People being angry about ~dem gays~ on Target’s Facebook.
I just want to give my two cents on this and tell you a story.
A couple weeks ago, I was hired at Target. I have a job at Target. Not a big deal right?
It is a big deal because i’m a transman.
It doesn’t take a genius to conclude that it’s hard for me, my brothers, and sisters to get a job. There are legal restraints regarding the job and if you don’t pass, it’s hard to be taken seriously at a job interview.
Right on the application, it asks what your preferred name is. It also asks if there is anything that target should know. I put the fact that I am a transman, expecting not to get a call because usually when you put that down, people will throw out the application. I got TWO interviews.
At the interview, they asked me about it. I told them I am on hormones and they told me that they didn’t care. Not in the sense that they don’t emotionally care, but that it didn’t matter. I was male and that’s all that mattered. They also told me that they give sex same couples benefits in states that do not recognize them as a married couple.
At my job orientation, I was not misgendered once. Even my supervisors who weren’t sure of my gender avoided pronoun use, which I found only happens when you’ve had pronoun training. They gave me a name tag with my preferred name and didn’t ask questions. I felt safe and respected, which is huge for a trans* person.
TLDR: Target is amazing not just for the LGB, but also the T. Shop there for the rest of your life.
How Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication
“Understanding the structure-function of these receptors allows us to discover new biology of serotonin signaling and also gives us better ideas about what biological questions to probe in a more intelligent manner,” said TSRI Professor Raymond Stevens, who was a senior investigator for the new research. The studies were published in two papers on March 21, 2013 in Science Express, the advance online version of the journal Science.
Pioneering Important Molecular Structures
Stevens’s laboratory at TSRI has pioneered the development of techniques for determining the 3D atomic structures of cellular receptors — particularly the large receptor class known as G protein-coupled receptors (GPCRs). GPCRs sit in the cell membrane and sense various molecules outside cells. When certain molecules bind to them, the receptor’s respond in a way to transmit a signal inside the cell.
“Because G protein-coupled receptors are the targets of nearly 50 percent of medicines, they are the focus of several major National Institutes of Health (NIH) initiatives,” said Jean Chin of the NIH’s National Institute of General Medical Sciences, which partly funded the work through the Protein Structure Initiative. “These detailed molecular structures of two serotonin receptor subfamilies bound to antimigraines, antipsychotics, antidepressants or appetite suppressants will help us understand how normal cellular signaling is affected by these drugs and will offer a valuable framework for designing safer and more effective medicines.”
In the past several years, using X-ray crystallography, the Stevens laboratory has determined the high-resolution structures of 10 of the most important GPCRs for human health — including the β2 adrenergic receptor, the A2a adenosine receptor (the target of caffeine), HIV related CXCR4 receptor, the pain-mediating nociceptin receptor, S1P1 receptor important for inflammatory diseases, H1 histamine receptor (antihistamine medications) and the D3 dopamine receptor which is involved in mood, motivation and addiction.
Serotonin receptors are no less important. “Nearly all psychiatric drugs affect serotonin receptors to some extent, and these receptors also mediate a host of effects outside the brain, for example on blood coagulation, smooth muscle contraction and heart valve growth,” said Bryan Roth, a collaborator on both studies who is professor of pharmacology at the University of North Carolina (UNC).
Untangling Two Serotonin Receptors
Roth’s laboratory teamed up with Stevens’s as part of the National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative. For this project the two labs also worked with the laboratories of Professors Eric Xu and Hualiang Jiang at the Shanghai Institute of Materia Medica, part of the Chinese Academy of Sciences. “By collaborating with the Chinese teams we were able to complete a much more thorough study and get the most out of our fundamental structural results,” said Stevens.
In the first of the new studies, co-lead author Chong Wang, a graduate student in the Stevens laboratory, and his colleagues determined the structure of the serotonin receptor subtype 5-HT1B, the principal target of several drug classes. (5-HT, or 5-hydroxytryptamine, is a technical term for serotonin.) The team produced the 5-HT1B receptor while it was bound by either ergotamine or dihydroergotamine — two old-line anti-migraine drugs that work in part by activating 5-HT1B receptors.
With the help of the special fusion protein, nicknamed BRIL (apocytochrome b562RIL), Wang and colleagues were able to stabilize these structures and coax them to line up in a regular ordering known as a crystal. X-ray crystallography revealed, at high resolution, an atomic structure of 5-HT1B with a main binding pocket and a separate, extended binding pocket.
Harmful Off-Target Effects
In the second study, TSRI graduate student and lead author Daniel Wacker and colleagues used similar techniques to determine the structure of the 5-HT2B receptor bound to ergotamine. The 5-HT2B receptor was chiefly of interest because drug developers want to avoid activating it.
“Drugs that are meant to target other serotonin receptors in the brain can have harmful off-target effects on 5-HT2B receptors, which are found abundantly on heart valves, for example,” said Roth. The weight-loss drug fenfluramine and closely related dexfenfluramine were withdrawn from the US market in 1997 after being linked to heart valve disease. Roth’s laboratory later showed that this side effect was mediated by heart valve 5-HT2B receptors.
Analyses of the 5-HT1B and 5-HT2B receptor structures revealed a subtle difference between them. “Although their main binding pockets look very similar, their extended binding pockets are not as similar — the one for 5-HT2B is narrower and in a slightly different position,” said Wang.
With the two receptor structures in hand, the Xu and Jiang team simulated the bindings of various drugs. They showed, for example, that anti-migraine drugs called triptans should bind well to 5-HT1B receptors but poorly to 5-HT2B receptor structures, in which the extended binding pocket is less accessible. Similarly, the team’s calculations confirmed that fenfluramine’s active metabolite should bind very tightly to the 5-HT2B receptor.
In the second study, the researchers used the 5-HT2B and 5-HT1B structural data to better understand a recently discovered GPCR signaling pathway.
When a neurotransmitter such as serotonin binds to its GPCR receptor and triggers the primary, G protein-mediated activation signal, it also usually triggers another signal, often mediated by a protein called β-arrestin. This second signaling cascade may simply have the effect of “arresting” or inhibiting the primary, G protein-mediated signaling. But it can also have other effects on the cell, and although most molecules bind to their target GPCRs in a way that activates these primary and secondary signals equally, others preferentially activate one or the other. “Such functional selectivity, as we call it, adds another layer of complexity to drug effects on GPCRs,” said Roth, a co-senior author of the study.
Roth’s laboratory produced several 5-HT receptor subtypes in test cells, and compared the strength of G-protein and β-arrestin signaling when these receptors were bound by ergotamine or various other drugs, including the ergotamine-derived hallucinogen LSD (lysergic acid diethylamide). Most of the tested drugs showed no bias. However, ergotamine, LSD and some of their relatives turned out to be clearly biased in favor of β-arrestin signaling at the 5-HT2B receptor. Comparison of the ergotamine-bound 5-HT2B structure with the ergotamine-bound 5-HT1B structure revealed the likely reason. “We could see that when ergotamine is bound to the 5-HT2B receptor it stabilizes the receptor structure in a conformation that interferes with G protein signaling,” said Wacker.
The findings allow scientists to start probing this arrestin-mediated signaling pathway and its downstream effects in a more targeted manner. “These structural data are teaching us to ask better questions about receptor biology,” said Stevens.
Josephine Baker, later known as ‘Bronze Venus’, ‘Black Pearl’ and ‘Créole Goddess’ was born in America in 1906 and later moved to France to become a singer, dancer, and actress. She was the first African-American woman to star in a major motion picture, and became famous worldwide.
Though she grew up as a maid in wealthy white households she eventually became an exotic dancer in France, famously appearing in next to no clothing, and became a French citizen in 1937.
Ernest Hemingway referred to Baker as ‘the most sensational woman anyone ever saw’ and she received approximately 1500 marriage proposals in her life time. She became a muse for Hemingway, F. Scott Fitzgerald, Pablo Picasso, and Christian Dior. She had a variety of exotic pets including a cheetah named Chiquita, a chimpanzee named Ethel, a pig named Albert, a snake named Kiki, a goat, a parrot, parakeets, fish, three cats, and seven dogs.
When WWII broke out, Baker became a volunteer spy for France, and assisted the French Resistance by smuggling messages written in invisible ink on sheet music. She made great efforts to aid those in danger of enemy attack, sent Christmas presents to French soldiers, and smuggled information she gathered in Spain back to France by pinning notes containing the information on the inside of her underwear. She was awarded the Medal of Resistance with Rosette and later named a Chevalier of the Legion of Honour.
Baker also aided many civil rights movements by refusing to perform to segregated audiences and storming out of a club in Manhattan with actress Grace Kelly after she was refused service. She worked with the NAACP and spoke at a Washington march alongside Martin Luther King Jr. as the only official female speaker. Baker was actually asked by Martin Luther King Jr.’s widow to take his place as leader of the American Civil Rights Movement, but Baker declined on the grounds her twelve adopted children ‘were too young to lose their mother’.
Baker died in 1975, four days after her final show, attended by such names as Mick Jagger, Shirley Bassey, and Liza Minnelli.
Oh and she was queer and had a relationship with Frida Kahlo. All around badass.
Josephine Baker has been one of my favourite people since I was 13 or 14 years old, such an amazingly brave, wonderful person ahh
I like that she was even included in the triplets of Belleville