M, & Souder L. (2014) The Ethics of Ironic Science in Its Search for Spoof. Science and engineering ethics. PMID: 25510233
by Neuroskeptic in Neuroskeptic_Discover
A regular theme here at Neuroskeptic is the worrying issue of head movement during brain scans. We've seen that motion can alter measures of functional and structural connectivity, and that common approaches to dealing with this problem may be inadequate.
Now a new study reveals that even measures of the gross structure of the brain can be biased by excessive motion: Head motion during MRI acquisition reduces gray matter volume and thickness estimates.
Harvard neurologists Martin Reuter ... Read more »
Reuter M, Tisdall MD, Qureshi A, Buckner RL, van der Kouwe AJ, & Fischl B. (2014) Head motion during MRI acquisition reduces gray matter volume and thickness estimates. NeuroImage, 107-115. PMID: 25498430
by Neuroskeptic in Neuroskeptic_Discover
The CHDI Foundation, a charitable organization who fund a lot of research into Huntington's disease, are interested in reforming the scientific process.
The story comes from a paper written by British neuroscientist Marcus Munafo and colleagues (the authors including CHDI staff) published in Nature Biotechnology a couple of months ago: Scientific rigor and the art of motorcycle maintenance.
Munafo et al. begin by pointing to the history of car manufacturing as an analogy for the scie... Read more »
Munafo M, Noble S, Browne WJ, Brunner D, Button K, Ferreira J, Holmans P, Langbehn D, Lewis G, Lindquist M.... (2014) Scientific rigor and the art of motorcycle maintenance. Nature Biotechnology, 32(9), 871-3. PMID: 25203032
by Neuroskeptic in Neuroskeptic_Discover
Is there a relationship between poetry and psychosis?
The idea that 'genius' is just one step removed from 'madness' is a venerable one, and psychiatrists and psychologists have spent a great (perhaps an inordinate) amount of time looking for correlations between mental illness and creativity.
Now a new British study has examined whether poets exhibit more traits of psychosis than other people. One of the authors is a published poet, Helen Mort.
The researchers recruited 294 poets i... Read more »
Mason, O., Mort, H., & Woo, J. (2014) Research Letter: Investigating psychotic traits in poets. Psychological Medicine, 1-3. DOI: 10.1017/S0033291714002670
by Neuroskeptic in Neuroskeptic_Discover
In a paper just published, a group of neuroscientists report that they've changed their minds about how the brain processes social pain. Here's the paper: Separate neural representations for physical pain and social rejection
The authors are Choong-Wan Woo and colleagues of the University of Colorado, Boulder. Woo et al. say that, based on a new analysis of fMRI brain scanning data, they've found evidence inconsistent with the popular theory that the brain responds to the 'pain' of social... Read more »
Woo CW, Koban L, Kross E, Lindquist MA, Banich MT, Ruzic L, Andrews-Hanna JR, & Wager TD. (2014) Separate neural representations for physical pain and social rejection. Nature Communications, 5380. PMID: 25400102
by Neuroskeptic in Neuroskeptic_Discover
A 52 year old woman suffered from a strange problem: she saw dragons wherever she looked.
Here's the medical case report in The Lancet: Prosopometamorphopsia and facial hallucinations from a team of researchers including the famous Oliver Sacks.
In July, 2011, a 52-year-old woman presented to our psychiatric outpatient clinic with a life-long history of seeing people's faces change into dragon-like faces and hallucinating similar faces many times a day.
What does a dragon look like? A... Read more »
Blom JD, Sommer IE, Koops S, & Sacks OW. (2014) Prosopometamorphopsia and facial hallucinations. Lancet, 384(9958), 1998. PMID: 25435453
Do you write about peer-reviewed research in your blog? Use ResearchBlogging.org to make it easy for your readers — and others from around the world — to find your serious posts about academic research.
If you don't have a blog, you can still use our site to learn about fascinating developments in cutting-edge research from around the world.
Research Blogging is powered by SMG Technology.
To learn more, visit seedmediagroup.com.


text:
Royal Kona Resort is a proud sponsor of the Hawaii Marlin Tournament Series Early Entry Promotion. Enter the Hawaii Marlin Tournament Series now to be eligible to win free room nights at Royal Kona Resort. Sign up now at www.konatournaments.com
Hawaii Marlin Tournament Series Offer Valid now - October 2, 2014 & October 12 , 2014 - December 19, 2014 Receive reduced rates plus free resort self-parking & complimentary in-room wi-fi Standard Room from $125 Ocean View room from $145
Rates are seasonal, vary by travel date and are date inclusive. All rates are per night based on double occupancy and do not include tax, unless otherwise indicated. Offers are not combinable and are subject to availability and blackout dates.


text:
Recipe by: DEERING91
Original recipe yields 8 servings
Amount per serving ({{servings}} total)
Based on a 2,000 calorie diet
Sort by
Ready In
I just made this for Thanksgiving dinner tomorrow and it taste wonderful! I can't wait to see how it taste after it sets over night. I want to eat the whole bowl! Very easy too!!!!
Delicious, pretty, and simple. It needed a squeeze of lemon juice to cut the sweetness.
I took another reviewer's suggestion and added a bit of lemon juice to cut the sweetness. I also used reduced fat cream cheese. This is delicious--we ate every bite.


text:
Youth Camps
UB offers academic and recreational programs for children and teens. These camps and programs are held at UB and are open to all children of faculty, staff, returning families and the community.
Field Ecology Adventures
July 27 - 31, 2015
This program, for students ages 8-12, focuses on environmental themes such as earth awareness, wildlife studies, habitat analysis, aquatic/terrestrial ecology and survival skills. Students will participate in outdoor hikes, games, activities and demonstrations that will be conducted at both the UB North Campus and at 2 field trip locations.
Summer String Institute
June 27 - July 2, 2015
Intermediate and advanced strings students from middle school level to young professionals will work intensively to improve their skills in solo, chamber music and orchestral playing. The workshop will include hourly lessons, chamber music coaching, master classes, contemporary music workshop, string orchestra rehearsals, faculty recital, student recitals and string orchestra concert.
Chinese Bridge Summer Camp in China
July 16 - 31, 2015
This is an incredible opportunity for qualified high school students to spend two weeks in China, learning the language and culture. During the camp, students will travel to different provinces and cities for Chinese language classes and group cultural experiences. Space is limited to 30 participants and the application deadline is March 9.
Experience China Summer Camp
This 2-week program is designed for K-12 students who are interested in learning Chinese language, practicing Chinese art and handicrafts, and experiencing Chinese culture and traditions. The last day of the camp will feature students' performances in a culminating showcase for classmates, family and community members.
UB Sports Camps & Clinics
UB coaches and faculty welcome your child to participate in a host of youth camps offered during the summer on the UB campuses. No matter what your child's skill level — from beginner to advanced — there are opportunities for them to learn, play and make new friends while getting personal attention from faculty and Division I coaches.