Maven is - at its heart - a plugin execution framework; all work is done by plugins. I could hardly the document for jetty 6. ; With Maven Jetty through its plugin as the server ; speeding up development with JRebel; 1.
JDKのみと同じように、 JAVA_ HOME 環境変数の設定も行ってください。 Maven 3の入手と手動インストール ダウンロード MavenサイトのDownload Apache Maven 3. RESTful Web service introduction. The information on this page refers to the plugin versions for Jetty 7 and above. It is now called the jetty- mavete. 3から、 ご自身のPC環境にあったファイルをダウンロードします。 私は、 Maven 3. 5 of the Standard Taglib. The Apache Tomcat Project is proud to announce the release of version 1. From the community for the community | | |.
The documentation for Jython 2. Jetty 6 1 5 jar download. Get notifications on updates for this project. This page lists the core plugins and rving the application.
This tutorial is based on Spring 2. These components are open source available for commercial use distribution.
A standard Maven project structure. Hadoop still depends on Jetty 6 and servlet 2. Yatta Launcher for Eclipse.
META- INF/ LICENSE MET | Email: info at | © Demo Source and Support. Jetty 7 Jetty 8 are now EOL ( End of Life) All development stable releases are being performed with Jetty 9. Note: The canonical repository for Jetty is Maven Central. Jetty 6 1 5 jar download.
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Ян Скоробогатый-Якубовский (, 4 июля 1878 — 12 ноября 1955) — польский военачальник, бригадный генерал Войска Польского.

Биография
С 1914 по 1917 воевал в Польских легионах, позже — во 2-м Польском корпусе в России. С 17 августа 1918 года командующий 1-м полком польских стрелков им. Тадеуша Костюшко, 5 января 1919 полк перешел в состав 5-й дивизии польских стрелков под командованием полковника Казимира Румши. С сентября 1921 командующий 43-м Стрелковым полком легиона Байонцев, в декабре 1922 назначен командующим 13-й пехотной дивизией.

Постановление Министерства обороны Польши от 8 мая 1926 года был переведен в Корпус охраны пограничья и назначен командиром 3-й Бригады пограничной охраны в городе Вилейка. В ноябре 1927 года переведен в Штаб корпуса № III города Гродно. С 1938 года по 1939 был председателем совета директоров центрального Союза сибиряков.

В 1939 году принял участие в Сентябрьской кампании, попал в плен, ему также удалось единственному из своего отряда бежать из советского плена и пробиться на Запад. В 1940 году был отправлен Владиславом Сикорским с миссией в оккупированную Польшу. С 1942 года был командующим национальных резервов главного командования Армии Крайовой. Похоронен в Варшаве на воинском кладбище в Повонзках.

Награды
 Орден Белого орла (в 1995 году, посмертно)
 Серебряный крест ордена Virtuti militari № 7009 (1922)
 Командорский крест Ордена Возрождения Польши(1938)
 Крест Независимости с мечами
 Офицерский крест Ордена Возрождения Польши
 Крест Храбрых (четырежды)

Примечания

Литература

Генералы бригады (Польша)
Похороненные на кладбище Воинские Повонзки
Солдаты 5-й дивизии польских стрелков в Сибири
Военнослужащие Польских легионов (1914–1918)
Участники Советско-польской войны (Польша)
Участники Второй мировой войны (Польша)
Армия крайова
Бежавшие из плена
Военнопленные Первой мировой войны (Австро-Венгрия)

redpajama_set_name: RedPajamaWikipedia


text:
Dionysiac sarcophagus discovered serving as "flower pot" at Blenheim Palace
As reported by The Daily Mail, The BBC, The Telegraph, and The New York Times, among others, a Roman sarcophagus (or at least, the front slab of one) has been discovered on the grounds of Blenheim Palace, where it has spent the last century in service as a tulip planter.
This lenoid piece (a coffin shaped like a lenos: a wine vat) features the lions-head bosses typical for this shape, while the figural frieze itself — a Dionysiac scene of the inebriated god approaching the sleeping form of his beloved Ariadne, her own pose echoed by that of Hercules reclining boozily at left (an unusual addition) — plays on the lenos's associations with wine.
The dates reported for the piece are a mess. Most of the sources above describe it as "dating back to A.D. 300" or "300 AD" — but then go on to quote spokesmen who place the carving in the 2nd century (i.e., well over a century earlier), with no notice of the resulting chronological inconsistency.
In truth, neither set of reported dates can be correct. AD 300 is far too late for this work. But the 2nd century is just as clearly too early, as an eye to the carving technique reveals. (Just look at the drill-heavy treatment of the lions' manes.) A 3rd-century date, tilting earlier rather than later — the 220s AD, or perhaps even the 230s — seems most likely.
another Roman sarcophagus found near İznik
Istanbul's Daily Sabah reports that yet another Roman sarcophagus has been discovered in Turkey's Hisardere district, five kilometers northeast of İznik, less than a year after the discovery of this piece in the same district.
The İznik Museum, it is related, plans to put the specimen on display.
A Roman sarcophagus recently discovered in Turkey's Hisardere district, five kilometers northeast of İznik. DHA photo.
Etruscan and Roman sarcophagi stashed in Geneva Freeport are returned to Italy
At least three sarcophagi — one Roman specimen, joined by two Etruscan terracotta pieces featuring kline portraits — were among thousands of archaeological artifacts recently repatriated to Rome from Geneva's Freeport warehouse complex, as reported by the Guardian.
Uncovered by a sting operation in 2014, the artifacts, filling 45 crates and reportedly worth some 9 million Euros (although one wonders on what the valuation is based...), where retrieved from the storage unit of Robin Symes, a notorious dealer in illegal antiquities who smuggled the objects, stolen from south Italian digs in the 1970s and 1980s, into Geneva decades ago.
Roman sarcophagus found near İznik by farmer
As originally reported by Today's Zaman (no longer available) and reposted by News Network: Archaeology: in November of last year a Roman sarcophagus was unearthed by a farmer in the Hisardere area of Turkey, northeast of İznik.
The format of the coffin seems typical of those from Docimium/Dokimeion; but Esen Öğüş, a colleague more familiar with eastern sarcophagi than I, tells me she thinks it is actually a local product carved in imitation of the expensive Docimean pieces. She intends to publish the finding.
Docimean Hercules sarcophagus seized in Geneva to be returned to Turkey
As reported by the Tribune de Genève — and later covered in greater detail by the Tages-Anzeiger (many thanks to Christian Russenberger for the link) — a Swiss public prosecutor has ordered that a Roman sarcophagus deposited in the Geneva Freeport warehouse in 2010 and subsequently seized by Swiss Customs during an inventory check later that year be returned to Turkey.
The piece itself is exquisite: a creamy Docimean specimen, likely Antonine in date, showing the Twelve Labors of Hercules.
As detailed in earlier blog posts (here, here, and here), Metropolitan sarcophagi (i.e., those from the city of Rome itself) devoted to the Labors of Hercules typically array the hero's first ten labors on the front of the chest in narrative order, with the eleventh and twelfth depicted on the short ends, and nothing on the back (as usual for Metropolitan works), This piece, in contrast, strews the vignettes around all four sides — as expected for an eastern product — in no discernable order.
Building contractors at Ashkelon discover, then attempt to conceal, Roman sarcophagus
Israel's Haaretz reports the discovery of a Roman sarcophagus at Ashkelon by building contractors who, fearing delays in their construction of luxury villas if its existence were reported to the authorities, instead decided to conceal it. Using a tractor to pull it from the ground — in the process scarring the stone and damaging the relief on multiple sides — they then poured a concrete floor over the findspot to efface any signs of excavation, and hid the sarcophagus beneath a stack of boards and sheet metal. (Additional details here and here.)
With a length of 2.5 meters (8.2 feet), this is a massive piece. The lid features a portrait of the deceased shown reclining: not in itself unusual, were it not for the hollow eyes, clearly originally inlaid. This, several other decorative idiosyncrasies, and the fact that the coffin is carved from limestone rather than marble all point to a local product.
Roman sarcophagus unearthed near a well in Sidon's Bustan al-Kabir quarter
Lebanon's Daily Star reports the excavation of a Roman sarcophagus, as well as remnants of an ancient well, at a construction site in Sidon's Bustan al-Kabir neighborhood. From the photograph below the sarcophagus appears to be of standard eastern garland type, pressed into service as a blank.
Two burial grounds, yielding skeletons, pottery, and coins with Latin inscriptions, were found at the same site a month ago. The relationship of the sarcophagus and the burials to the well has not yet been clarified.
Turkish officials foil attempted smuggling of a child's sarcophagus
Istanbul's BGN News reports that Turkish authorities near Izmir recently foiled an attempt by two men to smuggle a Roman child's sarcophagus out of the country in a light commercial vehicle.
According to the report, official analysis of the recovered sarcophagus revealed that it had never before been opened. (So what were the contents when the piece was finally uncorked? — we're not told.) It was subsequently delivered to the Directorate of the Izmir Museums.
The fuller story is here. That the specimen — from the pictures, a wee piece featuring garlands suspended from rams' heads — is "at least 2,000 years old" seems unlikely.

redpajama_set_name: RedPajamaCommonCrawl


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I am frequently asked about where to find vintage clothes and accessories. There are plenty of shopping spots out there and this doesn't begin to cover them! This page includes online sites and shopping in your home town.
If you have a favorite shopping spot that you'd like to share or if you're a shop owner (ebay and etsy counts too!) please leave a link in a comment below and I will add it to the list. Listings are added in alphabetical order.
Cats Like Us "Rockabilly Mens Clothing and Pinup Womens Clothing and Accessories"
Amerimark- Affordable Vintage Style Shoes. I have bought several pairs and love them!
Oh, darling! I LOVE your blog. I am so happy I happened upon it! I am looking for a place in the STL area to find a vintage-reproduction bathing suit. Any ideas??
Oh, please do add my brand new (i opened december 14th) online gift shop GemsandJam.com! We've got some fabulous, unique and affordable vintage and handmade jewelry, accessories, and housewares. I am an almost 30 female entrepreneur who has a passion for entertaining guests, and wearing amazing vintage earrings and accessories. Check it out! Thanks ahead for your listing consideration. Rock on lady. Your site is fabulous.
What a fabulous vintage blog you've created! Bet you're a great shopping partner as well.
Just wanted to thank you for adding great visuals to the virtual vintage world, and see if we could exchange links. I sell midcentury modern fashion and finds on etsy and in antique markets, based in Atlanta, and selling at shows along the East Coast. Just returned from doing the Sturbridge & Brimfield Antique Shows in Massachusetts, where my wonderful neighbor was one of your previously featured subjects: Donna of Donnaland Vintage Variety.
Looking forward to seeing more of you!
Please feel free to share with friends. Great site here.
Great website and blog, can't believe I've only just discovered you. It would be wonderful if you could add my little vintage empire to the above lists please. I have a bricks and mortar shop called Top Notch Vintage in Somerton, Somerset UK (TA11 7NH) and my website is https://topnotchvintage.co.uk, my instagram is /topnotchvintageshop.
Thanks ever so much - now I'm going to spend the rest of the evening reading your fb blog.
Thanks for sharing this informative online vintage clothing directory. Would you please added https://neorgasm.com/ in your directory. It's a e-commerce website that offering home decor accessories and women's clothing & accessories. Thanks!
Hi Brittany, we just discovered your blog! Please add our vintage site https://www.blue17.co.uk/ to your list, Many thanks!
Thank you for creating this list, it is very helpful.
Awesome post, I like everything retro, especially vintage hair styles, clothes and accessories.
Wow, I love this post! Hello there, Lots of good suggestions on your blog, Thanks for sharing this post. It has included valuable information for enhancing our experience of online shopping. I'd like to share some useful links with you on modest dresses, I hope this will help you to write more inspiring and useful content on modest clothes. Have a great day dear, and thank you for sharing this awesome content with us.
Love your blog! Lots of great info, inspiration and great shops! Please add our new shop ROCK AROUND THE CLOTH to your list. We are an online boutique with Rockabilly Mens Apparal and Pinup Style Dresses for women including plus sizes and Pinup Accessories!
You are clearly knowledgeable on this topic and you have unique views to share.


text:
Patrick's proposal "dead on arrival??"
By Patricia Kilday Hart
Ed. Note: We'd like to welcome back Patricia Kilday Hart, who will be covering and blogging the Legislature with Paul. This is her first post. Ah, opening day of the 81st Session, where the mood in the Capitol is one of grand expectations for Peace on Earth, now that Tom Craddick has been deposed. So, of course, the Texas Senate wasted no time to devolve into partisan bickering over the hallowed two-thirds rule. Senate Democrats met this morning in an caucus billed as "urgent" to discuss a Republican proposal for a Senate rules change permitting a vote by the Committee of the Whole on two issues: redistricting and voter ID. The committee of the whole setting means there's no "blocker bill" requiring the two-thirds threshold for debating bills. One Senate Republican told me there was "no consensus" in the Republican caucus on the proposal, while another called it "ill-conceived." Then there's the passion-stirring proposal by Sen. Dan Patrick, set out in a letter to his Republican colleagues, transforming two-thirds into a three-fifths rule. Patrick would require 19 votes to overcome a blocker bill, would mirror the U.S. Senate's 60 vote threshold for passing legislation without a filibuster. "I like and respect our colleagues across the aisle. I'm also proud we can work with them, however, when it comes to key legislation that matters most to our constituents the minority has a different view. Texans did not elect us to the majority so that we would succumb to the minority in the Texas Senate," Patrick wrote. At least one senator was entirely dismissive of Patrick's suggestion…and of Patrick. "It's dead on arrival," said Sen. John Carona. "In large part because of the author." (A little stunned at his frankness, I asked, "Is that on the record?" "Sure," Carona shrugged.) With twelve Democrats in the Senate, defensive strategies are limited, but intense: First, the caucus could call the Republican bluff by advocating ditching the two-thirds rule for everything. (If it is good enough for voter ID, why not election-day voter registration?) Or they could simply refuse to suspend on any bill. From Day One. Shut things down before they get started. This is going to be a fun session.
How to Survive the Texas Legislature
Confessions of an Aging Pothead
The Seduction of Jane Doe
The Long, Strange Trip of Ed Bass
The Rise and Fall of the Bush Family Dynasty
By Christopher Hooks
Christopher Hooks
Christopher Hooks writes mostly about Texas politics and occasionally about more serious subjects.
and Forrest Wilder
Forrest Wilder
Forrest Wilder writes about politics and the outdoors.
Michael McCaul Is the Most Powerful Texan in the House. Will He Be Able to Lead Foreign Affairs With a Divided Caucus?
By Jonathan Tilove
Update: Family Members Press Congress on the Korean War Memorial Wall's Errors
By Michael Hall
Mike Hall writes about criminals, musicians, the law, and barbecue.
Opinion: Texas Should Accept Medicaid Expansion
By Anisha Ganguly
Celebrating 50 Years of Texas Monthly
The "Come and Take It" Flag Now Symbolizes Something It Never Stood For
Get All Our Stories in One Daily Email
It's free. It's daily. And it's full of great reads, y'all.
TM Today All our stories in one daily email.
By José R. Ralat
José R. Ralat
José R. Ralat is Texas Monthly's taco editor, writing about tacos and Mexican food.
Is the Fourth Slice the Barometer for a Well-Cooked Brisket?
By Daniel Vaughn
Daniel Vaughn
Daniel Vaughn is the country's first barbecue editor, and he has eaten more barbecue than you have.


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Fellows' Corner
Optimizing Care of Spinal Muscular Atrophy in an Advancing Treatment Era
January 03, 2020 – Matt Hoffman
Judgment Call: Exploring Treatment Tactics in Clinically Isolated Syndrome
January 02, 2020 – Linda Peckel
Managing Vestibular Migraine: Optimizing Diagnosis and Treatment
January 01, 2020 – Heidi Moawad, MD
A Neurology Pipeline for the Ages
December 31, 2019 – Stephen D. Silberstein, MD
Eisai Stays the Course on Amyloid Despite Setbacks
December 30, 2019 – Alicia Bigica
A New Era of Treatment for Chronic Migraine
December 28, 2019 – Matt Hoffman
Exploring the Potential of Immunotherapy for Movement Disorders
December 27, 2019 – Nicola Davies, PhD
Addressing Insomnia in the Elderly
Studies Investigate 2 Doses of Fenfluramine in Dravet Syndrome
Targeting the NF-κB Pathway in Duchenne Muscular Dystrophy
December 24, 2019 – Krithika Subramanian, PhD
Treating Rare Epilepsies: Overcoming Issues With Tolerability and Adherence
Navigating Disease-Defining Events in Multiple Sclerosis
Treating MS: A Simplified Strategy Boosts Patient and Provider Satisfaction
December 02, 2019 – Aaron Boster, MD
The Need for Prognostic Indicators in Pediatric Multiple Sclerosis
December 01, 2019 – Heidi Moawad, MD
Tapping Technology to Improve Mental and Cognitive Health in MS
November 30, 2019 – Tori Rodriguez, MA
Why Alternatives to Systemic Steroids Deserve a Second Look
November 29, 2019 – Alicia Bigica
Multiple Sclerosis Centers Offer Value
November 28, 2019 – Michael K. Racke, MD
Exploring the Role of B Cells and CD20 in Multiple Sclerosis
November 27, 2019 – Krithika Subramanian, PhD
MMPOWER-3 Seeks to Resolve Cell Dysfunction in Primary Mitochondrial Myopathy
November 02, 2019 – Matt Hoffman
Treating Huntington Disease: New Trials Aim to Explore Uncharted Territory
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NeurologyLive does not provide medical, diagnostic, or treatment advice.
Exploring the VMAT2 Pathway in Tardive Dyskinesia
VMAT2, given its role in presynaptic packaging, storage, and release of dopamine, has emerged as a promising target for therapeutic interventions to manage movement disorders.
By: Krithika Subramanian, PhD
Classical synaptic transmission, the primary mode of communication between the synaptic and postsynaptic neurons, involves the release of neurotransmitters from the presynaptic cell into the synaptic cleft, followed by the interaction of the neurotransmitter with receptors on the postsynaptic cell, leading to signal transduction.1,2 The active removal of the neurotransmitter from the synaptic cleft by sodium-coupled transporters, and the subsequent removal of neurotransmitters from the cytoplasm and storage in secretory vesicles by vesicular neurotransmitter transporters, terminate the synaptic signal.1
Investigators have identified several types of vesicular neurotransmitter transporters, including transporters for γ-amino butyric acid, glutamate, glycine, acetylcholine, and monoamines.3 Vesicular monoamine transporters (VMATs) are the primary mediators of the uptake and sequestration of monoamine neurotransmitters, including dopamine, serotonin, and histamine, in vesicles prior to subsequent Ca2+-stimulated exocytotic release.2,4 Defective or aberrant functioning of dopamine transporters or VMATs profoundly alters the intra- and extracellular concentrations of neurotransmitters.5
Monoaminergic neuronal dysfunction is associated with neurologic and psychiatric disorders such as Parkinson disease (PD), attention-deficit hyperactivity disorder, Huntington disease (HD), depression, and movement disorders.2,4,5 Two isoforms of VMAT exist in mammals, VMAT1 and 2, which are homologous members of the solute carrier 18 (SLC18) family of transporters, a subfamily of the major facilitator superfamily, and are encoded by separate genes.1,4,6 SLC18 is the largest family of secondary active membrane transporters, which includes antiporters, symporters, and uniporters.1 VMAT1 (SLC18A1) is expressed exclusively in neuroendocrine cells in the periphery, with expression reported in the sympathetic nervous system, adrenal chromaffin cells, and endocrine/paracrine cells of the gut.1,2,4 VMAT2 (SLC18A2) is expressed in monoaminergic neurons in the peripheral, central, and enteric nervous systems; notably, VMAT2 is expressed in all monoaminergic neurons of the brain.2,4 VMATs have similar structures and share common substrates, with the exception of histamine, which is packaged exclusively by VMAT2. VMAT2 also demonstrates higher affinity for catecholamines.7-9 In addition to its natural substrates, VMAT2 can transport certain drugs as "false" substrates; these drugs, such as amphetamine and methylenedioxymethamphetamine, can act as competitors to the natural neurotransmitter.3
VMATs have been shown to play a crucial role not only in sorting, storage, and release of neurotransmitters but also in modulating the neuronal and endocrine informational output.6 Given their critical functions in monoaminergic signaling pathways, VMATs have gained interest as potential therapeutic targets for modulating monoamine homeostasis in disorders characterized by disruption or aberrant functioning of monoaminergic systems.2,4
VMAT2 Pathway
VMAT2 is an acidic transmembrane glycoprotein, and primary amino acid sequence analyses predict the presence of 12 transmembrane domains, cytosolic C- and N-termini, and a large glycosylated intraluminal loop between the first and second transmembrane regions (Figure 1).2,6 The significance of VMAT2 in neuronal monoaminergic signaling is highlighted by the high degree of conservation of the VMAT2 amino acid sequence across mammals; VMAT2 protein exhibits 96% sequence homology between rats and mice and 92% sequence homology between rats and humans.5
VMAT2 is localized predominantly on small synaptic vesicles in the central nervous system, with some VMAT2 also detected in dense-core vesicles.2 On the synaptic vesicles of the presynaptic terminal, VMAT2 acts as a stoichiometric H+–ATPase antiporter, using the energy from ATP hydrolysis to transport H+ into vesicles, thereby creating an acidic environment inside the vesicle (Figure 2).2,6 This proton transfer generates the electrochemical gradient necessary for VMAT2-mediated monoamine transfer into vesicles.2,6 For every molecule of monoamine transported into the vesicular lumen, 2 protons are estimated to be transferred out of the vesicle and into the cytosol.6 The efflux of the first proton is proposed to facilitate a transporter conformation with a high-affinity amine-binding site in the cytosolic phase, whereas the efflux of the second proton is coupled with a conformational change that promotes amine transfer from the cytosol to the matrix, with a concomitant decrease in amine-binding affinity (Figure 2).6 Inhibition of VMAT2, such as with tetrabenazine (TBZ; Xenazine),10 deutetrabenazine (DTBZ; Austedo),11 or valbenazine (Ingrezza),12 preferentially blocks dopamine uptake into synaptic vesicles and depletes dopamine in the presynaptic terminal via cytosolic monoamine oxidase activity, essentially reducing monoamine storage and release (Figure 2).5,13,14
The Role of VMAT2 in Tardive Dyskinesia
As noted above, dysregulation of dopamine neurotransmission contributes to the pathogenesis of many nervous and psychiatric disorders, including PD, HD, and movement disorders.2,15 Dopaminergic hyperactivity has been linked to hyperkinetic movement disorders, such as tics, tremors, and chorea, whereas hypoactivity of dopaminergic signaling is associated with hypokinetic movement disorders, such as those in PD.2 VMAT2, given its role in presynaptic packaging, storage, and release of dopamine, has emerged as a promising target for therapeutic interventions to manage movement disorders. Indeed, VMAT2 inhibitors have been used for treatment of such disorders for many years and were available under a compassionate use, open-label protocol at a limited number of centers for over 30 years.14
In particular, VMAT2 inhibitors may be of use in treatment of tardive dyskinesia (TD) and movement-associated adverse effects (AEs) of antipsychotics and other dopamine receptor blockers.2,14 Indeed, following the regulatory approval of 2 VMAT2 inhibitors, dTBZ16 and valbenazine17 by the FDA, these agents are now considered the mainstay of treatment for TD.13 Targeting vesicular transporters, rather than receptors or plasma membrane transporters, offers some advantages; a review of the role of VMAT2 as a pharmacologic target states that "direct targeting of the vesicle, alone or in combination with existing therapies, may allow for modulation of neurotransmission while maintaining the proper kinetics of exocytotic [dopamine] release and termination of the signal," rather than allowing for temporary suppression of endogenous dopaminergic signaling, concomitant with increased risk of compensatory regulatory mechanisms.4
The tardive form of dyskinesia gets its name from the slow, or tardive, onset of involuntary hyperkinetic movements of the face, lips, tongue, trunk, and extremities.18,19 In TD, persistent iatrogenic movement disorders are evident secondary to exposure to dopamine receptor–blocking agents (DRBAs), such as antipsychotic medications, but also other medications, such as tricyclic antidepressants and antiemetics.13,19 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, defines TD as ''involuntary athetoid or choreiform movements (lasting at least a few weeks) generally of the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal, diaphragmatic, or trunk muscles) developing in association with the use of a neuroleptic medication for at least a few months.''20
Although the pathophysiology of TD has not been characterized completely, chronic blockade of dopamine receptors and resultant dopamine hypersensitivity are thought to underlie TD development.3,19 In a recent review,3 Stahl proposed a model for TD as an imbalance between the "stop" and "go" signals from the motor striatum (Figure 3).3 In this model, dopamine hypersensitivity leads to hyperinhibition of the stop signals from the upregulated dopamine-stimulated dopamine receptor 2 (D2), in conjunction with unopposed go signals, thus generating the hyperkinetic movements observed in TD.3 In this context, inhibition of VMAT2 lowers dopamine stimulation without blocking dopamine receptors, which has demonstrated efficacy in the short term for some patients with TD but at the expense of AEs and worsening of TD longer term.21 A model for VMAT2 inhibition–mediated modulation of both indirect (stop) and direct (go) signaling pathways to reduce involuntary hyperkinetic movements was described in the review by Stahl (Figure 3).3 Stahl noted that "VMAT2 inhibition can 'train' motor pathways of TD to compensate for their abnormal 'learning' after chronic D2 receptor blockade." The effect of VMAT2 inhibition on TD in the long term and its ability to treat TD rather than transiently reverse symptoms require further study, Stahl added.
VMAT Inhibitors
Three VMAT2 inhibitors have been described historically, the 2 naturally occurring alkaloids reserpine and lobeline and the synthetic compound TBZ.2 Unlike reserpine, TBZ is a VMAT2-selective reversible inhibitor that acts at a site that is distinct from the substrate-binding site of VMAT2.6,22 The inhibitor effect of TBZ on VMAT2 is significantly more potent than on VMAT1 (IC50 of 0.3 μM for VMAT2 vs 3.0 μM for VMAT1).22 Lobeline acts at the same site as TBZ to decrease amphetamine-evoked dopamine release, suggesting that lobeline selectively inhibits amphetamine effects; VMAT2 inhibition by lobeline has recently regenerated interest as a therapeutic strategy in treatment of psychostimulant abuse.2,22 Originally approved in 1958 for the treatment of neuroses and psychoses in schizophrenia, TBZ use subsequently became limited with the discovery of more efficacious DRBAs, like phenothiazines.23 In the past 2 decades, TBZ has been used in a multitude of movement disorders, including TD, dystonia, and tremor and tic disorders.23 A deuterated form of TBZ, dTBZ, and valbenazine are 2 other VMAT2 inhibitors of interest in the management of TD; the latter 2 have been approved by the FDA for the treatment of TD.14,16,17,24
High first-pass metabolism of TBZ generates the metabolites α-dihydrotetrabenazine (active) and β-dihydrotetrabenazine (biochemically inert), with 4- to 8-hour and 2- to 4-hour half-lives, respectively, requiring dosing 3 times daily.14 In dTBZ, deuterium atoms replace the hydrogen atoms on the 2 methoxy groups of TBZ. The carbon–deuterium bond undergoes oxidative metabolism approximately 10 times slower than the carbon–hydrogen bond, leading to slower degradation of the active metabolites and a longer half-life, without altering protein interactions; the longer half-life allows for twice-daily dosing.11,14,25 Valbenazine is metabolized more slowly than TBZ and dTBZ, with a half-life of 15 to 22 hours; valbenazine and its metabolites reach a steady state approximately 8 days after the initiation of medication.14
Utilizing VMAT2 Inhibitors
Valbenazine and dTBZ have been evaluated in several trials in patients with TD for efficacy and safety24; in contrast, despite support for efficacy of TBZ in TD from some studies, TBZ has not been formally studied for this indication, and TD is not listed on the package label.
The KINECT study included subjects with schizophrenia or schizoaffective disorder, with untreated neuroleptic-induced TD for at least 3 months, and receiving a stable dose of antipsychotic medication for a minimum of 30 days before the study's start, or with stable psychiatric status.24 The study had 3 treatment arms: placebo for 6 weeks; valbenazine (50 mg) daily for 6 weeks; or valbenazine (100 mg) daily for 2 weeks, followed by valbenazine (50 mg) daily for 4 weeks. The change in AIMS [Abnormal Involuntary Movement Scale] scores from baseline to 6 weeks did not differ significantly between the treatment and placebo groups when assessed by an on-site rater (–3.3 vs –2.5, respectively; P >.05), but an assessment by blinded central video rater found a significant difference (–3.3 vs –1.5, respectively; P = .03).24,26 In the KINECT extension study, a mean change of –5.8 on AIMS was observed, and 61% of patients were assessed to be "much improved" or "very much improved," according to their Clinical Global Impression–Tardive Dyskinesia (CGI-TD) score.27 The AIMS change from baseline differed significantly (–2.6 vs –0.2 least squares mean change; P =.0005) between the treatment and placebo groups in the KINECT 2 study, and 67% of valbenazine-treated patients were assessed as "very much improved" or "much improved" versus 16% of the placebo group (P <.0001), according to CGI-TD score.28 In the KINECT 3 study, patients received either placebo or valbenazine (40 mg or 80 mg daily); the data indicated a significant difference in degree of TD symptom reduction between the placebo group (AIMS score change at 6 weeks, –0.1) and both the 40-mg (AIMS change, –1.9; P =.002) and 80-mg valbenazine groups (AIMS change, –3.2; P <.001). Although the CGI-TD scores did not differ among groups, subgroup analyses suggested significant improvement in those subjects with detectable plasma levels of valbenazine at week 6.29 The KINECT 3 extension study found significant reductions in mean AIMS scores, as well as clinically significant improvements, as indicated by decreases in CGI-TD and Patient Global Impression of Change scores, in both the 40-mg and 80-mg treatment groups.30 A more recent pooled, ad hoc analysis of data from the long-term exposure population of the KINECT, KINECT 3, and KINECT 4 studies indicated that valbenazine was well tolerated in adults with TD who received up to 48 weeks of treatment.31
The ARM-TD study demonstrated an improvement in AIMS score of 3.0 points for the dTBZ group versus 1.6 points for placebo (P = .019), with an average baseline score of 9.6 in both groups. Incidence of AEs, including psychiatric AEs, was comparable between the placebo and dTBZ arms of the study.32 In the AIM-TD study, at 12 weeks, the AIMS score improvements ranged from 2.1 points (in the 12-mg/day dTBZ group) to 3.2 and 3.3 (in the 24-mg/day and 36-mg/day dTBZ groups, respectively) versus 1.4 points in the placebo group, constituting a statistically significant net reduction (22%-34%) in AIMS score (baseline scores, 9.4-10.1) in the 36-mg/day and 24-mg/day groups but not in the 12-mg/day group.33 AEs occurred at a rate comparable with those for placebo.
Taken together, these studies indicate that dTBZ and especially valbenazine are effective in TD management, even against the background of continuation of baseline neuroleptics or underlying psychiatric diagnosis of schizophrenia/schizoaffective disorder or mood disorder.14,24,34 Consideration for selection of a specific VMAT2 inhibitor would include ease of administration and compliance, as well as the differing metabolic pathways, which may impinge on additional effects on dopaminergic/serotonergic receptors.14 In the latter context, valbenazine, because of its selectivity for VMAT2, may reduce the risk of monoamine deficiency syndrome, with symptoms including irritability, anxiety, apathy, somnolence, and cognitive slowing, which have been described with long-term use of psychiatric medications.14,35 Also, although the recommended dosing of TBZ is 3 times per day, dTBZ is dosed twice per day and valbenazine only once per day; in practical terms, the once-daily dosage with valbenazine may offer advantages in medication adherence and ease of use from a patient perspective.
On the other hand, although TBZ and dTBZ doses can be titrated in small increments relative to their maximal dose, only 2 dosage strengths for valbenazine (40 mg and 80 mg) are available currently, with 80 mg being the maximum recommended dose.14 In general, dTBZ and valbenazine have more favorable AE profiles than TBZ, likely relating to their improved pharmacokinetic profiles.
To date, 3 VMAT2 inhibitors have gained regulatory approval in the United States; a recent review noted that the "prescribing environment [of VMAT2 inhibitors] is actively changing" because of expansion of indications for these agents in neuropsychiatric disorders and the more favorable AE profiles of dTBZ and valbenazine.14 These advantages may help counterbalance their limited use in the past due to the high cost of medication along with limited familiarity with VMAT2 inhibitors outside specialized movement disorder centers, noted the authors.14 The authors anticipated expansion of VMAT2 inhibitors in management of Tourette syndrome symptoms, especially "in late adolescent or adult patients where the development of TD with ongoing DRBD [dopamine receptor–blocking drug] use is of particular concern."14 The development of VMAT2 inhibitors represents an important advancement in treatment of movement disorders. With additional data from long-term studies of this class of drugs in representative patient populations,36 clinical evidence from real-world utilization and comparisons of VMAT2 inhibitors,35,36 an increased understanding of the genetic and pathophysiological underpinnings of TD development,37,38 and improved awareness of TD in patients receiving DRBAs and its appropriate management with VMAT2 inhibitors, the path to management of TD is being paved for the future.
1. Yaffe D, Forrest LR, Schuldiner S. The ins and outs of vesicular monoamine transporters. J Gen Physiol. 2018;150(5):671-682. doi: 10.1085/jgp.201711980.
2. Harriott ND, Williams JP, Smith EB, Bozigian HP, Grigoriadis DE. VMAT2 inhibitors and the path to Ingrezza (valbenazine). Prog Med Chem. 2018;57(1):87-111. doi: 10.1016/bs.pmch.2017.12.002.
3. Stahl SM. Mechanism of action of vesicular monoamine transporter 2 (VMAT2) inhibitors in tardive dyskinesia: reducing dopamine leads to less "go" and more "stop" from the motor striatum for robust therapeutic effects. CNS Spectr. 2018;23(1):1-6. doi: 10.1017/S1092852917000621.
4. Bernstein AI, Stout KA, Miller GW. The vesicular monoamine transporter 2: an underexplored pharmacological target. Neurochem Int. 2014;73:89-97. doi: 10.1016/j.neuint.2013.12.003.
5. German CL, Baladi MG, McFadden LM, Hanson GR, Fleckenstein AE. Regulation of the dopamine and vesicular monoamine transporters: pharmacological targets and implications for disease. Pharmacol Rev. 2015;67(4):1005-1024. doi: 10.1124/pr.114.010397.
6. Wimalasena K. Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Med Res Rev. 2011;31(4):483-519. doi: 10.1002/med.20187.
7. Peter D, Jimenez J, Liu Y, Kim J, Edwards RH. The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J Biol Chem. 1994;269(10):7231-7237.
8. Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci U S A. 1996;93(10):5166-5171. doi: 10.1073/pnas.93.10.5166.
9. Schafer MK-H, Weihe E, Eiden LE. Localization and expression of VMAT2 [across] mammalian species: a translational guide for its visualization and targeting in health and disease. Adv Pharmacol. 2013;68:319-334. doi: 10.1016/B978-0-12-411512-5.00015-4.
10. Xenazine (tetrabenazine) [package insert]. Deerfield, IL: Valeant Pharmaceuticals North America LLC/Lundbeck; 2018. lundbeck.com/upload/us/files/pdf/Products/Xenazine_PI_US_EN.pdf. Accessed May 1, 2019.
11. Austedo (deutetrabenazine) [package insert]. North Wales, PA: Teva Pharmaceuticals USA; 2017. austedo.com/globalassets/austedo/prescribing-information.pdf. Accessed May 1, 2019.
12. Ingrezza (valbenazine) [package insert]. San Diego, CA: Neurocrine Biosciences; 2018. ingrezza.com/PI. Accessed May 1, 2019.
13. Niemann N, Jankovic J. Treatment of tardive dyskinesia: a general overview with focus on the vesicular monoamine transporter 2 inhibitors [erratum in Drugs. 2018;78(5):609. doi: 10.1007/s40265-018-0893-7]. Drugs. 2018;78(5):525-541.
14. Tarakad A, Jimenez-Shahed J. VMAT2 inhibitors in neuropsychiatric disorders. CNS Drugs. 2018;32(12):1131-1144. doi: 10.1007/s40265-018-0874-x.
15. Dickey AS, La Spada AR. Therapy development in Huntington disease: from current strategies to emerging opportunities. Am J Med Genet A. 2018;176(4):842-861. doi: 10.1002/ajmg.a.38494.
16. FDA OKs deutetrabenazine (Austedo) for tardive dyskinesia. Medscape website. medscape.com/viewarticle/885051. Accessed May 2, 2019.
17. FDA approves first drug to treat tardive dyskinesia [news release]. Silver Spring, MD: FDA; April 11, 2017; www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-tardive-dyskinesia. Accessed May 2, 2019.
18. Cornett EM, Novitch M, Kaye AD, Kata V, Kaye AM. Medication-induced tardive dyskinesia: a review and update. Ochsner J. 2017;17(2):162-174.
19. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (N Y). 2013;3. doi: 10.7916/D88P5Z71.
20. American Psychiatric Association. Medication-induced movement disorders and other adverse effects of medication. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. DSM Library; 2013.
21. Caroff SN, Campbell EC. Drug-induced extrapyramidal syndromes: implications for contemporary practice. Psychiatr Clin North Am. 2016;39(3):391-411. doi: 10.1016/j.psc.2016.04.003.
22. Lohr KM, Masoud ST, Salahpour A, Miller GW. Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur J Neurosci. 2017;45(1):20-33. doi: 10.1111/ejn.13357.
23. Paleacu D. Tetrabenazine in the treatment of Huntington's disease. Neuropsychiatr Dis Treat. 2007;3(5):545-551.
24. Touma KTB, Scarff JR. Valbenazine and deutetrabenazine for tardive dyskinesia. Innov Clin Neurosci. 2018;15(5-6):13-16.
25. Dean M, Sung VW. Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease. Drug Des Devel Ther. 2018;12:313-319. doi: 10.2147/DDDT.S138828.
26. Müller T. Valbenazine for the treatment of tardive dyskinesia. Expert Rev Neurother. 2017;17(12):1135-1144. doi: 10.1080/14737175.2017.1386556.
27. Jimenez R, Shiwach R, Bari M, O'Brien C. Twelve-week treatment of tardive dyskinesia with NBI-98854. Mov Disord. 2014;29:304-305.
28. O'Brien CF, Jimenez R, Hauser RA, et al. NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: a randomized, double-blind, placebo-controlled study. Mov Disord. 2015;30(12):1681-1687. doi: 10.1002/mds.26330.
29. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484. doi: 10.1176/appi.ajp.2017.16091037.
30. Factor SA, Remington G, Comella CL, et al. The effects of valbenazine in participants with tardive dyskinesia: results of the 1-year KINECT 3 extension study. J Clin Psychiatry. 2017;78(9):1344-1350. doi: 10.4088/JCP.17m11777.
31. Josiassen RC, Kane JM, Liang GS, Burke J, O'Brien CF. Long-term safety and tolerability of valbenazine (NBI-98854) in subjects with tardive dyskinesia and a diagnosis of schizophrenia or mood disorder. Psychopharmacol Bull. 2017;47(3):61-68.
32. Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: the ARM-TD study. Neurology. 2017;88(21):2003-2010. doi: 10.1212/WNL.0000000000003960.
33. Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017;4(8):595-604. doi: 10.1016/S2215-0366(17)30236-5.
34. Citrome L. Valbenazine for tardive dyskinesia: a systematic review of the efficacy and safety profile for this newly approved novel medication—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2017;71(7). doi: 10.1111/ijcp.12964.
35. Niemann N, Jankovic J. Real-world experience with VMAT2 inhibitors. Clin Neuropharmacol. 2019;42(2):37-41. doi: 10.1097/WNF.0000000000000326.
36. Caroff SN, Aggarwal S, Yonan C. Treatment of tardive dyskinesia with tetrabenazine or valbenazine: a systematic review. J Comp Eff Res. 2018;7(2):135-148. doi: 10.2217/cer-2017-0065.
37. Zai CC, Maes MS, Tiwari AK, Zai GC, Remington G, Kennedy JL. Genetics of tardive dyskinesia: Promising leads and ways forward. J Neurol Sci. 2018;389:28-34. doi: 10.1016/j.jns.2018.02.011.
38. Zai CC, Lee FH, Tiwari AK, et al. Investigation of the HSPG2 gene in tardive dyskinesia - new data and meta-analysis. Front Pharmacol. 2018;9:974. doi: 10.3389/fphar.2018.00974.
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Q: Detect orientation in reverse landscape and portrait mode I want to detect reverse landscape and portrait orientation. Configuration does not support  ORIENTATION_REVERSE_LANDSCAPE or ORIENTATION_REVERSE_PORTRAIT.
I have also tried Activityinfo.ORIENTATION_REVERSE_PORTRAIT but it's also not working.help me.
if(newConfig.orientation==Configuration.ORIENTATION_LANDSCAPE){

    Log.e("On Config Change","LANDSCAPE");
}else{

    Log.e("On Config Change","PORTRAIT");
}

A: I found that if your device has a magnetometer you can differentiate between landscape and reverse landscape by calculating the rotational attitude of the device (azimuth, pitch, and roll) using the SensorManager methods getRotationMatrix() and getOrientation().  If the roll is positive, you're in reverse landscape (landscape right), and if the roll is negative you're in landscape (landscape left).
Similarly, you can use the pitch to differentiate between portrait and reverse portrait.  If the pitch is positive, you're in reverse portrait, and if the pitch is negative you're in portrait.
If your device doesn't have a magnetometer, you can use the x-axis and y-axis values of the accelerometer to differentiate between landscape and reverse landscape.  A negative x-axis value indicates reverse landscape (landscape right), and a positive value indicates landscape.  Similarly, a negative y-axis value indicates reverse portrait, and a positive y-axis value indicates portrait.

redpajama_set_name: RedPajamaStackExchange


The 2014 Quadrantids, a little-known meteor shower named after an extinct constellation, will present an excellent chance for hardy souls to start the year off with some late-night meteor watching.
Peaking in the wee morning hours of January 3, the Quadrantids have a maximum rate of about 80 per hour, varying between 60-200. The recent New Moon will set around 8:30 p.m. local time, leaving excellent meteor observing before dawn. It's a good thing, too, because unlike the more famous Perseid and Geminid meteor showers, the Quadrantids only last a few hours -- it's the morning of January 3, or nothing.
Like the Geminids, the Quadrantids originate from an asteroid, called 2003 EH1. Dynamical studies suggest that this body could very well be a piece of a comet which broke apart several centuries ago, and that the meteors you will see before dawn on January 3 are the small debris from this fragmentation. After hundreds of years orbiting the sun, they will enter our atmosphere at 90,000 mph, burning up 50 miles above Earth's surface -- a fiery end to a long journey!
A live video feed of the Quadrantid meteor shower is embedded below and will begin approximately at 6 p.m. EST. The camera is mounted at NASA's Marshall Space Flight Center in Huntsville, Ala.


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Save é a povoação sede do posto administrativo de Save, localizado a sul do distrito de Machaze, província de Manica, Moçambique. Contém quatro localidades: Save, Mavende, Sambassoca e Mevissanga.

Bibliografia

Distritos de Moçambique
Postos administrativos de Moçambique


•	Lorazepam – for anxiety; 0.5mg at night to help me sleep. I've been looking into magnesium as a natural way to calm down, and get me off this med. I've tried weaning myself off, but the result is poor sleep.
It's a benzo in the Valium class – it's a personal decision. Most would say get off the sleep meds but, from my experience extreme insomnia is far from a healing atmosphere.
•	Progesterone SR – 50mg at night. I had my hormone levels tested a few months ago by my doctor, and progesterone and testosterone were low. I know that increased progesterone can contribute to vaginal yeast infections.
•	Testosterone Cream – 0.5mL applied topically at night.
•	Allergy shots: 2 shots weekly; I don't know what is in the allergy shots, but I know that they are very small levels of the things I tested allergic to, like weeds, grasses, pollens from wheat, corn, and some trees, and molds. I'm going to call my allergist's office tomorrow to get more specifics.
If you ARE NOT ALLERGIC to bee stings, bee pollen – particularly local bee pollen from around where you live helps with allergies. It's what the bee brings back from the flowers to the nest on it's legs after going flower to flower. I just take a little pinch under my tongue and let it dissolve while trying not to swallow but spit out the bee pollen saliva and rinse my mouth out to limit as much as possible the sugars from getting into the GI track….the pollen gets absorbed sub-lingual. It's also a great source of pantothenic acid.
I'll let the forum experts respond to your list of vits but, I can say right off the top you should consider increasing your Vit C levels MUCH higher: like between 5,000mgs to 8,000mgs per day. Studies have proven your body absorbs and needs much more vit C when ill, then when healthy. I'm at around 8,000 + MGS per day and haven't reached GI tolerance (you'll know what that is when it hits). A nurse at a clinic I used to volunteer with 2- years ago told me once as soon as she starts to feel sick, she increases vit C till she get's "the squirts" and then backs off from there to figure out what level her body needed.
Your supplement list is much smaller than mine, that's for sure but, I've been so mal nourished for so long, I feel my body needs it. Though, Able thinks I'm wasting my money but, he's got knowledge of how to balance out vits, particularly the B's which I don't so, rather than try to learn all that know on my own, I figure the good vits companies know what they are doing better than I do….I'm over 24 bottles of vits/mins per day, some I take only one capsule per day, others I take up to 9 per day: depending on what vit/min. Also, I buy into how vits/mins work as co-factors to each other: another topic too complicated for me to try to unravel at this juncture.


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How Cannabinoids Work: Part IV – Physiological Conditions
Itzhak Kurek, Ph.D. ∙ April 22, 2019 11:55 am PDT |
Whether they know it, anyone who has ever consumed cannabis has sparked an interaction between cannabinoids and a network of receptors in the human body. But even the most seasoned cannabis connoisseur might not know how the relationship involving the plant's compounds and our cannabinoid receptors actually works. And, moreover, what physiological conditions affect the experience of each cannabis consumer?
In the first three installments of our "How Cannabinoids Work" series …
Part I — Paths into the Body
Part II — Paths Through the Body
Part III — Metabolism and Elimination
… we described the various paths and fates of cannabis molecules. Product, consumption method, metabolism, and the body's detoxification processes all affect bioavailability, the portion of the active ingredient that affects our bodies.
There are also three other factors that affect this interaction:
The entourage effect
The levels of the internal messengers that bind to the cannabinoid receptors (endocannabinoids)
The availability of cannabinoid receptors
The Entourage Effect (No, Not the HBO Series)
The entourage effect is the synergistic effect of cannabis molecules in the body. It was first described by cannabis researchers Dr. Shimon Ben-Shabat and Dr. Raphael Mechoulam in a 1998 study that found a significant increase in activity of endocannabinoids in the presence of several newly identified molecules that seemed inactive. In fact, the endocannabinoids were active alone. With all the entourage of cannabinoids in tow, the endocannabinoids were highly active. In their study, Ben-Shabat and Mechoulam posited about the entourage effect: "[t]his type of synergism may play a role in the widely held (but not experimentally based) view that in some cases plants are better drugs than the natural products isolated from them." The researchers concluded that further research was needed to fully describe these effects.
Photo by bshamblen via Flickr
In a 2011 study published in the British Journal of Pharmacology, Dr. Ethan B. Russo of GW Pharmaceuticals observed how synergy between active and inactive ingredients in cannabis might work, identifying four ways in which they might affect things:
Interacting with multiple targets simultaneously
Making cannabinoids more bioavailable or soluble
Having an anti-bacterial impact; and
Controlling side effects, including psychoactive effects
These inactive – but evidently still effective – components not only impact the inhibition of the Cytochrome P450 enzymes, as were discussed in Part III, but also the body's greater physiological response.
Internal Messengers and the Competition Between Them them
The human body produces the endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG), both of which naturally bind to the cannabinoid receptors CB1 and CB2 to regulate functions involved in stress, appetite, sleep, the immune system, reproduction, energy balance, and metabolism. Cannabinoids, such as the commonly recognized THC, tetrahydrocannabivarin (THCV), and cannabidiol (CBD) compete with AEA and 2-AG for the same receptors.
In general, there are three types of interactions that take place with the CB1 receptor:
Agonist reactions bind with a receptor to excite or increase a response
Antagonist reactions inhibit a response by preventing the agonist from binding
Inverse agonist reactions also inhibit a response, but do so by binding to the receptor and doing the opposite of whatever the antagonist was going to do.
Within all the cannabinoids naturally found in cannabis, only THC and THCV bind more strongly to the CB1 receptor than AEA and 2-AG. THC acts as a partial or full agonist, depending on the tissue and organ, and THCV as an antagonist.
While CBD binds poorly to the CB1 receptor, this compound can still block THC by occupying the receptor and preventing the binding of THC or AEA and 2-AG.
Under different physiological conditions in the same person, the body may generate different amounts of AEA and 2-AG. Stress, diet, pain and other factors may increase AEA, potentially altering outcomes even when the same product and dosage are consumed. For instance, after a 12-day restriction diet, 2-AG levels will significantly decrease in the brain, while a 24-hour starvation significantly increases 2-AG levels. It's likely that a person who is starving will need different amounts of cannabis to replicate the effect obtained by someone on a normal diet.
Elevated levels of AEA in athletes may play a role in physiological and mental conditions such as pain relief, sedation, anxiety inhibition and the phenomenon known as the "runner's high," which has been reported as similar to the effect of THC consumption. In a study, 50 minutes of treadmill or stationary bicycle at 70–80% of maximum heart rate resulted in a significant increase of AEA and 2-AG in the blood tested immediately at the end of training. The direct impact of exercising on cannabis consumption was demonstrated in a two-week moderate exercise program for cannabis-dependent adults. The researchers found that cannabis cravings decreased during the exercise period, but increased once exercise was stopped.
Availability of Receptors
Changes in cannabinoid receptors can also affect the response caused by cannabinoids. A greater number of cannabinoid receptors can increase the potency and efficacy of treatment with THC or with a combination of THC, CBD, and terpenes.
In a 1993 study published in Neuroscience, researchers first reported a significant decrease in the levels of CB1 receptors in the midbrain area of patients who were suffering from Huntington's disease, meaning cannabis treatment may be less effective for these patients. In contrast, individuals who had neuropathic pain had an increased number of CB1 receptors, potentially allowing a better response to cannabinoid treatment. Similarly, individuals with certain forms of cancer, epilepsy, and schizophrenia also demonstrated a similarly significant increase in CB1 receptors, suggesting a need for further research on medical cannabis treatment for these conditions.
While the entourage effect is dependent on the chemical composition of the product consumed, the levels of endocannabinoids and the availability of the CB1 receptor is also affected by an individual's lifestyle and medical condition.
This series on "How Cannabinoids Work" has provided a biochemical perspective on the complexity that medical cannabis consumers are constantly facing. The questions of "What?" "How?" "How much?" and "When?" are all interconnected, and the answer varies from one individual to another. Even the same individual may require different products and dosages on different occasions.
Ultimately, approaches for individualizing medical cannabis treatment like pharmacometabolomics and precision medicine may hold the greatest promise for finding the best match of product and dosage for each individual.
Itzhak Kurek, Ph.D.
Itzhak Kurek, Ph.D., is the CEO and co-founder of Cannformatics Inc. He has 25 years of experience in biochemistry and molecular biology, specializing in plant photosynthesis, yield enhancement, metabolism and cellulose biosynthesis. He received his Ph.D. in plant sciences from Tel Aviv University in Israel and completed his postdoctoral research at the University of California, Davis. He has also conducted research at the Technical University of Munich in Germany; John Innes Center in Norwich, England; the National Center for Scientific Research (CNRS) in Bordeaux, France; and the Lawrence Berkeley National Laboratories in California.
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A really bad film can be a glorious thing. When early reactions started emanating about Diana, the possibility that it could be a camp disaster on the level of Mommie Dearest or Showgirls revealed itself. Alas, there is no flair or pomp to Diana's terribleness – it's bad in the blandest way possible. Bad bad, not good bad.
I've been describing the experience as the cinematic equivalent of flipping through an old issue of celebrity tabloid rag Hello! – there are some moderately attractive people and furnishings to behold, but the entire enterprise smacks of pointlessness.
The film focuses on the relationship between Diana (Naomi Watts) and Dr Hasnat Khan, the Pakistani surgeon played by Naveen Andrews (Lost). There is a fatal lack of chemistry between the pair and Diana comes off as a shrill, demanding, er, princess for the most part. Watts is let down by the Mills & Boon-level script, and I couldn't stop wondering how the originally-cast (and more age-appropriate) Jessica Chastain might've done in the role.
If the whole project didn't stink of tastelessness to begin with, Diana suffers considerably when compared to its obvious tonal inspiration – 2006's The Queen. Attempts to lend this story any meaning or authenticity fail completely, and all we're left with is a raggedy sub-Notting Hill dynamic that sees Diana sneaking around with her secret lover.
If you absolutely must see this film, wait until you can do so at home with a bunch of friends and plenty of wine.


Creative Development Partners submitted a formal appeal to the staff recommendation prior to the CED Committee meeting based on process and substantive issues related to the selection of a developer for the Oakland Auditorium. While we were strongly discouraged to submit an appeal by the director of Contract Compliance, we felt that the stakes were high enough for the future of development in Oakland, that we must ensure that the City of Oakland uphold the Mayor's stated pledge to an open and transparent government, along with pursuing viable and equitable economic development opportunities and demonstrating a commitment to the participation of ALL of Oakland's residents.
We do not believe that putting the citizen's trust in a TBD strategy, over a comprehensive and well developed approach is reasonable, responsible, nor responsive to the needs of the average Oakland citizen. CDP has assembled a highly credible development team, put forth a detailed plan, attracted an impressive amount of capital and garnered the support of many of the major cultural and community organizations as partners in progress. Our approach respects the past while participating in Oakland's future in a manner that embraces our core tenet -- community benefit by design, not by negotiation.
Oakland desperately needs hotel rooms, economic stimulus, training opportunities and jobs, and we deliver that. Contrary to the position of the historic preservation NIMBY contingent, there is no better site for an thoughtfully placed arts-integrated hotel than next to an existing convention center and museum. Further, the Oakland Auditorium Arena is unique in the mid-size venue market, and re-purposing the arena would not only destroy a significant part of Oakland's history, but also send the message that Oakland was closed for business -- take your convention, meeting and special event business elsewhere.
● Review panel was misaligned with the RFP criterion, and lacked key expertise and representation from the arts community, economic, community and workforce development.
● Activist panelist, Naomi Schiff, was unable to be impartial or objective in her evaluation of the CDP proposal, based on long prior-stated opposition to the hotel development siting, which was disclosed prior to the panel and should have been cause for disqualification.
● Published review process was inconsistent with the actual review process.
CDP and its development partners have secured commitments of of $66 million toward the project and a letter of interest for another $70 million from our bond financing partner. In addition, we have standing relationships with other financing entities that are very interested in supporting our team to secure additional funds, relieving all doubt of CDP's financial capacity. The competing proposal's total budget for re-purposing the building is $52 million, with $5 million dollars in equity proposed.
While the financing structure is complex, it is not at all uncommon based on the nature of the project and the goal to include a range of stakeholders. The team has completed similar deals and the investors are all very confident in CDP's ability to successfully execute. The recommendation mentions philanthropy multiple times, giving the impression that CDP would be writing grants to help fund this project, when in fact, $10-$20 million in INVESTMENTS from philanthropic institutions will be secured to create a sustainable platform for community benefits.
Our development team, a joint venture, was highly under-valued and under-scored in the review in terms of experience, and has excess capacity to successfully complete this project- specifically in hotel development, management and investment. Furthermore, the local team of architects, engineers and contractors matches or exceeds the competition in skill and experience.
CDP's embedded training and employment program, 1LM Works, is supported by an impressive continuum of educational institutions, along with organized labor organizations including UNITE HERE 2850, Alameda County Building Trades and IATSE 107. With 1LM Works, we've identified a market-rate solution to solve a community-based problem, which creates a self-sustaining program. Additionally, our deep green development strategy, integration with neighboring institutions, community partnerships and cultural arts programming far outpaces our competition and anything that Oakland has ever seen.
In addition to significantly more permanent jobs than projected in the City's RFP, the new tax revenue that our project will produce from the hotel and event center, with the arena preserved for a full range of large concerts, sports and conventions, is $5.1 million, which far surpasses the projections anticipated by the City. Additionally, our jobs are career and union-track jobs in a variety of mid-to-high-range industries, not just retail and foodservice, which are not considered "good" jobs.
Our partnership with the Peralta Community College District and specifically Laney and Merritt Colleges, is a long-standing and deep relationship that will integrate One Lake Merritt physically and programmatically. We have an MOU with the Chancellor and the two Oakland campus Presidents, that will integrate six (6) core Career Technical Education programs, along with a facility sharing agreement for additional meeting space and use of the 1,000 parking spaces at Laney College. The physical and programmatic integration with Laney College far exceeds that put forth by the competing proposal.
The recommendation suggests that a hotel was not contemplated for the site and is incompatible with the Lake Merritt Specific Area Plan, posing an entitlement risk, while in fact, the EIR for the Lake Merritt Specific Area Plan refers specifically to a "boutique hotel somewhere in the Lake Merritt Station planning area, which this building falls within. There's no specific reason from a planning perspective, then, that said the EIR couldn't accommodate our proposed hotel, as the plan's own economic study said 400 rooms are supportable within the study area.
● Based on the City's stated goal to get this extremely important historic landmark open and alive again, and to bring activity on the weekend and evening in this part of the city is a major priority, CDP's proposal accomplishes this is much less time.
CDP has a simpler, phased development strategy, with the HJKCC redevelopment coming first, which will get the building open and active faster than the competition's plan to redevelop the interior arena space as office and retail. After getting the major systems in order, CDP will immediately open and activate the space, while continuing with upgrades. The competition's plan drastically and permanently alters the original (and historic) use of the arena and, from a preservation standpoint, there is a significant loss of the historic fabric of Oakland through a concept that builds-out the arena with interstitial floors and converts into private office space instead of maintaining its original use and re-engaging into the public sphere.


text:
Judge Salley Huggins McIntyre
Judge Salley Huggins McIntyre was born in Florence, South Carolina in 1969. She is the daughter of the late Lacy Carl Huggins and Jean Daniel Huggins Berry.
In 1991, Judge McIntyre received a Bachelor of Arts degree in Accounting from the University of South Carolina. She obtained her Juris Doctorate degree from the University of South Carolina School of Law in 1995.
Upon graduation from law school, she served as a law clerk to the Honorable James E. Lockemy for one year prior to entering into private practice with the firm Greene & Bailey. She later became partner at Greene & Huggins in 1996, where she remained until her election to the family court bench by the South Carolina General Assembly in May 2011.
Judge McIntyre has extensive civic and volunteer experience. She has served as a member of the Dillon County Bar, Welvista Pee Dee Advisory Board, the South Carolina Paralegal Task Force, the South Carolina Young Lawyers Division, the Human Rights Committee of the Marion/Dillon Board of Disabilities and Special Needs, the Dillon Junior Charity League, the Dillon County Communities in Schools and the Dillon County Economic Development Partnership. She has chaired the Gordon Elementary and South Elementary School Improvement Councils, Walk America, the Dillon County March of Dimes, the Main Street United Methodist Church Board of Trustees and Endowment Fund, and has served as President of the Dillon County Bar Association. She has also served as Pro Bono Attorney for the Dillon County Guardian ad Litem Program, the South Carolina Bar, and served as Pro Bono Probate Court Judge for Dillon County. In addition to serving as Mayor for the City of Dillon from 1999-2003, Judge McIntyre was voted Dillon County's Best Lawyer in 2008, received the Elected Official Honor Award for Leadership and Dedication in the Field of Historic Preservation and won the Young Career Woman award.
A member of Main Street United Methodist Church, Judge McIntyre is married to Marty McIntyre. They have four children, Davis, Mattie, Lacy, and Jasper.
The Honorable Salley Huggins McIntyre
1033 Old Latta Highway
Dillon, SC 29536
Admin Assistant: Robin Scott


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text:
"The gratest unsuccessful band ever"
-Guie Rossini, from his landmark Youtube comment
referencing a HORSE the band performance
at the "With Full Force" metal festival,
somewhere in Germany, in 2010
The gratest unsuccessful band ever.
Living at the top.
It's lonely up here.
Always expecting someone to "climb that mountain" and "Throw it in".
To join you. To usurp you. But no. . .
We have no peers.
We are lonely.
We participated in KONY 2012, and a Color Run.
We felt lonely.
We did a Reddit AMA.
We still felt lonely.
We watched every TED talk ever. We joined Tinder.
We still felt, deep down, a fear of an overwhelming and instinctual confirmation of the reality of our intellectual isolation.
However, this time, instead of turning to the time-tested remedies for this sort of silly feeling (namely: women of the highest order, bridge burning, Niacin, China, animals, big numbers). . .
. . .we started a fully decentralized, open-source community and, aside from following the harm principle, instituted a fully anarchic society on a remote, previously uninhabited island (featured on BoingBoing and by invite only on reddit.com). We installed fiberoptic Internet and created a wiki. We had high hopes as this was the first time such a thing had been done since the existence of the Internet and Computers (aka the first time humans have been capable of doing anything / have ever had ideas). We video taped every interaction and discarded the idea of intellectual property, spending our days rating the most trivial and commonplace activities of others, throwing privacy out the window in the name of progress and utopia, and uploading everything to the big data on THE SERVER. We ate ghee from cows who roamed freely on land that had not been fracked, cows who exclusively ate quickly-growing grasses. We neglected to take Niacin. Everything was absolutely perfect and Bitcoin ended all of society's woes. Having invested in both gold and Bitcoin we were very rich, however, we had nothing to spend our money on except self-help central-metaphor business organizational books from the Mainland. One night out of sheer boredom, we initiated a massive Bitcoin transaction to purchase every physical and digital copy of every central metaphor business/self help book that had ever been written, with the intent to create a fecal ziggurat out of the books and our own waste (since we had no sewers) in the center of our island and ignite it after having a weeklong party in which any member could join a special "coterie" and MOD THE SHIT out of anything: we called it The Fecal Ziggurat: pure anarchy and humanity! That transaction may or may not have done harm to a transgender-aligned-however-not-actually-transgender member of our society who had invested heavily in "wearable technology" as well as "health apps". As the technological industry fell apart on the Mainland due to the lack of any guiding business principles and career development based on sports metaphor, the member of society fell into destitution and began to sell their body to children. Their rating settled on an exact 2.5 out of 5 stars, and no one was sure whether or not to transact with them. It was unclear whether the harm principle was being violated, or the violated were being harmed? We hadn't actually thought about that . . . huh. Anyway, the entire community began watching the video feed of this individual and forgot to rate other transactions. Our whole rating system fell to shit, as we realized an Account Manager from Yelp.com had moved in and had rigged the system in exchange for counterfeit Bitcoin credits. An angry Bitcoin miner, who had spent his entire physical life setting up powerful supercomputers to mine Bitcoins but had not found any, killed the Account Manager from yelp.com and although according to the harm principle it should not have, his rating mysteriously spiked. It didn't feel right. We had lost our belief in the silver bullet to cure society's failings through the Internet by abstracting and depersonalizing human interactions, making ideas worthless, and ignoring a human being's need for privacy out of wrongly applying our own personality traits to every single human being on the planet! as well as decentralized open source anarchy founded on a paleolithic diet allowed only by great advances in technology. We tried to go into THE SOURCE CODE, which was open and we thought SOMEONE would have fixed by then, but realized only 2 of us knew what it said or actually did. We got into a fight over how to edit the source code in the comments of the revision history - a real FLAMEWAR that made it onto the front page of reddit.com (which was so cool), it was unclear if the harm principle was really being violated as one of the dudes was a pretty big doucher, and eventually both of ours "DEVS" lost interest and started to masturbate in their units instead of looking at the SOURCE CODE. Everyone knew what had happened but the actual act was occurring in a corner where the camera could not capture the "deed" IYKWIM, LOL, thus there was no proof. Things crumbled quickly after that. Eventually our beautiful, first-ever group of "people who had the Internet" needed a scapegoat for not being able to "make everything in the world perfect according to one person's point of view of how things should be". Our ratings went down quickly and before long we had been ostracized from our own society, not even able to buy a can of sardines as disgusted vendors saw our low rating on their Google Glasses just as we were trying to email them some Bitcoins. As Proudhonian Mutualists, collective action against us was called for. Gary Lachance was executed by a dispute resolution organization (or DRO, for short - not to be mistaken for the police) that mediates disputes / issues. We were banished from the island. We arrived on the Mainland, which was in FUCKING DISARRAY. The governments were trampling on people's rights and freedoms (LIKE ALWAYS LOL), we were mortified at the harms done to us driving on the roads, drinking the (fluoridated!) water, and seeing the children in schools. One Reddit AMA later, our Bitcoin account was hacked by some fucking dweeb from Romania, FUCK him, and all our money was gone. We decided to go back to the only thing that works in this life.
Niacin.
Burning bridges.
Women of the highest order.
Doing Activities.
Mocking the very people who help us survive.
Being in The Loft of a European Sprinter Van.
Misery.
Big numbers.
We are going to play some shows. In Europe. And, more importantly, Russia.
EXPECT:
THE HIGHEST OF HIGHS
THE LOWEST OF LOWS
A REAL NICE TRIP
Aug 02	Saarbrucken, Germany - Kleiner Club Garage
Aug 03	London, UK - The Borderline
Aug 04	Paris, France - Batofar
Aug 05	Stuttgart, Germany - Juha West
Aug 06	Munchen, Germany - Backstage
Aug 07	Wiesbaden, Germany - SCHLACHTHOF
Aug 08	Hamburg, Germany - Hafenklang
Aug 09	Ieper, Belgium - Ieperfest
Aug 10	Dusseldorf, Germany - Cube
Aug 11	Berlin, Germany - Magnet
Aug 12	Moscow, Russian Federation - Plan B
Aug 13	St. Petersburg, Russian Federation - Dusche


Digital Scrapbooking Designs: Why do I love Scrapbooking ?
Why do I love Scrapbooking ?
When my ex husband announced that his employer wanted to send him to New York as a financial analyst for 2 years, a strange mix of feelings overcame me.
I started to contemplate the realities of moving Rocío, our 10-month-old daughter, to another country, of adjusting to life and work abroad, and of becoming a trailing partner who was leaving behind her own career.
We moved to New York in September 1989. Two years later, Morena, our youngest daughter was born there, and 3 months later we moved to Boca Raton, Florida.
What started as a 2 year assignment in New York, turned out to be a 10 year expat life experience. New York, Boca Raton, FL, Venezuela, Greenville, SC… many places, many memories.
As an expat you work and shop, and do laundry, and clean out your basement much like your neighbors; you watch television and go to movies or plays; you celebrate local holidays and take part in festivals; you support local sports teams and, most importantly, you make new friends, who become your new family and help you deal with homesickness, and navigate a new language and culture.
Living the expat life gave us lots of magical memories that we'll cherish always.
This is the main reason why I love scrapbooking… It allows me to dig deep for those memories, people who touch my life, places I have been, family and friends, and share them with my daughters, since I don't want them to forget all those little moments in their lives.


2004 Long Ave - SOLD!
Nashville. It is located at the entrance of Shelby Park, only minutes from Five Points, Interstates, Shopping, Dining, and Downtown. Sit on your front porch and look out at Shelby Park. Walk to the Dog Park and the Duck Pond. This home was built in 1899 and completely renovated in 2007. All the work has been done, just move in and enjoy the East Nashville lifestyle.
Your Front Yard is Shelby Park!


Mariana and her 2 friends Melisa and Paola lived in "Giulio" apartment for 4 months.
Stuti used to live together with one of her friends, Sanya, in "Piano" apartment for 3 months.
They are NABA students and stayed in Milan for 5 months. They really liked their stay and the "Leonardo" apartment.
Melanie stayed in "Leonardo" apartment for 6 months.