Blog Archives

Homeostasis 2015: Publius’ Cannabinoid Science Champions

12/30/2014

The Cannabis Papers by Publius (2011)

The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius

2014 Cannabinoid Champions ~ Bivalency and Heteronomy

Publius’ 2014 cannabinoid science champions, Bivalency (it doubles) and Heteronomy (not autonomous), are spotlighted for their contributions to future knowledge. Both are CS homeostatic processes within the human body that work without notice or acclaim. Forward looking to 2015 and beyond, bivalency and heteronomy are cannabinoid science players with a high-knowledge upside. For now, here are four 2014 PubMed articles discussing: heteromerization and CB2, unexpected (intrinsic) bivalent CS properties, and two on Orexin, involved in arousal, wakefulness and appetite, and CB1 heterodimers and heteromeric signaling complexes.

I. Heteromerization of GPR55 and CB2 to form Unique Signaling Units
“Heteromerization of GPCRs is key to the integration of extracellular signals and the subsequent cell response via several mechanisms including heteromer-selective ligand binding, trafficking and/or downstream signalling. As the lysophosphatidylinositol GPCR 55 (GPR55) has been shown to affect the function of the cannabinoid receptor subtype 2 (CB2 receptor) in human neutrophils, we investigated the possible heteromerization of CB2 receptors with GPR55. … Heteromers, unique signalling units, form in HEK293 cells expressing GPR55 and CB2 receptors.”
Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling.
Balenga NA, Martínez-Pinilla E, Kargl J, Schröder R, Peinhaupt M, Platzer W, Bálint Z, Zamarbide M, Dopeso-Reyes IG, Ricobaraza A, Pérez-Ortiz JM, Kostenis E, Waldhoer M, Heinemann A, Franco R.
Br J Pharmacol. 2014 Dec;171(23):5387-406. doi: 10.1111/bph.12850. Epub 2014 Sep 5.
PMID: 25048571 [PubMed - in process]
Related citations

II. Bivalent Cannabinoid Receptor Ligands and Unexpected Intrinsic Properties
“The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB₂R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists.”
Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB₂R selective benzimidazoles reveal unexpected intrinsic properties.
Nimczick M, Pemp D, Darras FH, Chen X, Heilmann J, Decker M.
Bioorg Med Chem. 2014 Aug 1;22(15):3938-46. doi: 10.1016/j.bmc.2014.06.008. Epub 2014 Jun 13.
PMID: 24984935 [PubMed - in process]
Related citations

III. Orexin OX1 and Cannabinoid CB1 Heterodimers and Oligomers
“Cannabinoid CB1 and orexin OX1 receptors have been suggested to form heterodimers and oligomers. … Bivalent ligands targeting CB1-OX1 receptor dimers could be potentially useful as a tool for further exploring the roles of such heterodimers in vitro and in vivo.”
Toward the Development of Bivalent Ligand Probes of Cannabinoid CB1 and Orexin OX1 Receptor Heterodimers.
Perrey DA, Gilmour BP, Thomas BF, Zhang Y.
ACS Med Chem Lett. 2014 Mar 25;5(6):634-8. doi: 10.1021/ml4004759. eCollection 2014 Jun 12.
PMID: 24944734 [PubMed]
Related citations

IV. Heteromeric Complexes, Orexin OX1 and Cannabinoid CB1 Receptors
“Human OX1 orexin receptors have been shown to homodimerize and they have also been suggested to heterodimerize with CB1 cannabinoid receptors. The latter has been suggested to be important for orexin receptor responses and trafficking. … As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors.”
Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors.
Jäntti MH, Mandrika I, Kukkonen JP.
Biochem Biophys Res Commun. 2014 Mar 7;445(2):486-90. doi: 10.1016/j.bbrc.2014.02.026. Epub 2014 Feb 13.
PMID: 24530395 [PubMed - indexed for MEDLINE]
Related citations

Video: Cannabinoid System in Neuroprotection, Raphael Mechoulam PhD

Happy New Year and a Forward Looking 2015 ~ Thanks All!
Posted by Bryan W. Brickner

0 Comments

Synaptic Serotonin (5HT): Gut Work to Work Better in 2015

12/26/2014

0 Comments

Holstein dairy cows and serotonergic energy

The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius

Mammalian Holstein Edition

Mammals produce serotonin (5HT); it’s transported from our gut, where 80-90% is produced (the rest made in one’s brain), until it connects with our serotonin receptors, our most prolific set with 15. Today’s serotonin system science update covers modulating our digestion: specifically, our gut. Below are three (brief) science stories from the National Institutes of Health (PubMed). The serotonin gut tales include: serotonin transporters and colitis pathogenesis, serotonergic and glutamatergic dual signaling, and, one for our mammalian clade (a single branch of the tree of life), 5HT liver glucose homeostasis during transition from pregnancy to lactation (making milk) in Holstein dairy cows.

Bonus: Medical News Today posted a good (gut) serotonergic summary in September 2014, What is serotonin? What does serotonin do? Learning about our serotonin systems will make us healthier; that’s really why they are studying the Holstein dairy cows, for example. Stress on a lactating dairy cow hurts profits; life's modulations, such as the stress of pregnancy, birth, and lactation, are serotonin system dependent – in all mammals, not just in Holstein dairy cows.

I. Colitis Pathogenesis, Serotonin and the Serotonin Reuptake Transporter (5-HTT)
“Serotonin (5-HT) release and serotonin reuptake transporter (5-HTT) expression have been reported to be decreased in experimental colitis, in interleukin-10 knockout-associated colitis, and in patients with ulcerative colitis. Serotonin is known to play an important role in the pathogenesis of colitis, but individual genetic variants of 5-HTT gene in microscopic colitis and ulcerative colitis are not known. … A significant association was observed between LL genotype of 5-HTTLPR polymorphism and microscopic colitis, suggesting that 5-HTTLPR is a potential candidate gene involved in the pathogenesis of microscopic colitis. Serotonin levels were significantly higher in microscopic colitis and ulcerative colitis patients compared to healthy controls.”
Association of Serotonin Transporter Promoter Polymorphism (5-HTTLPR) with Microscopic Colitis and Ulcerative Colitis.
Sikander A, Sinha SK, Prasad KK, Rana SV.
Dig Dis Sci. 2014 Dec 23. [Epub ahead of print]
PMID: 25532499 [PubMed - as supplied by publisher]

II. Serotonin, Glutamate and Selective Serotonin Reuptake Inhibitor (SSRI)
“Neuroscientists have been puzzled by the fact that acute administration of a selective serotonin reuptake inhibitor (SSRI) produces results that are, at times, compatible with either decreases or increases in serotonergic neurotransmission. Furthermore, the underlying cause of the delayed onset of antidepressant effects of SSRI treatment has remained obscure. It has recently been reported that serotonergic raphe neurons co-release glutamate and that serotonergic and glutamatergic components constitute a dual signal with behaviorally distinct effects.”
Dual serotonergic signals: a key to understanding paradoxical effects?
Fischer AG, Jocham G, Ullsperger M.
Trends Cogn Sci. 2014 Dec 10. pii: S1364-6613(14)00237-X. doi: 10.1016/j.tics.2014.11.004. [Epub ahead of print] Review.
PMID: 25532701 [PubMed - as supplied by publisher]

III. Serotonin, Liver Glucose Homeostasis and Lactation (Holstein dairy cows)
“Nonneuronal serotonin (5-HT) participates in glucose metabolism, but little is known regarding the actions of 5-HT in the liver during the transition period in dairy cattle. Here, we explore circulating patterns of 5-HT and characterize the hepatic 5-HT receptor and glucose transporter profiles around calving in multiparous Holstein dairy cows (n = 6, average lactation = 4 ± 1.9). … These results indicate that 5-HT could be important for liver glucose homeostasis possibly through receptor mediated signaling at specific times. Additional research is needed to further explore the functional role of these receptors in the liver during the transition from pregnancy to lactation.”
Serotonin receptor expression is dynamic in the liver during the transition period in Holstein dairy cows.
Laporta J, Hernandez LL.
Domest Anim Endocrinol. 2014 Nov 26;51C:65-73. doi: 10.1016/j.domaniend.2014.11.005. [Epub ahead of print]
PMID: 25528206 [PubMed - as supplied by publisher]

Video ~ Digestive Wellness: The Brain-Gut Connection with Liz Lipski, PhD, CCN (2010)

Posted by Bryan W. Brickner

0 Comments

Christmas 1944: Bastogne Perseverance, Patience and Victories

12/24/2014

0 Comments

Bastogne 19-23 December 1944: German encirclement

Part II: Victories

Victories have peripheries. The failure of the 1944 German offensive in the Ardennes against Allied forces precipitated the collapse of the Nazi regime; Auschwitz would be captured in one month (25 January 1945) and Hitler would commit suicide in five.

Perseverance is a quality George Washington is noted for and one the American forces exhibited while bearing the siege of Bastogne. Leo Barron and Don Cygan's book No Silent Night: The Christmas Battle for Bastogne (2012), is the story of a fulcrum battle in the German siege of Bastogne, Belgium, 20-27 December 1944. Today we’ll use Barron and Cygan’s work to see the campaign from Lt. Colonel John T. Cooper's viewpoint; the colonel has a Christmas day like Lt. James Monroe did in 1776 at Trenton:

101st in besieged Bastogne retrieving air-drop supplies (December 1944)

16 December 1944
German offensive begins; General Eisenhower orders the 101st to Bastogne in response. Cooper’s command, the 463rd Parachute Field Artillery Battalion, had been refitting and resting along with the 101st, though a bit incognito.

18 December
The reputation of the 101st was well established by 1944 in Europe: D-Day for one, and Operation Market Garden, portrayed in the movie A Bridge too Far, for another. Cooper’s command had been assigned to the 101st for less than a week; they had been in other theaters of the war (Italy and Sicily) and around the 101st veterans had kept quiet about their own prowess. Cooper pleads to go along and General McAuliffe, commander of the 101st, finds him a spot.

20-23 December
The American forces get to Bastogne ~ mostly in open-air cattle trucks ~ and once there, are surrounded by the Germans. Supplies are para-dropped in; on the 22nd the Germans ask General McAuliffe to surrender: his response was “NUTS!” Cooper’s artillerymen fortify their position near Hemroulle, Belgium, on the outskirts of Bastogne, and wait.

24 December Christmas Eve
The German Luftwaffe bombs Bastogne. Cooper’s 463rd hold a Christmas Eve service in a Hemroulle stable, with the gathered soldiers singing “Silent Night” to conclude the service.

25 December Christmas Day
The German tanks attacked Bastogne via Hemroulle. The 463rd was prepared, due to Lt. Colonel John T. Cooper’s perseverance and patience; he had defenses constructed and offenses employed and inflicted fulcrum, battle-changing, force: infantry, with field artillery support, beat tanks.

Time was perhaps the biggest victor that Christmas day long ago, as Germany and the United States have shown for 70 years that two who fought from 1776 to 1945, in varying ways, can turn it around: the US and Germany don’t fight militarily anymore. That is a real change; in fact, one could say the former adversaries Germany and the US now work together For something – even something like yesterday’s illuminating lament, that 70-year peace reprise from Ein Deutscher Offizier, a known unknown inspiration:

“Let the world never see such a Christmas night again!
To die, far from one’s children, one’s wife and mother, under the fire of guns, there is no greater cruelty.
To take away a son from his mother, a husband from his wife, a father from his children, is it worthy of a human being?
Life can only be for love and respect.
At the sight of ruins, of blood and death, universal fraternity will rise.”

Video: Battle at Bastogne
Bonus Video: Historic Stock Footage WWII Battle of the Bulge – Siege of Bastogne

*Announcement: In January, look for Ew Publishing’s first booklet of 2015, Bryan W. Brickner’s Shivitti: A Review of Ka-Tzetnik 135633’s Vision. The booklet will be available by (or before) 25 January 2015.

Posted by Bryan W. Brickner

0 Comments

Christmas Eve Laments 1944: No Silent Night in Bastogne

12/23/2014

0 Comments

Silent Night Memorial Chapel Oberndorf (Austria)

Part I: Lamentations

Silent night, Holy night

A replica Austrian chapel depicts the place of the initial 1818 performance of Stille Nacht (Silent Night). Two pious dudes had an idea for a Christmas Eve show; one had words, the other beats. The wordsmith was Josef Mohr, the man with the beats, Franz Xaver Gruber, played church organ. Stille Nacht was put together like most great things (out of necessity); Mohr had a midnight Christmas Eve performance and needed something new. Including guitar and choir accompaniment, the two crafted the performance that evening – and the show went on at midnight. In 2011, UNESCO declared Stille Nacht part of our intangible cultural heritage.

 All is calm, all is bright,
Round yon Virgin Mother and Child 

No Silent Night: The Christmas Battle for Bastogne, written by Leo Barron and Don Cygan (2012), is the story of a fulcrum battle in the German siege of Bastogne, Belgium, 20-27 December 1944. This German siege within the American Ardennes Counteroffensive hinged on a Christmas Day battle between US infantry, with the 101st Airborne on point, against German tanks, specifically, the feared Panzer and its three inches of steel plating. Tomorrow we’ll view the Christmas Day battle from one officer’s perseverance and patience, Lt. Colonel John T. Cooper. The colonel has a soldier’s day like Lt. James Monroe did in 1776 at the New Jersey Battle of Trenton. In 1776 it was German Hessians hired as mercenaries for the King of England to fight the Yankee Doodle Dandy rebels; in 1944 it was the last of Germany’s Jerries against more of those US rebel Yanks.

Ardennes American Cemetery and Memorial (Belgium)

In Belgium (and not far from Bastogne) the Ardennes American Cemetery and Memorial is the final resting place for 5,329 WWII US vets: 792 are buried as Unknowns. The memorial itself is grand; the rows of headstones providing background for an emboldened American eagle accompanied by three goddesses: Justice, Liberty and Truth. There are also thirteen stars for America’s founding, when thirteen independent states united to become one nation.

Holy infant, so tender and mild,
Sleep in heavenly peace,
 Sleep in heavenly peace.

Lamentations are passionate expressions of grief or sorrow; they are illuminated wails. Barron and Cygan show their spirit, and the spirit of their book, by prefacing No Silent Night with a German officer’s Christmas night lamentation; the sorrow was chalked in a school after tomorrow’s 1944 Christmas Day battle. Seventy years on and the German’s sorrow rings eternal in its human, all too humanness: besieged by ruins, blood and death, the human nonetheless cries for – laments for – a vision of universal fraternity:

“Let the world never see such a Christmas night again!
To die, far from one’s children, one’s wife and mother, under the fire of guns, there is no greater cruelty.
To take away a son from his mother, a husband from his wife, a father from his children, is it worthy of a human being?
Life can only be for love and respect.
At the sight of ruins, of blood and death, universal fraternity will rise.”

This evening, pause in Peace for that holy infant, so tender and mild … in all of us.
~
Posted by Bryan W. Brickner

Part II Tomorrow: 70 years from Christmas Day 1944 ~ Perseverance, Patience and Victory in Bastogne.

0 Comments

Nazi Ethics in America’s Operation Paperclip ~ An Abens Review

12/19/2014

0 Comments

Former Nazi Scientists, White Sands NM (1946): Wernher von Braun is first row, seventh from the left, handkerchief in breast pocket.

Science Political

Written by Annie Jacobsen, Operation Paperclip: The Secret Intelligence Project that Brought Nazis to America (2014), is a tale long suspected by those of my generation (baby boomers). The truth found in Jacobsen’s book is that departments of the American government, specifically the State Department, FBI, CIA (originally the OSS) and the Pentagon, went way beyond “hiring” Wernher von Braun and a few other rocket scientists to help run the American Space Program.

As a child, I remember seeing pictures of a smiling von Braun, living in Huntsville Alabama, helping us with our nascent space program. After all, it made sense that you’d want to grab the cream of the crop from the Nazis, if for no other reason than keeping them from falling (willingly or otherwise) into the hands of the British, French, Russian and others who would want to make use of their rocketry knowledge. Long ago after I grew up I learned it was an American GI who slipped Hitler’s second in command, Reichsmarschall Herman Goering, a potassium cyanide capsule to help him cheat the hangman’s noose at Nuremberg. Later still I heard it was the Americans who concealed uber-criminal Klaus Barbie from the French, who desperately wanted to try him for war crimes (atrocities) committed during the war in France.

Dr. von Braun became Director of the NASA Marshall Space Flight Center on 1 May 1964.

At the time our government had a prohibition on allowing hard-core Nazis to emigrate to the US, so former Nazis had their dossiers cleaned up so that one American agency of government could get individuals past other American government agencies. To cite an example, Wernher von Braun had not only been a Major in the Nazi SS, he selected and directly negotiated with other high-level Nazis for slave labor to work at Peenemunde Army Research Center and other German rocket installations.

And now, at the end of 2014, Americans are shocked to learn that Nazis were paid US Social Security benefits. Annie Jacobsen enlightened us as to our involvement in Operation Paperclip; more now from Congress, who just overwhelmingly approved a bill stripping Nazis of the pensions we the US government offered them to just go back to Europe without an argument. That’s right, giving Nazis pensions to leave the country even though they’d entered illegally.

All in all nearly 1,600 Nazis were sneaked into the US under the rubric “Operation Paperclip” (for the paper-clipped info on Nazi dossiers so the truth could be removed when necessary). Using various forms of subterfuge, the operation paid, fed, housed and utilized former Nazis in US government agencies without the knowledge of Congress or the general population of American citizens. There were comic instances as well; one former Nazi working at Fort Bliss had passed himself off as trained in rocketry – in reality, he had been a cafeteria worker at a Nazi rocket facility.

There are many reasons to go to war: stupidity, self-preservation if attacked, striking preemptively an enemy thought to be ready to strike you, and others. There are gains to be made in a war whether a country wins it or not. For example, in the Battle of Kadesh, when Egyptians met Hittites in Palestine some thousands of years ago, it was generally thought to be a draw, but as far as we can tell reading hieroglyphics and other historical writings, Ramesses claimed victory and his version was accepted … in Egypt that is. These advantages to come of war, such as material profits, territorial gain, and national prestige, play another role as well, one noted by Orwell in his 1984: “the object of waging a war is always to be in a better position in which to wage another war.”

William Abens, author

Video: Bringing Nazi Scientists to America – Annie Jacobsen

Next: a 70th Christmas Eve WW II story in two-parts beginning Wednesday 24 December, with Leo Barron and Don Cygan’s No Silent Night, The Christmas Battle for Bastogne.

Posted by Bryan W. Brickner

0 Comments

Homeostasis 2015: Publius’ Cannabinoid Science Champions

Synaptic Serotonin (5HT): Gut Work to Work Better in 2015

Christmas 1944: Bastogne Perseverance, Patience and Victories

Christmas Eve Laments 1944: No Silent Night in Bastogne

Nazi Ethics in America’s Operation Paperclip ~ An Abens Review

Author

Archives

Categories