The Larry Porter Trio is a versatile formation able to journey in different musical directions. They are well known for coming up with fresh and innovative interpretations of American popular songs. The group is also focused on exploring Porter's original compositions. The unusual forms of these pieces give the music a special flow, where the boundaries between beginning and end become blurred. Larry Porter brings four decades of experience to the table, not only in jazz with the likes of Chet Baker or Art Farmer, but also as a world music specialist. He is known for creating strikingly imaginative improvisations in his performance of standards as well as originals. In doing so he places great emphasis on maximizing the interplay with his fellow musicians. Andreas Lang and Joe Smith make it all possible bringing their prodigious talent and unique voices into the mix. Whether exploring sublime ballads or dancing through alluring song forms, the group sustains a crystalline tension and creates an entire spectrum of atmospheres.
The trio's current CD Don't Fence Me In on the renowned Swiss label Unit Records offers distinctly interactive takes on American standard tunes. Official release date: May 4, 2018.
Born in Cleveland, Ohio in 1951, received his first piano lesson at age 6. He founded the group Children At Play with vibraphonist Tom van der Geld in Boston in 1971. Larry went to Germany in 1973 and played with Bobby Jones, Sal Nistico, Leszek Zadlo, Volker Kriegel, Kai Winding, Mel Lewis, Günter Lenz, and Head, Heart and Hands. In 1976 he journeyed through Asia studying music in Afghanistan and India. From 1977-80 he lived in New York, worked as a pianist in the jazz scene, as a rebab and sarod player in the Indian music scene, and accompanied storyteller Laura Simms and dancers such as Merce Cunningham. Porter returned to Germany in 1981, worked with Bobby Stern, Frank St. Peter, Airto Moreira and Thad Jones, and formed a quartet with Allan Praskin, which recorded "First Date" in Spain and stayed together 11 years. From 1986-1994 he was very active playing with Chet Baker, Art Farmer, Archie Shepp, Benny Bailey, Heinz Sauer, Leo Wright, Don Menza, Al Cohn, Monty Waters, Conexión Latina, and singers Sheila Jordan, Mark Murphy, Jay Clayton, Rachel Gould, and Jeanne Carroll, as well as recording two CDs for Enja. Back in New York in the late 90s, he recorded the highly acclaimed CD The Magical Rebab of Larry Porter. He moved to Berlin at the turn of the century where he produced many CDs of his music and performed and recorded with Mundell Lowe, Hendrik Meurkens, Barbara Mayr, Johannes Enders, Christian Grabandt, Maciej Fortuna. His piece "Kind Of Jazz Suite", a work for 8 French horns commissioned by the Berlin Philharmonic, was premiered in 2005. 2011-2016 Larry performed regularly with the Austrian guitarist Karl Ratzer.
Born on the small island of Strynø in southern Denmark in 1980. Started playing the bass at the age of 16. When he was 21, he began his studies at the conservatory "Carl Nielsen Academy of Music" in Odense, taking lessons with bassist Bo Stief. Andreas performed in Denmark with Anders Mogensen, Hans Ulrik, Kresten Osgood, Håvard Wiik and Mads la Cour. In 2007 he settled in Berlin and quickly established himself in the jazz scene there as a bassist in great demand. He has worked with Felix Wahnschaffe, Rudi Mahall, Christian Lillinger, Oliver Steidle, Gunter Hampel, Henrik Walsdorff, Tobias Delius, John Schröder and many others. As a member of the group Hütte, he won the New German Jazz Award in 2013. Between 2007 and 2018 Andreas has recorded 14 CDs on the WhyPlayJazz label with artists such as Kasper Tom Christiansen, Mads la Cour, Frederik Vedersø, Philipp Gropper, Wanja Slavin and Anna Maria Sturm.
Born in Chicago in 1971, attended the Cincinnati Conservatory and the Manhattan School of Music studying with Vernel Fournier, Jimmy Lovelace, John Von Ohlen, John Riley and Jeff Williams. He lived in New York City from 1991 until 2000 playing with some of the best musicians the scene had to offer. After moving to Barcelona in 2000, he released two discs as a leader on Fresh Sound Records, "Happy" and "Melodic Workshop" which features Bill McHenry, Gorka Benitez, Guillermo Klein, Chris Lightcap and Jorge Rossy. Joe has been a featured sideman on the recordings of John McNeil, Arthur Kell, Ryan Blotnick, Fredrik Carlquist, Brandon Miller (Sarsaparilla) and many others. He has toured extensively in Italy, Germany, Spain, Sweden, Denmark, Poland, Hungary, Serbia, Romania and Colombia. In 2008 Joe formed the Asociación Libre Orkesta, a free form Big Band which performs improvised music inspired by poetry and projected images. In 2010 the Orkesta took part in the summer festival Jazz al Parque in Bogotá, Colombia performing for more than 10,000 people. In 2011 he moved to Berlin where he is currently playing in the groups of George Donchev, Johannes Lauer, Christian Ugurel, Jessica Einaudi and continues to record and perform with the Sci-Folk group Sarsaparilla. He also took part in the Deutsches Theater's production of Shakespeare. Spiele für Mörder, Opfer und Sonstige, directed my Dimiter Gotscheff.
Das Larry Porter Trio ist eine vielseitige Formation, die in verschiedene musikalische Richtungen zu reisen vermag. Die drei Musiker sind dafür bekannt, frische und innovative Interpretationen von "American Popular Songs" zu entdecken. Der andere Fokus des Trios ist es, Original-Kompositionen von Porter zu erforschen. Die ungewöhnlichen Formen dieser Stücke verleihen der Musik einen besonderen Fluss, wo die Grenzen zwischen Anfang und Ende verwischt werden. Larry Porter bringt vier Jahrzehnte Erfahrung ein, nicht nur im Jazz mit Größen wie Chet Baker oder Art Farmer, sondern auch als World-Music-Spezialist. Er ist für auffallend ideenreiche Improvisationen bei seiner Darbietung von Standards und eigenem Material bekannt. Dabei legt er viel Wert auf ein Maximum an Zusammenspiel mit seinen Mitmusikern. Andreas Lang und Joe Smith machen das alles möglich, in dem sie ihr ungeheures Talent und einzigartigen Stimmen mitbringen. Ob sie erhabene Balladen erforschen oder durch verlockende Liedformen tanzen, die Gruppe hält eine kristallklare Spannung und schafft ein ganzes Spektrum von Atmosphären.
Die aktuelle CD des Trios Don't Fence Me In auf dem renommierten Schweizer Label Unit Records bietet eine besonders interaktive Perspektive auf amerikanische Standards. Offizielles Release-Datum: 4. Mai 2018.
1951 in Cleveland, Ohio geboren. Larry bekam mit 6 Jahren den ersten Klavierunterricht. Er gründete 1971 in Boston mit dem Vibraphonisten Tom van der Geld die Gruppe Children At Play. 1973 ging er nach München und spielte mit Bobby Jones, Sal Nistico, Leszek Zadlo, Volker Kriegel, Kai Winding, Mel Lewis, Günter Lenz und Head, Heart and Hands. 1976 machte er eine einjährige Studienreise nach Afghanistan und Indien. Porter lebte 1977-80 in New York, arbeitete als Pianist in der Jazzszene, als Rebab- und Sarodspieler in der indischen Musikszene und begleitete Storyteller Laura Simms und Tänzer, u.a. Merce Cunningham. 1981 kehrte er nach München zurück, spielte mit Bobby Stern, Frank St. Peter, Airto Moreira und Thad Jones und gründete ein Quartett mit Allan Praskin, das "First Date" aufnahm und 11 Jahre zusammenblieb. 1986-1994 hatte Larry eine sehr rege Konzert- und Aufnahmetätigkeit, u.a. mit Chet Baker, Art Farmer, Archie Shepp, Benny Bailey, Heinz Sauer, Leo Wright, Don Menza, Al Cohn, Monty Waters, Conexión Latina und Vokalisten Sheila Jordan, Mark Murphy, Jay Clayton, Rachel Gould und Jeanne Carroll. In New York, Ende der 90er, nahm er die höchst anerkannte CD The Magical Rebab of Larry Porter auf. Seit der Jahrhundertwende lebt er in Berlin. Er nimmt viele CDs unter eigenem Namen und auch mit Mundell Lowe, Hendrik Meurkens, Barbara Mayr, Johannes Enders, Christian Grabandt, Maciej Fortuna auf. 2005 wurde sein Stück "Kind Of Jazz Suite", ein Auftragswerk der Berlin Philharmoniker für 8 Hörner, uraufgeführt. 2011-2016 trat Larry regelmäßig mit dem österreichischen Gitarristen Karl Ratzer auf.
1980 auf der kleinen Insel Strynø im Süden von Dänemark geboren. Im Alter von 16 Jahren fing er an, Bass zu spielen. Mit 21 begann er ein Studium auf der Carl-Nielsen-Musikakademie in Odense bei dem Bassisten Bo Stief. Andreas spielte in Dänemark mit Musikern wie Anders Mogensen, Hans Ulrik, Kresten Osgood, Håvard Wiik und Mads la Cour. Im Jahre 2007 zog er nach Berlin und hat sich schnell als sehr gefragter Bassist in der dortigen Jazzszene etabliert. Er arbeitet mit Felix Wahnschaffe, Rudi Mahall, Christian Lillinger, Oliver Steidle, Gunter Hampel, Henrik Walsdorff, Tobias Delius, John Schröder und vielen anderen. Als Mitglied der Gruppe Hütte, hat er den Neuen Deutschen Jazzpreis in 2013 gewonnen. 2007-2018 hat Andreas 14 CDs auf dem WhyPlayJazz Label mit Musikern wie Kasper Tom Christiansen, Mads la Cour, Frederik Vedersø, Philipp Gropper, Wanja Slavin und Anna Maria Sturm aufgenommen.
1971 in Chicago geboren, besuchte das Cincinnati Conservatory und die Manhattan School of Music, wo er klassisches Trommeln und Jazz-Schlagzeug bei Vernel Fournier, Jimmy Lovelace, John Von Ohlen, John Riley and Jeff Williams studierte. 1991 ging er nach New York, wo er zehn Jahre lang mit einigen der besten Musiker spielte, die die Szene zu bieten hatte. Er zog im Jahre 2000 nach Barcelona und hat seine ersten zwei Alben als Bandleader auf Fresh Sound Records, "Happy" und "Melodic Workshop" mit Bill McHenry, Gorka Benitez, Guillermo Klein, Chris Lightcap und Jorge Rossy veröffentlicht. Als Sideman war Joe an Aufnahmen verschiedener Alben, u.a. von John McNeil, Arthur Kell, Ryan Blotnick, Fredrik Carlquist, Brandon Miller (Sarsaparilla) und vielen anderen beteiligt. Er war viel auf Tour durch Italien, Deutschland, Spanien, Schweden, Dänemark, Polen, Ungarn, Serbien, Rumänien und Kolumbien. 2008 gründete Joe die Asociación Libre Orkesta, eine Big Band, die ausgehend von Gedichten und Bildern frei improvisiert. 2010 spielte die Band auf dem Sommerfestival Jazz al Parque in Bogotá, Kolumbien vor mehr als 10.000 Zuschauern. Seit 2011 lebt Joe in Berlin und spielt in verschiedenen Formationen, u.a. von George Donchev, Johannes Lauer, Christian Ugurel, Jessica Einaudi und der Sci-Folk-Band Sarsaparilla. Er spielte außerdem am Deutschen Theater in dem Theaterstück Shakespeare. Spiele für Mörder, Opfer und Sonstige von Dimiter Gotscheff.


Abstract base class used to build new callbacks.
params: dict. Training parameters (eg. verbosity, batch size, number of epochs...).
model: instance of keras.models.Model. Reference of the model being trained.
The logs dictionary that callback methods take as argument will contain keys for quantities relevant to the current batch or epoch.
on_epoch_end: logs include acc and loss, and optionally include val_loss (if validation is enabled in fit), and val_acc (if validation and accuracy monitoring are enabled).
on_batch_begin: logs include size, the number of samples in the current batch.
on_batch_end: logs include loss, and optionally acc (if accuracy monitoring is enabled).


text:
"""Speakers for Phamarsim

Speakers translate the signal of a SoundSource to (direction dependent) plane
sound waves.  They must provide a method

>>> get_pressure_signal(t, theta, phi),

which produces an ndarray of the wave form in the specified direction. Theta
and phi are to be interpreted as relative to the speaker, *not* as absolute
angles in the environment. The units of t, theta and phi are s, deg and deg
respectively.

Since all speakers are assumed to be point like, the waveform will be
attenuated with 1/r, where r is the distance in metres. This means that the
unit of the plane wave is mPa * m.

Another way to look at it is that get_wave() produces the pressure signal [mPa]
that would be measured 1 m away from the speaker in the direction specified by
theta and phi, albeit ignoring the time delay.

According to Wikipedia, a normal conversation has a sound pressure of 2~20 mPa.

"""

from __future__ import division
import numpy as np

import logging
log = logging.getLogger(__name__)

import objects

class Speaker(objects.SimpleObject):
    """Base class for speakers

    Parameters
    ----------
    src : SoundSource, optional
        A SoundSource the speaker will connected to.
    amplification : SoundSource, optional
        Amplification factor for the translation of sound signals to sound pressure.
        Unit: mPa * m
    kwargs : dictionary
        Will be passed to the `SimpleObject` constructor.

    """
    def __init__(self, src=None, amplification=1.0, **kwargs):
        objects.SimpleObject.__init__(self, **kwargs)
        self._source = None
        self._amplification = amplification
        if src is not None:
            self.connect_to_source(src)

    def get_pressure_signal(self, t, theta=0.0, phi=0.0):
        """Return the pressure signal for a plane wave in the specified direction.

        Parameters
        ----------
        t : array-like
            Times at which the signal signal should be evaluated [s].
        theta : array-like
            The polar angle of the outgoing wave as measurde from the speaker's z-axis [deg].
        phi : array-like
            The azimuthal angle of outgoing wave as measured from the speaker's x-axis [deg].

        Returns
        -------
        p : ndarray
            The pressure signal for the specified direction.

        Notes
        -----
        This simple speaker emulates an isotropic sound source with the same
        gain in all directions, so the signal is independent of the chosen
        theta and phi.

        """
        return self.get_source().get_sound_signal(t) * self.get_amplification()

    def set_amplification(self, amplification):
        self._amplification = amplification

    def get_amplification(self):
        return self._amplification

    def connect_to_source(self, src):
        """Connect the speaker to a sound source.

        Parameters
        ----------
        src : SoundSource
            The sound source the speaker should be connected with.

        Notes
        -----
        Speakers can only be connected to a single source.
        If the speaker is already connected to another sound source, it will be
        disconnected from it.

        Raises ValueError if the speaker is already connected to the source.

        """
        if src == self._source:
            raise ValueError("The speaker is alread connected to the source.")

        # Disconnect from possible old source.
        if self._source is not None:
            self.disconnect_from_source(self._source)

        # Connect new source
        self._source = src
        try:
            src.connect_speaker(self)
        except ValueError:
            # Catch ValueErrors so a mutual connect does not raise an Error.
            pass
        except:
            # The speaker was not able to connect. Reset and raise Error.
            self._source = None
            raise
        log.debug("%s is now connected to %s."%(self, src))

    def disconnect_from_source(self, src):
        """Disconnect the speaker from a sound source.

        Raises ValueError if the source is not connected.

        """
        if self._source != src:
            raise ValueError("The source is not connected to the speaker.")

        self._source = None
        try:
            src.disconnect_speaker(self)
        except ValueError:
            # Catch ValueErrors so a mutual disconnect does not raise an Error.
            pass
        log.debug("%s is now disconnected from %s."%(self, src))

    def get_source(self):
        return self._source

redpajama_set_name: RedPajamaGithub


text:
OtherRapid Publications
Insulin Activates ATP-Sensitive K+ Channels in Pancreatic β-Cells Through a Phosphatidylinositol 3-Kinase–Dependent Pathway
Farrukh A. Khan, Paulette B. Goforth, Min Zhang, Leslie S. Satin
DOI: 10.2337/diabetes.50.10.2192 Published 1 October 2001
Farrukh A. Khan
Paulette B. Goforth
Min Zhang
Leslie S. Satin
Insulin is known to regulate pancreatic β-cell function through the activation of cell surface insulin receptors, phosphorylation of insulin receptor substrate (IRS)-1 and -2, and activation of phosphatidylinositol (PI) 3-kinase. However, an acute effect of insulin in modulating β-cell electrical activity and its underlying ionic currents has not been reported. Using the perforated patch clamp technique, we found that insulin (1–600 nmol/l) but not IGF-1 (100 nmol/l) reversibly hyperpolarized single mouse β-cells and inhibited their electrical activity. The dose-response relationship for insulin yielded a maximal change (mean ± SE) in membrane potential of −13.6 ± 2.0 mV (P < 0.001) and a 50% effective dose of 25.9 ± 0.1 nmol/l (n = 63). Exposing patched β-cells within intact islets to 200 nmol/l insulin produced similar results, hyperpolarizing islets from −47.7 ± 3.3 to −65.6 ± 3.7 mV (P < 0.0001, n = 11). In single cells, insulin-induced hyperpolarization was associated with a threefold increase in whole-cell conductance from 0.6 ± 0.1 to 1.7 ± 0.2 nS (P < 0.001, n = 10) and a shift in the current reversal potential from −25.7 ± 2.5 to −63.7 ± 1.0 mV (P < 0.001 vs. control, n = 9; calculated K+ equilibrium potential = −90 mV). The effects of insulin were reversed by tolbutamide, which decreased cell conductance to 0.5 ± 0.1 nS and shifted the current reversal potential to −25.2 ± 2.3 mV. Insulin-induced β-cell hyperpolarization was sufficient to abolish intracellular calcium concentration ([Ca2+]i) oscillations measured in pancreatic islets exposed to 10 mmol/l glucose. The application of 100 nmol/l wortmannin to inactivate PI 3-kinase, a key enzyme in insulin signaling, was found to reverse the effects of 100 nmol/l insulin. In cell-attached patches, single ATP-sensitive K+ (KATP) channels were activated by bath-applied insulin and subsequently inhibited by wortmannin. Our data thus demonstrate that insulin activates the KATP channels of single mouse pancreatic β-cells and islets, resulting in membrane hyperpolarization, an inhibition of electrical activity, and the abolition of [Ca2+]i oscillations. We thus propose that locally released insulin might serve as a negative feedback signal within the islet under physiological conditions.
ATP-sensitive K+ (KATP) channels of the pancreatic β-cell play a pivotal role in stimulus-secretion coupling, setting the resting membrane potential below the activation threshold of voltage-gated Ca2+ channels (1). Cellular metabolism of fuel secretagogues raises the ATP/ADP ratio, resulting in the closure of KATP channels (1,2,3) and concomitant β-cell depolarization (3,4). This depolarization in turn activates voltage-gated Ca2+ channels, resulting in Ca2+ influx and Ca2+-dependent insulin exocytosis (1,2,4,5). Locally released insulin may bind to β-cell insulin receptors (6,7,8), triggering receptor autophosphorylation (8), receptor tyrosine kinase activation (8), insulin receptor substrate (IRS)-1 phosphorylation (7,8), and phosphatidylinositol (PI) 3-kinase activation (8,9). This autocrine action of insulin has been proposed to regulate a number of functions in β-cells, including insulin gene transcription (10,11). The importance of insulin signaling for normal β-cell function has been demonstrated by recent studies of insulin receptor knockout mice (12). These animals exhibit long-term insulin secretory defects and resemble human type 2 diabetic patients. However, changes caused by islet insulin receptor knockout could reflect the long-term trophic effects of insulin rather than acute effects of locally (and newly) secreted insulin on β-cells. Although the hypothesis that secreted insulin provides negative feedback to the islet to limit further insulin secretion has been studied for a number of years, the data in the literature are conflicting. Thus, whereas some in vivo (13) and in vitro (14,15) studies support this mechanism, other data support the converse hypothesis that insulin facilitates its own secretion, possibly by releasing Ca2+ from endoplasmic reticulum (ER) Ca2+ stores in an IRS-1– and PI 3-kinase–dependent manner (16,17). However, this action, which was demonstrated using β-cells bathed in 3 mmol/l glucose, apparently does not involve changes in β-cell membrane potential. In contrast, other studies show that inhibiting PI 3-kinase augments insulin secretion, in support of the negative feedback hypothesis (18,19).
The present study was prompted by an intriguing recent report showing that insulin activates the KATP channels of rat hypothalamic neurons (20). We hypothesized that if insulin had a similar action on the pancreatic β-cell KATP channels, the acute release of insulin from β-cells within the islet might be capable of uncoupling fuel metabolism from β-cell electrical activity. Because metabolism-induced electrical activity is an important component of stimulus-secretion coupling in islet β-cells, KATP channels opened by insulin could thus constitute a novel autocrine negative feedback mechanism to locally regulate islet insulin secretion. This mechanism might work in tandem with the more global negative feedback regulation of β-cell insulin secretion that occurs when secreted insulin binds to its peripheral target tissues, lowering the plasma glucose concentration. In this model, locally released insulin as well as decreased plasma glucose turn off islet secretion by opening β-cell KATP channels, leading to a cessation of β-cell electrical activity, Ca2+-influx, and Ca2+-induced insulin granule exocytosis.
We now report for the first time that exogenous insulin hyperpolarized isolated as well as in situ mouse pancreatic β-cells in a dose-dependent manner, inhibited their electrical activity and abolished their intracellular calcium concentration ([Ca2+]i) oscillations. These effects were mediated by insulin-induced activation of KATP channels, because insulin increased whole-cell KATP conductance in a tolbutamide-blockable manner and directly activated single KATP channels in cell-attached patches. Because wortmannin reversed insulin-induced β-cell hyperpolarization and closed insulin-activated KATP channels, this action of insulin is likely mediated by PI 3-kinase, a key signaling enzyme in insulin signaling.
Tissue culture.
Mouse pancreases were isolated from 25- to 30-g male Swiss-Webster mice. After cannulation of the bile duct, 2 mg/ml collagenase was injected into the pancreas, which was then removed and incubated for 5–10 min at 37°C to isolate individual islets. Single-cell suspensions were obtained by gently shaking islets in a low-calcium medium. Cell suspensions were plated onto glass coverslips in 35-mm petri dishes containing RPMI-1640 medium supplemented with fetal bovine serum, l-glutamate, and penicillin-streptomycin and were kept in a 95/5% air/CO2 incubator at 37°C. Single cells were fed every other day and were used for up to 1 week after isolation. Whole islets were cultured in a similar fashion and used within 48 h in culture. To record electrical activity from in situ β-cells, islets were held in place by a wide-tipped glass suction pipette, which was mounted on a micromanipulator (21) (Fig. 2D).
Electrophysiology.
A small-volume recording chamber containing β-cells or islets was mounted on an inverted microscope (Olympus IM-T2; Tokyo), which in turn was placed on a TMC air isolation table (TMC, Peabody, MA). Recording solutions were maintained at 35°C using a TC-1 temperature controller, a preheater, and a second transparent heater attached to the bottom of the recording chamber (Cell Micro Controls, Virginia Beach, VA). The electrophysiological recording solution contained (in millimoles per liter) 140 NaCl, 3.6 KCl, 2 NaHCO3, 0.5 NaH2PO4, 0.5 MgSO4, 5 HEPES, and 10 glucose, pH 7.4, with NaOH. Extracellular solution was superfused at a rate of 1–2 ml/min. Recording pipettes had resistances ranging from 5 to 10 MΩ and were pulled from borosilicate glass capillaries using a Sutter micropuller (P-97; Sutter Instrument, Novato, CA). The pipette tips were fire-polished and then filled with internal solution containing (in millimoles per liter) 76 K2SO4, 10 NaCl, 10 KCl, 1 MgCl2, and 5 HEPES, pH 7.35, with KOH. The pipettes were then back-filled with the same solution containing 0.1 mg/ml amphotericin-B. The pipette solution for cell-attached single KATP channel recordings contained (in millimoles per liter) 140 KCl, 1 CaCl2, 1 MgCl2, and 10 HEPES, pH 7.3, with KOH. Seal resistances were >1 GΩ. Wortmannin was obtained from Calbiochem (Calbiochem-Novabiochem, La Jolla, CA), whereas all other chemicals, including recombinant human insulin, were obtained from Sigma (Sigma Chemical, St. Louis, MO). Insulin solutions were prepared fresh daily from 1 mmol/l stock solutions. Cytochrome-C, at a concentration of 0.1 mg/ml, was added to insulin containing solutions to prevent insulin from adhering to the plastic tubing or the experimental chamber. Control solutions contained an identical concentration of cytochrome-C.
Using the perforated patch clamp technique (22), isolated β-cells were identified by their size and characteristic patterns of electrical activity in 10 mmol/l glucose (23), whereas in situ β-cells were identified by their medium bursting in 10 mmol/l glucose (21,24). Integrity of the gigaseals was checked periodically. Data were acquired using an Axopatch 1D amplifier (Axon Instruments, Foster City, CA) and a Macintosh Quadra G3 computer (Apple Computer, Cupertino, CA) using an ITC-16 computer interface (Instrutech, Elmont, NY) and Igor Pro software (Wavemetrics, Lake Oswego, OR). Data were also stored on videotapes for off-line analysis. Linear voltage ramps from −90 to +50 mV lasting 6.2 s were applied from a holding potential of −65 mV after switching the amplifier from current to voltage clamp mode. Whole-cell conductance was measured by averaging currents obtained using five voltage pulses of ±10 mV from a holding potential of −65 mV.
Single KATP channels were recorded in the cell-attached patch configuration at a pipette potential of 0 mV using electrodes containing 140 mmol/l KCl. Nifedipine (10 μmol/l) was added to the bath solution in this configuration to prevent capacitatively coupled action potentials. Data were acquired at 5 kHz after filtering at 2 kHz. Single KATP channel openings were analyzed using TAC software to generate an event list (Bruxton, Seattle, WA). Single-channel conductance was determined by stepping the pipette potential from −20 to +20 mV. The change in mean single channel current amplitude for the applied step voltage was used to calculate the single-channel conductance, using the equation g = ΔI/ΔV (g = single-channel conductance, ΔV = step voltage, and ΔI = change in mean single channel current amplitude). Mean channel activity (NPo) was calculated using 10-s sample traces, using the equation NPo = Iavg/i (Iavg = the average current of the analyzed trace and i = the mean single channel current amplitude). The fact that liquid junction potentials were not compensated and the resting membrane potential of the cell was unclamped may have influenced the amplitude of the unitary currents. KATP channels were identified in cell-attached patch recordings by their characteristic slope conductance and their sensitivity to changes in bath glucose concentration. To further establish that these events correspond to the opening of single KATP channels, we confirmed that they were strongly activated by the addition of 2 mmol/l sodium azide to bath solutions containing 10 mmol/l glucose and were promptly blocked by the addition of 1 μmol/l glyburide (data not shown).
[Ca2+]i measurement using Fura-2 fluorescence.
Islets were loaded with the Ca2+-sensitive probe Fura-2/acetoxymethyl. This probe (2 μmol/l) and 2 μl of 2.5% pluronic acid solution were added to culture dishes containing 1 ml of medium and were incubated for 30 min in an air/CO2 incubator at 37°C. After loading, islets were washed and incubated in recording solution for 20 min. [Ca2+]i was measured using an IX-50 inverted fluorescence microscope (Olympus, Tokyo) in conjunction with a xenon arc excitation source, a photomultiplier, and a photon counter (Ionoptix, Milton, MA). Data were acquired and analyzed with Ionwizard software provided by the manufacturer. Epifluorescence was measured from single islets, and the values in [Ca2+]i were determined as the fluorescence ratio (R) of Ca2+-bound Fura-2 (340 nm) to unbound Fura-2 (380 nm), with emission collected at 510 nm. R was converted to free Ca2+ concentration using an in vitro standard curve generated with a calibration kit (Molecular Probes, Eugene, OR).
Statistics.
Statistical analysis was done using paired t test or nonparametric one-way analysis of variance with Newman-Keuls Multiple Comparison Test to compare more than two values. P values <0.05 were considered statistically significant.
Insulin, but not IGF-1, hyperpolarized isolated single β-cells and islets and abolished regular [Ca2+]i oscillations.
The electrical activity of single dispersed β-cells in 10 mmol/l glucose consists of repeated large spikes, fast (e.g., <5-s) bursts, or plateau depolarizations (23), whereas medium bursting having a duration of 10–20 s only occurs in intact islets (21,24).
Using the perforated patch clamp technique (22) to record from single mouse β-cells bathed in 10 mmol/l glucose, we found that the application of insulin (1–600 nmol/l) resulted in a reversible inhibition of β-cell electrical activity in 73% (63 of 86) of the cells tested (Fig. 1A), with insulin doses >1 nmol/l producing statistically significant changes in β-cell membrane potential. The dose-response relationship for exogenous insulin yielded a maximal change (mean ± SE) in membrane potential of −13.6 ± 2.0 mV and a 50% effective dose (ED50) of 25.9 ± 0.1 nmol/l, with an R2 value of 0.9959, n = 63 (Fig. 1B). Although insulin-induced hyperpolarization was reversible, the recovery time appeared to be proportional to the total duration of insulin application.
Insulin is known to bind to and activate IGF-1 and insulin receptors (8,25). IGF-1 receptors are structurally and functionally homologous to insulin receptors and belong to the same family of receptors having tyrosine kinase activity (25). To rule out the possibility that insulin-induced β-cell hyperpolarization resulted from binding to IGF-1 receptors, equimolar concentrations of IGF-1 and insulin were tested on the same β-cells. As shown in Fig. 1C, 100 nmol/l IGF-1 applied alone for up to 5 min failed to suppress β-cell electrical activity in 10 mmol/l glucose (n = 6). However, the subsequent addition of 100 nmol/l insulin resulted in β-cell hyperpolarization within 2 min. Thus, the mean membrane potential after IGF-1 application was −45.0 ± 2.6 mV, which was not significantly different from control (−45.0 ± 3.2 mV), whereas the subsequent addition of 100 nmol/l insulin to the bath hyperpolarized these β-cells to −56.3 ± 4.5 mV (P < 0.001, n = 4).
Recordings from β-cells within intact islets exposed to 200 nmol/l insulin produced similar results (Fig. 2A). Thus, insulin hyperpolarized islets from −47.7 ± 3.3 to −65.6 ± 3.7 mV (P < 0.0001, n = 11). The mean change in membrane potential for islets versus single dispersed β-cells was −17.9 ± 2.8 mV (n = 11) vs. −12.7 ± 1.2 mV (n = 14), respectively (P > 0.05). However, the mean time to maximum response was 9.4 ± 1.7 min for islets (n = 11) and 3.7 ± 0.5 min for isolated β-cells (n = 14, P < 0.05), indicating that insulin took a significantly longer time to produce its effect on in situ β-cells. This difference likely reflects the longer diffusion time required for insulin to activate a sufficient number of β-cells within the intact islet (R. Bertram and L. Satin, unpublished observations).
We next tested whether insulin was capable of abolishing the regular [Ca2+]i oscillations of intact mouse islets bathed in 10 mmol/l glucose. Using the ratiometric Ca2+-sensing dye Fura-2 (see research design and methods), regular [Ca2+]i oscillations were observed (Fig. 2B) between 251.0 ± 26.8 and 457.6 ± 42.9 nmol/l (P < 0.05, n = 5) (Fig. 2C), corresponding to the silent and peak phases of the [Ca2+]i oscillations. As shown in Fig. 2B, the [Ca2+]i oscillations were completely abolished within ∼9 min of exposure to 100 nmol/l insulin, resulting in a new steady-state [Ca2+]i level of 300.4 ± 40.0 nmol/l (n = 5) (Figs. 2B and C). These data clearly demonstrate that insulin not only hyperpolarizes islets but abolishes the regular [Ca2+]i oscillations, which are known be important for pulsatile insulin secretion.
Insulin-induced β-cell hyperpolarization is caused by an increase in whole-cell K+ conductance.
Insulin has been shown to hyperpolarize hypothalamic neurons by activating their KATP channels (20). We therefore hypothesized that a similar mechanism might account for the insulin-induced hyperpolarization of β-cells. In support of this hypothesis, we found that tolbutamide, a specific blocker of KATP channels (26), completely reversed insulin-induced β-cell hyperpolarization (Fig. 3A). Thus, whereas 100 nmol/l insulin hyperpolarized β-cells from −46.7 ± 2.4 to −62.1 ± 1.9 mV (P < 0.001, n = 7), the subsequent addition of 100 μmol/l tolbutamide depolarized membrane potential back to control levels (−44.1 ± 2.1 mV). Whole-cell conductance measured using voltage pulses in voltage clamp was 0.6 ± 0.1, 1.7 ± 0.2 (P < 0.001), and 0.5 ± 0.1 nS for control, insulin, and insulin plus tolbutamide-containing solutions (n = 10), respectively. Thus, insulin-induced hyperpolarization was associated with a threefold increase in cell membrane conductance, which was completely reversed by tolbutamide (Fig. 3B). Whole-cell conductance corresponding to the period of insulin-induced hyperpolarization was within the reported range (e.g., 0.27–7.6 nS) for the calculated whole-cell KATP conductance of single rodent β-cells (1,27). Figure 3B shows cell conductance after normalization for cell capacitance under various conditions.
Application of voltage ramps to single β-cells voltage-clamped to −65 mV in 10 mmol/l glucose revealed an outward-rectifying whole-cell current that reversed at −25.7 ± 2.5 mV (n = 9). Insulin (100 nmol/l) increased the slope of the linear part of the current-voltage relationship between −90 to −40 mV, which is known to reflect the contribution of KATP channels to β-cell whole-cell current, and shifted the reversal potential to −63.7 ± 1.0 mV (P < 0.001 vs. control, n = 9), toward the calculated K+ equilibrium potential of −90 mV (Fig. 3C). The subsequent application of tolbutamide inhibited the insulin-activated current and shifted its reversal potential to near control values (−25.2 ± 2.3 mV). These data thus strongly suggest that insulin hyperpolarizes β-cells by activating KATP channels and increasing β-cell K+ conductance.
Wortmannin reversed insulin-induced activation of KATP channels and hyperpolarization of β-cells.
PI 3-kinase is a pivotal enzyme in insulin signal transduction both in classical insulin target tissues (28) and insulin-secreting β-cells (8,9). A PI 3-kinase–dependent pathway has also been implicated in leptin activation of KATP channels in the insulin-secreting CRI-G1 cell line (29) and in insulin activation of neuronal KATP channels (20). We thus tested whether wortmannin, a PI 3-kinase inhibitor, could reverse insulin-induced β-cell hyperpolarization. As expected, the application of 100 nmol/l insulin hyperpolarized β-cells from −53.6 ± 1.6 to −69.8 ± 2.2 mV (P < 0.001, n = 5) and terminated their electrical activity (Fig. 4A). The subsequent application of 100 nmol/l wortmannin to inhibit PI 3-kinase slowly depolarized these cells to −53.2 ± 2.1 mV (P < 0.05) over a mean period of 4.5 ± 1.1 min (n = 5). In separate experiments, we found that pretreating β-cells with wortmannin fully blocked the inhibitory effects of insulin (data not shown).
We next tested the effects of insulin and wortmannin on unitary KATP channel activity measured in cell-attached patch recordings from single mouse β-cells. As shown in Fig. 4B, in the absence of glucose, single channels having a slope conductance of 44.8 ± 4.8 pS (n = 5) were observed. This conductance corresponds to the reported unitary conductance for β-cell KATP channels (∼50 pS) (1,2,3). NPo in glucose-free solution was 0.49 ± 0.1 (n = 4) (Fig. 4C), whereas increasing the bath glucose concentration to 10 mmol/l decreased channel activity to 0.08 ± 0.04 (P < 0.005). The subsequent application of 100 nmol/l insulin reversed the action of glucose, resulting in an increase in mean KATP channel activity to 0.37 ± 0.07 (P < 0.005), supporting the hypothesis that glucose-inhibited KATP channels are activated by insulin. Because single KATP channels in this recording configuration were not directly exposed to insulin, the efficacy of bath-applied insulin suggests that insulin opens KATP channels through an intracellular second messenger. The subsequent addition of 100 nmol/l wortmannin resulted in the suppression of NPo to 0.04 ± 0.01 (P < 0.005), which was not significantly different from that observed in solutions containing 10 mmol/l glucose (P > 0.05) (Fig. 4C).
We thus report that insulin activates the KATP channels of mouse pancreatic β-cells through a PI 3-kinase–dependent pathway, resulting in β-cell hyperpolarization, a cessation of glucose-induced electrical activity, and inhibition of islet [Ca2+]i oscillations. The peptide hormones leptin (29,30,31), somatostatin (32), and galanin (33) and "KATP-opener" drugs, such as diazoxide (34) and minoxidil (35), hyperpolarize β-cells and inhibit insulin secretion by activating KATP channels, as we found for insulin. In the case of leptin, which activates KATP channels in ob/ob mouse β-cells (31) and rat CRI-G1 insulinoma cells, a PI 3-kinase-dependent pathway also appears to be involved (30), as we found for insulin activation of β-cell KATP channels.
The actions of insulin that we describe are likely to be mediated by insulin receptors because IGF-1 failed to hyperpolarize β-cells, and the EC50 we obtained for insulin compared favorably with the reported EC50 (∼4 nmol/l) of β-cell insulin receptors (8,16,17). Although we and others (8,11,16,17) have exposed β-cells to higher concentrations of insulin to observe acute effects (e.g. 100 nmol/l), even low nanomolar doses of insulin significantly activated β-cell KATP channels. Circulating insulin levels in this range have been reported in the plasma of insulin-resistant human subjects after a glucose load (36,37,38,39) and in the portal circulation (40). Additionally, we would expect that still higher insulin concentrations occur within islets because of the local accumulation of newly secreted insulin into their tight interstitial spaces. Thus, the mechanism that we describe is likely to functionally alter β-cell electrophysiology and modify insulin secretion.
β-cells began to hyperpolarize within tens of seconds of adding exogenous insulin, whereas maximal hyperpolarization occurred after several minutes. These kinetics are consistent with a large number of studies of insulin action in its classic target tissues, where insulin-induced insulin receptor phosphorylation, phosphorylation of IRS proteins, and activation of PI 3-kinase and Akt/protein kinase B occur tens of seconds to minutes after exposure to insulin (41,42,43,44,45), whereas the translocation of glucose transporters and glucose transport takes many minutes (46). In βTC-3 cells, the autocrine action of insulin to stimulate insulin receptor phosphorylation occurs within ∼2 minutes (8). It thus seems reasonable to conclude that the time lag we observed for insulin activation of β-cell KATP channels reflects the time course of the insulin receptor signal transduction cascade, as in muscle cells and adipocytes. We attribute the longer delays we observed using in situ versus isolated β-cells to the time required for insulin to diffuse within the intact islet. Although we do not yet know how insulin activates the KATP channels of β-cells, PI 3-kinase could conceivably activate KATP channels by altering membrane phosphoinositide levels, because these have been shown to reduce the ATP sensitivity of KATP channels (47).
Although this is the first report showing that insulin activates β-cell KATP channels, insulin activates the KATP channels of rat hypothalamic neurons through a similar mechanism involving PI 3-kinase (20). Thus, these authors found that 5–300 nmol/l insulin hyperpolarized a subpopulation of the hypothalamic neurons of lean Zucker rats and decreased their input resistance. Voltage clamp studies established that insulin activated an ionic current under these conditions that reversed at the K+ equilibrium potential and was blocked by 200 μmol/l tolbutamide. The authors extended these studies to the single-channel level and showed that insulin activated single KATP channels in cell-attached patches. As we found in β-cells, insulin-induced hyperpolarization of hypothalamic neurons required PI 3-kinase activation, as it was blocked by wortmannin or LY294002. Based on these findings, Spanswick et al. (20) proposed that insulin serves as a negative feedback signal in the hypothalamus to reduce food intake through the inhibition of glucose-responsive neurons.
However, in contrast to our findings, Aspinwall et al. (16,17) reported that 1–100 nmol/l insulin applied to single mouse β-cells increased rather than decreased insulin exocytosis, as assayed using 5–hydroxytryptamine amperometry, and did so independently of changes in β-cell membrane potential. These authors proposed that insulin stimulates insulin secretion by releasing Ca2+ from ER Ca2+ stores via a mechanism involving IRS-1 and PI 3-kinase, because the insulin-induced changes they observed were wortmannin-sensitive. However, because Aspinwall et al. (16,17) carried out their studies in 3 mmol/l glucose, it is reasonable to expect that most of the β-cell's KATP channels were already open and were thus relatively insensitive to further modulation (1). Under basal conditions such as these, minimal amounts of insulin would be secreted, which further questions the relevance of these findings for glucose-stimulated insulin secretion. In another recent study, Harvey and Ashford (29) reported that whereas leptin activated CRI-G1 cell KATP channels, insulin did not. Although we do not know why insulin failed to open KATP channels in this preparation, CRI-G1 cells differ in several respects from the adult mouse β-cells we used and are glucose insensitive. Thus, it may be that metabolic differences between the two preparations might account for this discrepancy.
Insulin activation of β-cell KATP channels has a number of implications for understanding islet function. First, in general, this negative feedback mechanism would be expected to restrain excessive insulin exocytosis when intra-islet insulin is sufficiently high, preventing hyperinsulinemia. Second, in terms of islet electrophysiology, the mechanism may help explain why intact islets have regular 10- to 60-s electrical oscillations (21,24), compared with the fast bursting or spiking of isolated β-cells (23). Thus, it may be that insulin released within islets during glucose-stimulated electrical activity in turn inhibits islet electrical activity by activating β-cell KATP channels. Secretion would then decrease, as [Ca2+]i decreases, and the cycle would be repeated as secreted insulin diffuses away from β-cell insulin receptors and KATP channels close. However, in isolated β-cells lacking tight intercellular spaces, insulin once secreted would be likely to dissipate quickly, precluding autocrine or possibly paracrine effects. Thus, a loss of intra-islet signaling might account for the lack of islet-like electrical activity displayed by isolated β-cells (21,23,24).
We have quantitatively tested the feasibility of this proposed mechanism using a recent paradigm of bursting, the phantom burster model (48). In this model, islet bursting results from the interaction of two slow processes, one (S1) with a time constant of a few seconds, and another (S2) with a time constant of a few minutes. The slow kinetics of activation of KATP current by insulin makes this mechanism an attractive candidate for the slower S2 process. In support of this hypothesis, we found that a variation of the phantom burster model incorporating insulin activation of KATP channels as the slow S2 process was able to simulate the medium bursting of intact islets (A. Sherman, L. Satin, R. Bertram, unpublished observations). Furthermore, removing the slow process, which might be akin to dispersing islets into single β-cells and thus eliminating the intercellular spaces needed for insulin to accumulate in, resulted in faster, S1-dominated bursting resembling that of dispersed β-cells (23). These computations thus support the general feasibility of this proposed mechanism of bursting, although the hypothesis remains to be tested by experiment.
Dysregulated insulin signaling in this novel negative feedback system, perhaps resulting from biochemical or molecular defects in the β-cell insulin receptor signaling cascade, could be significant for diabetes, because it may result in abnormal insulin secretion including defective pulsatility if insulin activation of KATP channels is required for periodic islet electrical activity.
Effect of exogenous insulin and IGF-1 on the membrane potential of single mouse pancreatic β-cells. A: The application of insulin reversibly hyperpolarized single mouse β-cells bathed in 10 mmol/l glucose at 35°C. The trace shown is representative of 63 of 86 cells tested with 1–600 nmol/l insulin. B: The changes in membrane potential caused by insulin were dose-responsive in single β-cells over the range of 1–600 nmol/l. The numbers listed above the error bars indicate the number of cells tested in each group. The maximal change in membrane potential was −13.6 ± 2.0 mV, and the calculated ED50 from these data were 25.9 ± 0.1 nmol/l. C: The application of 100 nmol/l IGF-1 had little or no effect on β-cell electrical activity, whereas subsequent exposure to 100 nmol/l insulin hyperpolarized the cells. The mean membrane potential in control solutions and in solutions containing 100 nmol/l IGF-1 and 100 nmol/l insulin were −45.0 ± 2.6, −45.0 ± 3.2, and −56.3 ± 4.5 mV (P < 0.001, n = 6), respectively.
Insulin-induced hyperpolarization of in situ β-cells and inhibition of regular [Ca2+]i oscillations. A: Insulin (200 nmol/l) hyperpolarized β-cells within intact islets. The application of 200 nmol/l insulin hyperpolarized islets from −47.7 ± 3.3 to −65.6 ± 3.7 mV (n = 11). Insulin took significantly longer to act in intact islets compared with single β-cells (9.4 ± 1.7 vs. 3.7 ± 0.5 min, n = 11 and 14, respectively). B: Regular [Ca2+]i oscillations observed in 10 mmol/l glucose were inhibited by insulin addition within ∼9 min. C: [Ca2+]i levels corresponding to the silent and peak phases of glucose-induced [Ca2+]i oscillations were 251.0 ± 26.8 and 457.6 ± 42.9 nmol/l, respectively (P < 0.05, n = 5). The application of insulin (100 nmol/l) inhibited these oscillations, producing a new steady-state [Ca2+]i value of 300.4 ± 40.0 nmol/l. D: A graphic representation of the technique used to gather data from in situ β-cells.
Tolbutamide reversed insulin-induced hyperpolarization and increased KATP conductance in single pancreatic β-cells. A: Insulin-induced (100 nmol/l) hyperpolarization was reversed by the application of 100 μmol/l tolbutamide. The membrane potentials measured in control, 100 nmol/l insulin, or insulin + 100 μmol/l tolbutamide solutions were −46.7 ± 2.4, −62.1 ± 1.9 (P < 0.001), and −44.1 ± 2.1 mV (n = 7), respectively. B: Whole-cell conductance, adjusted for cell capacitance, is shown for control, 100 nmol/l insulin, or insulin + 100 μmol/l tolbutamide solutions. Insulin addition increased normalized cell conductance, which could be reversed to control levels by tolbutamide. C: Currents recorded from cells in control, 100 nmol/l insulin, or insulin + 100 μmol/l tolbutamide solutions are plotted against cell voltage. The reversal potentials corresponding to β-cells exposed to control, insulin, or insulin + tolbutamide solutions were −25.7 ± 2.5, −63.7 ± 1.0 (P < 0.001), and −25.2 ± 2.3 mV, respectively (n = 9). Insulin shifted the reversal potential toward KATP equilibrium potential. This shift was reversed by the application of tolbutamide.
Wortmannin reversed insulin-induced β-cell hyperpolarization. A: Insulin-induced (100 nmol/l) β-cell hyperpolarization (from −53.6 ± 1.6 to −69.8 ± 2.2 mV, P < 0.001) was reversed by the subsequent application of 100 nmol/l wortmannin to −53.2 ± 2.1 mV (n = 5). B: Representative traces from cell-attached patch recordings of single KATP channels, where the bath solution contained 0 mmol/l glucose, 10 mmol/l glucose, 10 mmol/l glucose + 100 nmol/l insulin, or insulin + 100 nmol/l wortmannin. C: NPo (N = the number of functional channels, Po = the channel open probability) was calculated using 10 s–long recordings of KATP channel activity obtained in solutions containing 0 mmol/l glucose (0.49 ± 0.1), 10 mmol/l glucose (0.08 ± 0.04), 10 mmol/l glucose + 100 nmol/l insulin (0.37 ± 0.07), or in insulin + 100 nmol/l wortmannin (0.04 ± 0.01).
This work was supported by National Institutes of Health grant DK-46409 to L.S.S.
We thank Drs. A. Sherman, R. Bertram, and C. Baumgarten for helpful discussions and H. Strange for technical assistance. We thank Dr. John Nestler for support and encouragement.
Address correspondence and reprint requests to Leslie S. Satin, Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Box 980524, Richmond, VA 23298-0524. E-mail:lsatin@hsc.vcu.edu.
Received for publication 10 May 2001 and accepted in revised form 2 August 2001. Posted on the World Wide Web at http://www.diabetes.org/diabetes_rapids on 6 September 2001.
[Ca2+]i, intracellular calcium concentration; ED50, 50% effective dose; ER, endoplasmic reticulum; IRS, insulin receptor substrate; KATP, ATP-sensitive K+ channel; NPo, mean channel activity; PI, phosphatidylinositol; R, fluorescence ratio.
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redpajama_set_name: RedPajamaCommonCrawl


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This award-winning brand respects time-honored traditions as one of the few tequilas produced in Guanajuato, Mexico.
They say you can't judge a book by its cover, but in the case of Corralejo, you can judge a bottle by its color. The clear bottle (Silver) is pure and clean just like the tequila inside; the blue bottle (Reposado) signifies healing and tranquility and alludes to blue agave; and the red bottle (Añejo) signifies prosperity, wealth and strength, which perfectly suits this strong tequila.
Tequila Corralejo is made with 100% Blue Weber agave, which is handpicked from agave fields in Guanajuato. The agave is slow-cooked in stone clay ovens for 27 hours then rested for 12 hours before going to the mill where they undergo a double distillation process. But what sets Corralejo apart from other tequilas is that second distillation occurs in an Alembic copper pot still imported from Tomelloso, Spain. Corralejo uses this 400-year- old Charentais method of distillation, which was perfected by the French in distilling cognac. It allows for excellent retention of aroma and flavor.
This is not your typical reposado with the kind of pear and apple aromas you'd expect from a brandy.
Perhaps it has something to do with its production methods: agave is slow-roasted in traditional clay ovens called hornitos, which allow the agave's terroir and other characters to remain in the liquid. A bouquet of sweet flowers and ripe fruits coats the palate.
The distinctive dark fruit aromas of this Tamaulipas tequila are accented by hints of vanilla.
The taste on the tongue is punchy and reminiscent of blossoming gardenia, which makes this spirit bright and airy for a sour cocktail while still being a great choice for neat drinking.
Credit the rich red Highlands soil (or maybe the distillery's secret process) for this un-aged white tequila.
emanates almonds and hazelnuts – almost like a latte, with a sweet and lingering finish. The body is silky and smooth, making it a light option for sipping or perfect in an old-fashioned.
Hold on to your hat – this tequila is 110 proof and "directo de Alambique" – that is, straight from an Alembic still more commonly used in cognac production.
The nose is greeted with crisp cucumber and herbs, with a hint of smoke. An all-encompassing mouthfeel is made more vibrant with lingering black pepper. Drink in a spritzer with soda or tonic water, or in a Paloma with grapefruit.
If there ever was a tequila to go with Italian food, this is it.
Made in the same fashion as the namesake's founder in 1795, this Jose Cuervo's vegetal, thyme-like qualities work well with citrus (hello, margarita!) while exemplifying the peppery character we've come to love in un-aged tequilas. Better still, you can't beat the value for price.
Aged in American oak barrels for up to seven months, this reposado takes on toasted notes at first whiff — think crème brulee or flan.
Consequently, the taste is rather surprising, with vegetal and tropical fruit notes. Santera Reposado Tequila makes for a balanced and dynamic choice for mixing.
Sure, this is Justin Timberlake's silver tequila, but it can stand on its own without the celebrity hype.
Its triple distillation (many tequilas are distilled only twice) limits the tang, creating a sweet, medium finish with banana, cinnamon and mango notes. Forget the rum in that Dark & Stormy — this is best enjoyed with with ginger beer and a pinch of lime.
Bottled with agave from a single estate, this Jalisco tequila smells rich and balanced, but with a buttery tease.
Gardenia follows on the palate and hits all the sensors on the inside of the cheeks, allowing it to play beautifully in savory and bitter cocktails. Each ranch from which the agave is derived is handily indicated on the bottle.
Waft this organic tequila under your nose and it'll smell just like fall – crisp apples with just a little smokiness, like a campfire.
The winner of the 2011 San Francisco World Spirits Competition, this well-rounded tequila packs a punch on the palate with notes of caramel apple and orange peel.


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Articles Mentioning Ko Samui Hotels
The 19 Most Beautiful Resorts in Thailand
By Oyster Staff
Beach at Rayavadee Resort Delicious street food, historic attractions, stunning beaches, and a rich culture — Thailand has it all. And yes, that extends to its properties, too. From boutique stays on the beach to luxe resorts tucked away in the jungle, the country has a plethora of beautiful hotels to choose from. To help…
11 Common Mistakes to Avoid in Thailand
By Neil Gladstone
Street Food in Bangkok, Thailand/Oyster While fluent English speakers make up only 15 to 20 percent of Thailand's population, many more locals know enough to give directions, make recommendations, and haggle (more about that later). But just because you hear a lot of spoken English doesn't mean that you'll avoid making gaffes. Travelers to Thailand…
5 of the Best Islands for Retirement
By Toby Orton
Whether you're fleeing for warmer temperatures, looking for a cheaper cost of living, or have a desire to experience a late-in-life adventure, retiring to an island is an option that ticks all the boxes. While various visa restrictions can mean some places are harder to move to than others, there are plenty of islands around…
The 10 Best Islands in Thailand
The bluest water, the whitest sand, the most scenic sunsets, and the lushest forests — it's hard to limit the superlatives when it comes to talking about the Thai islands. The truth is that, for many, a trip to any of these tropical gems is a once-in-a-lifetime escape. And that means there's a lot of…
The Best Itinerary for Thailand
By Margot Bigg
Thailand, arguably the most traveler-friendly country in southeast Asia, offers great food, gorgeous beaches, and tons of cultural opportunities. While travelers could easily spend months exploring the "Land of Smiles," most people don't have quite as much vacation time to do just that. However, even if you only have a week to explore the country,…
Where to Go in Thailand: A Complete Guide to the Most Popular Destinations
By Jordi Lippe-McGraw
Mouthwatering food, rich culture, historical landmarks, and drop dead gorgeous beaches — there's nothing that Thailand doesn't have. But this can be both a blessing and a curse. With so much to do and see, it can be tough to narrow down exactly where to spend those precious out-of-office days. The upside is that there's…
The Best Time to Visit Thailand (and the Worst)
By Krystin Arneson
If there are two words that can largely sum up Thailand's climate, they are hot and humid. The Southeast Asian country, which is known for its tropical beaches, ornate temples, and ancient ruins, has two seasons — wet and dry. Some say there's also a third — the shoulder season, which occurs between peak and…
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4 Super-Cool Hotel Rituals
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We all have our rituals when we stay in hotels, whether they be indulging on the minibar every time or superstitiously avoiding rooms with "unlucky" numbers. But plenty of hotels have rituals of their own that guests can enjoy during their stays. Of course, many hotels have offerings that have become traditions, like free afternoon…
The 12 Best Cooking Classes at Hotels Around the World
Free demonstration cooking class in Thailand If social media has proved anything over the last few years, it's that we are all a bunch of not-so-closeted foodies — especially when we travel. Those who have eaten their way through foreign lands not only know that a great meal can be one of the most memorable…
Find Hotels in Ko Samui
Ko Samui Hotels By Area
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During the Spring months we look ahead to our "busy season" with excitement and just a bit of anxiety, sort of like a runner at the starting line. Then the gun goes off and the craziness begins. Now don't get me wrong, that's what we got into innkeepeing for: welcoming hundreds of guests both new and old and helping them discover all that Hudson and Columbia County have to offer. The energy we derive from running the inn comes directly from our guests. If they are having a good time, so are we. If there is a problem it's ours to solve. If they have a question, it's ours to answer.
Each morning we never know what feedback lays in store: How was dinner? What did you do yesterday? What's on the agenda today? Days go by. Guests check in. Guests check out. Then we do it all over again. Not having the time to experience all there is to do and see in town and the county we very frequently rely on our guests to tell us what discoveries are out there to pass on to the next visitor. Time marches on. Wedding celebrations take over the whole town. Annual events mark the progression of Summer: Flag Day, Hudson Pride, Fourth of July, Hudson's Waterfront Music Festival, Labor Day weekend, and HOH's Harvest Ball.
Then Fall Foliage arrives. Scores of guests want to know "how are the leaves?" or "when's the best time to come up?". Each year the answer varies. This year wasn't so great – lots of rain, temperatures up – then down, then more rain. Nothing we can control, and guests still have a good time. Halloween looms on the horizon and with it the proverbial finish line (although we never really finish – just slow down a little). "Winterwalk", Hudson's kickoff to the holidays held the first Saturday in December, brings thousands of visitors in from all over. A slice of Americana this annual event marks an important point in the town's cultural calendar – the beginning of a sort of semi-hibernation, but like us at the inn, things never truly end just the pace eases up. Then the New Year arrives and with it the prospect of what is in store.
Before we know it we're at the starting line again. Right after that the gun goes off and we're back at it.


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Tag: keto erectile dysfunction
Could keto help relieve erectile disorders?
The U.S. Food and Drug Administration has approved the use of keto acid in the treatment of erectile difficulties.
The agency said the drug is being tested in the use as an adjunct to menopausal therapy, as well as in the management of severe erectile impairment, including ED.
"Ketosis is a critical component of the therapeutic response to ED," FDA commissioner Dr. Mary Jo White said.
"Ketogenic acid may help reduce the incidence of the disease in patients who have been prescribed the ketogenic diet, especially if these patients have already received a regimen of other medications."
The FDA says the drug could be used for patients who are not taking other medications.
It will be available in pill, liquid and gel form.
The ketogenic acid is a naturally occurring form of carbohydrates derived from the starch of the corn plant.
The FDA said the keto diet is a nutritional plan that can help treat erectile problems and erectile pain.
It says there are no other medications or supplements that can be used as an alternative to ketosis.
The FDA is recommending that keto-acid tablets be given daily for patients with erectile symptoms.
They are also recommended for patients taking any other medications that have been suggested as alternatives to the ketos.
Patients with severe erections may need more than one dose of the drug, the FDA said.
The drug has been approved in the United States for the treatment, prevention and management of ED.
Tags:	erectile dysfunction synonym, keto erectile dysfunction, wellbutrin erectile dysfunction
How to treat erectile Dysfunction? Here's what you need to know
By: Dr. David Dao | September 11, 2018 06:18:00It's no secret that many of us are struggling with erectile problems.
Unfortunately, a lot of us have been dealing with it for a long time.
But a new study published in The Journal of Sexual Medicine has found that there is hope, and it's based on a lot more than just your anatomy.
In a study led by Dr. Michael T. Hannon, a sexual health specialist at the University of Texas Health Science Center at Houston, researchers looked at a variety of other factors, including social support, medication use, and relationship problems.
In the end, there was a link between erectile difficulties and other sexual health problems, including depression and anxiety.
Hannon said that this is the first study that really looks at the connection between erectility and a variety the factors that can cause it.
It shows that not just the anatomy, but also the social support of a relationship is related to a reduction in erectile function.
"Our results show that there's a lot to be gained from looking at a lot different factors, which is good news," said Dr. Dr. Tanya Trenary, the study's lead author.
The study also found that social support for men who struggle with erectility was associated with less depression and more positive mental health.
"We're talking about a lot that's pretty common in the general population, but is not necessarily well known," Hannon said.
"So if we can get the people who have these issues, the people in the community, to recognize it, and get them the help they need, then it can lead to more positive outcomes."
Dr. Hucker said that it's important to know that the link between social support and erectile functioning is not a one-to-one relationship.
"There are so many things that contribute to erectile disorders," Hucker told MTV News.
"Some people don't know it.
Some people don, but they have it.
And the other group, the group who are the most affected, are the people that are experiencing the most stress.
So you're talking with people that have these problems, and they're often in relationships where they're struggling."
It's not just just that they have a problem, they also have a lot going on in their lives that are impacting their erectile health," Huckan added.
Hucker said this is why he started his study.
He wanted to learn more about what is contributing to erectility.
He looked at how people in general are affected by erectile issues."
People who have erectile trouble, it's probably a lot like someone who has a mental health issue.
You don't always know exactly what's going on.
I would think that for those who have it, they're not necessarily doing a good job of coping.
They're also not making a good effort to improve their health, and that's why they're having this problem," H Cannon said.
Dr. Michael Hannon is an associate professor of sexual medicine at the university.
He says the study shows that a good relationship can make a huge difference.
Dr Hannon has found a way to help people with erectiles.
He believes that by improving social support from people in a relationship, and also talking to them about erectile dysfunctions, he can help them improve their sexual health and even prevent future erectile troubles."
If people are having erectile struggles, and people are really supportive of their partners, they can actually prevent the onset of erectile problem in the future," Hock said."
The other thing is that it makes people feel like they're contributing to a relationship in a positive way, which can make them feel more confident and more comfortable, which in turn can lead them to feel more connected to their partners.
Huckans study, published in the Journal of Sex Medicine, involved about 100 people. "
It's very important to make sure that we're having a relationship where you're not making assumptions," he said.
Huckans study, published in the Journal of Sex Medicine, involved about 100 people.
It focused on what happens in relationships with women, men, and a range of other partners.
The study was conducted at the San Diego-based Kinsey Institute, where Dr. H Cannon works as a research scientist.
Dr Trenaries study, conducted at Duke University, was published in March of 2019.
Huckans research was conducted in Texas and was conducted with the support of the National Institute of Mental Health.
Tags:	erectile dysfunction commercial, erectile dysfunction pictures, erectile dysfunction prognosis, erectile dysfunction pump, keto erectile dysfunction


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The future is unknown but be of good courage. This is a pep talk for anyone who is facing an uncertain future. As a Christian, I believe that God is in control. He knows the number of hairs on our heads (and their actual color….just sayin' here) and the days of our lives. He has a future planned for all of us that may be absolutely amazing, as we trust in Him.
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