You are currently browsing the monthly archive for January, 2009.
let me give you the back story. see, i have this favorite receptor R. and R has an antagonist drug known as Z. finally, Z is also known to have some inverse agonist properties at receptor R.
inverse agonists are interesting. they are able to cause the receptor to do the opposite of it’s normal action. so if you have a receptor that increases cAMP in the cell, then the inverse agonist can actually cause a decrease in cAMP- and vice versa.
now Z also has very good affinity for R. the Kd value is actually in the very low nanomolar concentration range. that’s pretty damn good. for you non-pharmacologists, the lower the concentration at which a drug will bind a receptor, the higher the affinity the drug is said to have for that receptor. if you need to have lots of drug molecules hanging around a receptor to observe one bound to the receptor, chances are none of them are really hanging on when they bind- they transiently bind, fall off, and transiently bind again when they run into each other again- that is low affinity. but if a molecule will bind to its receptor as soon as it runs into one, and hang on, that’s high affinity. that means you don’t need to put a lot of drug into the system in order to see an effect.
so back to how Z has very good affinity for R. we know that Z has antagonist effects at pretty low concentrations too. but the problem comes in when you go to look for the inverse agonist effects. i replicated my binding curve, expecting to see inverse agonist effects at the maximal binding concentration i previously used, 2 nanomolar. (yes, 2×10-9 M.) and i found no inverse agonist effect.
no, the inverse agonist effect doesn’t even start to show up until 1 micromolar (1×10-6 M). this is outrageously higher than the Kd value of the drug, which is 0.2 nM (or 2x 10-10 M). that’s 5000-fold higher than the Kd. and i haven’t even found the maximal effect using a concentration of 15 micromolar (1.5x 10-5 M). that means that every receptor available has to be saturated and then some, before this effect occurs.
it was suggested to me that there might be a very low-affinity binding site at which the inverse agonist action occurs. but there’s no way in hell something with that low of an affinity is even receptor mediated.
i conclude there is no way that is a receptor-mediated effect and this thing i’m working on is not particularly relevant to anything. it has appeared in the literature in this format exactly once and was not brought up again since. but somebody important wants to see it, and i aim to please this person.
really. aim to please. this person.
grr.
how did all that time go by? all of a sudden i have to go to bed so that i can work another day just like this one, tomorrow.
and i was actually gonna watch a tv show on the internet tonight! damnit! my attempts at having a life totally fail.
next day off appears to be 2/11- i am the goddess of overscheduling. but the goddess needs a hot shower and some sleep now.
occasionally, i like to blog about personal finance topics that grad students can identify with. i’m kind of a personal finance nut, but i’ve learned that i have to be to keep the household running. you don’t pull off a dual student, single income, long distance marriage without going into the red- unless you have a purpose for every dollar.
my personal finance motto come tax time is this: if i owe them money, they can wait till april. if they owe me money, i want it back now!
as a grad student, i don’t make much and i pay a pretty significant amount of what the IRS thinks i make [ie, stipend + tuition that the uni takes away immediately] on education expenses. this is only a good thing come tax time, thanks to the lifetime learning credit.
basically, if your income is within certain limits and you meet the qualifiers, you get 20% of those expenses back as a credit. it doesn’t quite make up for being bumped into a higher tax bracket and paying tax on all that tuition money you never see, but the refund at the end of the year is always nice. unless your department screws you… been there, done that. let’s say i’m very vigilant about checking my withholding now.
another complication i’m dealing with is filing multiple state tax forms. as an undergrad, i stayed within state borders and got a pretty sweet deal on tuition. so there were no interstate student/resident complications to worry about. in grad school, since i’m not the one paying tuition, i’m more than willing to cross state borders and go to a private university. works for me! but then i have to decide, in what state am i a resident?
i chose to keep my home state residency. i do intend to return there- in fact, after the last 5 years, i have no intent on staying here a day longer than i absolutely need to. but that makes several things complicated. like, getting cited by the cops for not having a proper vehicle registration. [gah!] and having to file current state income tax forms, and home state income tax forms, to maintain my resident situation. fortunately, home state has a lower tax rate and it doesn’t cost me extra money.
but the residency thing is a little bit of a pain to deal with. also makes the “know your state laws” game a little harder. [it's easier to flirt with the law when you know it- is my car's window tint legal? technically, hell no. but home state says...]
so uncle sam, how long till i get my refund money? leigh needs a couple bucks to go visit family and find a new place to live in her home state.
[side note: i can't believe january is almost over... the more i try to get done, the faster time goes. not cool.]
today has been one of those days. and i’m in for about 5 more like it before the week is over. as a result, my fuse is so short that i just might light off without provocation.
i worked a very long day to get 2 big things running at once. the result was awesome (r-squared= 0.98 and a dead match with published values, yes!), everything turned out flawlessly and all systems are running. so the throttle just kicked wide open, and i got myself another case of caffeinated goodness to get me through this. i swear i will not stop until the last side project is over.
writing is now back on the sideline for the time being. i have no more intellectual energy to give today.
that’s not enough, though. i am also handling some issues with the oh-so-stellar student health insurance they pretend to offer us around here. they have a perfect record! a perfect record of failure, that is- either they conveniently lose claims or process them at lower benefit rates. or both! it’s a total scam, and i have caught them in outright lies that would have cost me several hundred dollars. what part of “grad student” screams “has hundreds of extra dollars laying around”? i know what i’m paying for, i’ve been cranked through the system one too many times to be naive about it.
leigh despises these imbeciles and their theiving ways.
i just finished talking to one of my friends who is serving our country and is stationed in remote afghanistan. the power of facebook chat!
it’s breakfast time over there, and it’s time for us to be thankful for the comforts of home.
eggs over there are “egg concentrate with citric acid” and as my friend put it, let’s hope those yahoos cook it all the way through.
coffee lovers, prepare to cringe. coffee concentrate is what they drink over there, i think it was 5 drops for every 2 liters of coffee you make? apparently, two drops of this stuff on the tongue will cause a grown man to want to die.
very high on the sergeant’s agenda when he gets home: trip to IHOP.
real coffee is going in the next planned care package. it’s time to make more cookies, too. gotta find the time…
Neuroticism
Neuroticism (sometimes also called Emotional Instability) is the tendency to experience negative emotions such as sadness or anxiety. People who score high on neuroticism are vulnerable to stress and tend to experience negative feelings more often. People who score low in neuroticism tend to be less susceptible to stress, and experience negative feelings relatively infrequently.
You scored 26 out of 50. This score is higher than 51.3% of people who have taken this test.
Extraversion
Extraversion (or Extroversion) is the tendency to experience positive emotions and seek out stimulating situations. People who score high on extraversion tend to be active, energetic, and enjoy being around other people. In contrast, people who score low on extraversion, known as introverts, tend to be quiet, low-key, and are typically less involved in the social world.
You scored 31 out of 50. This score is higher than 36.2% of people who have taken this test.
Openness to experience
Openness to experience is a general tendency to appreciate emotion, adventure, and unusual ideas or experiences. People who are open to experience are intellectually curious, appreciative of art, and sensitive to beauty. People with low scores on openness tend to have more conventional, traditional interests.
You scored 45 out of 50. This score is higher than 77.1% of people who have taken this test.
Conscientiousness
Conscientiousness is the tendency to show self-discipline and persistence. People who score high on conscientiousness tend to be persistent, responsible, and duty-driven, but are sometimes perceived as being overly perfectionistic and concerned with order. Individuals low on conscientiousness tend to show less persistence and may have trouble seeing things through.
You scored 48 out of 50. This score is higher than 99.3% of people who have taken this test.
Agreeableness
Agreeableness is the tendency to be sympathetic and cooperative towards others. People who score high on agreeableness strive for social harmony and value getting along with others. Disagreeable people tend to be more suspicious and hostile towards others.
You scored 28 out of 50. This score is higher than 9.0% of people who have taken this test.
ok… so i’m pretty emotionally stable and can handle stress at least competently. i am definitely an introvert, that was never really even a question. i’m open to new things but i do like my regular routine too- and i never did understand things like interpretive dance. i have incredible self-discipline but kinda fall into that perfectionist rut. and finally, i do have trust issues and have a hard time believing that people are basically good.
we’re all shaped by our various experiences. that was an interesting test.
i’m facing the fact that i will very soon have to figure out what i want to do with my life. i have several different directions i’m looking at, but probably two of them are things i really can see myself doing.
also, i’m working withing a pretty limited geographical range, so this kinda limits some of the options that i have to choose from. while part of me says that’s stupid, most of me agrees that it’s a worthwhile sacrifice to spend my time in a place where i know i want to live, and of course the proximity to family is most of the reason i am going back.
among other things, i’m considering a teaching college position. i’ve mentioned before, that my college advisor has encouraged me to apply for a new tt faculty position in the department. it’s a 9 month appointment, which from what i understand is typical. i’ve talked to my boss about it, and in the R1 world, you’re expected to procure grants to pay your salary outside the 9-month period. over at the teaching college, there is some grant money to write for (but not usually much) and most professors go to part time over the summer to do research with master’s candidates and then take a small vacation. this is fine by me, i’m not really worried about the money aspect right now, so long as it’s within livable range. my primary concern is feeling that what i do is important- i’ve spent 5 years on a project that i think is very important, and the low pay and shit for benefits haven’t been enough to deter me. in fact, i’ve put in a lot of 80 hour weeks despite it. so money’s really not at the top of my list. but the benefits are damn good, i have to admit.
there is research at the college, or i wouldn’t be where i am today, and i wouldn’t be considering going back. i have found working with bright undergrads in a lab setting to be a lot of fun. they have good lab space, and offer a decent startup package considering the 30% research time and the facilities already available. (they already have a lot of the bigger equipment i would need, for example.)
but most importantly of all of this, i’m considering what my life would be like outside work. in all honesty, i work to live, i don’t live to work. we want a family, we want to have time together, we want to live in a safe town where the schools are good, living isn’t horribly expensive. i want to have support from my peers in the workplace when i choose to have a family and start that phase of my life. and a very big factor in my considering a return to my alma mater is that three of the professors i know well and love from my college years, are moms. i saw them do well in their career with kids, i saw the hand paintings posted proudly on their office doors, school pictures proudly on their desks. obviously they would be huge allies and important mentors to me, and from what i could gather as an undergrad, the department as a whole seemed very supportive of women. a lot of the men have kids of their own, a lot of the faculty in general are parents of fairly young children. (and the same story is true in the neighboring chemistry department.) and this seems like the kind of environment where i could kick ass, have a family, and make a difference in undergraduate education. (of course, there is that possibility that i have mis-perceived everything.)
i know i’m not cut out for the politics and toxicities of the R1 environment. i’ve been thinking about running away from my current uni since the day i got here. but i refuse to let that win over me, so i’m here till i’m done. i guess i was kinda surprised to hear similar things about the university from people who are farther along in their careers than i am- junior faculty- hell, even senior faculty. especially as of late, now that i’m talking about leaving, the real sentiment comes out. “i really hate this place some days,” is not a new phrase to my ears.
i am also considering an industry position. my industry contact has not replied to my email in some time- either he is too busy or no longer interested in helping me out. i have accepted that, it happens. (though i am kind of surprised, we met up last year and had a wonderful lunch together and a very helpful discussion on getting my foot in the door. he offered his unreserved recommendation as a reference. so maybe he just changed his email address.) i have a lot of experience managing people in the non-science corporate world- it’s how i paid the bills from the time i became independent until i got into this grad school thing. i actually enjoyed the aspects of bringing a team together and working toward a common goal. then my concerns become how family-friendly the company is, what kind of environment will i be working in, etc. that’s a big unknown to me, because i’ve spent my scientific life to date in academia. but as the family trailblazer, i can’t say that jumping into the great unknown is a foreign thing for me. and there are always other places i could go if things don’t work out. there are quite a few industry companies in one of the cities we are considering. and i do know people there who know people. how influential those people are, i am not sure.
finally, there are 2 places i could do a decent postdoc in the region of question. i am really saving this for last resort, because i want a change from the R1 institution lifestyle. like, really, really want a change. fortunately, there are abundant income opportunites for my wonderful husband throughout the state, so he’s very flexible. i really am lucky to have a guy like him, because he’ll support me no matter what i decide to do. even if it means moving to the one city where he does not want to live. (though he claimed the right to grumble about it for a while, if we went that route.)
but the more i think about it, the more i like the faculty opening… the very concept of this amuses me. maybe i’ll be right, maybe i won’t. i guess time will tell. for now, i’m working on putting together the best applications that i can, and getting outside opinions on how to make them better.
have you ever been asked a very uncommon personal question, and the answer is everything you don’t want it to be?
i wish i could have told my little sis a happier story. i wish i shared her feelings on the issue. i wish it was an issue for me during the time in question.
but i was running away, as fast as i possibly could. i was shouldering huge burdens. i was trying to survive. and as much as i desperately wish i could have given her a different answer, the real one cannot be changed.
i am deeply saddened by looking at that in detail… [sigh]
childhood abuse is sad enough as it is, but it’s important to recognize that the nightmare does not just end when you pack up and get the fuck out. most survivors have a long uphill battle to fight to achieve some kind of normalcy, and often we settle for something that we view as better-than but probably not ideal. the road is full of traps like social maladaptive behaviors, psychological disorders, oh the residual anger and frustration, and especially that bitch post-traumatic stress disorder. but one thing most people don’t think about is the long-term effects on memory, of all things.
that’s right, it’s hard enough out here to make a real life without having to also fight against an inherent obstacle that makes getting an education harder, too.
i’ve talked about the hippocampus before, because i think it’s totally cool. this structure in your brain is responsible for a lot of things related to memory, most notably processing of certain types of memory. in the interest of keeping everything together, i am going to pull out a small chunk of another post i wrote on PTSD where i describe the hippocampus:
a big player in the learning and memory arena is the hippocampus. this seahorse-shaped part of your brain is generally involved in a few different areas of memory detailed below:
semantic memory- meanings of words, in general declarative facts. example: there are 50 stars on the flag of the USA.
episodic memory- experiences and events. example: i voted in the last election.
also spatial memory- spatial orientation. example: to get to work every day, i use spatial memory to navigate my vehicle to the correct location.
the hippocampus is also active during several types of associative tasks- for example, when associating a name and a face when you meet somebody new. it is finally a major processing center, integrating many types of information into logical chunks as the information flows through the major pathways. we can conclude that the hippocampus is extensively involved in processes that could respond to a traumatic memory.
next i’m going to cover another one of my bases and talk briefly about stress. there are a TON of different things that occur in your body as a result of stress, but one of the critical signaling events that happens is the release of cortisol. cortisol mediates a lot of the fight-or-flight response in a stressful situation. it makes us uneasy by design, and causes a desire to get the hell out. it also has effects on learning and memory- i’m sure this comes as no surprise. events that are stressful probably are worth remembering so that we can avoid future recurrences.
there’s a problem, though.
stress hormones like cortisol may save you in the short run, but can cause degenerative effects in the hippocampus in the longer term- including loss of dendritic arbor branching, remodeling of synaptic terminals, and loss of neurons. as you can imagine, these changes aren’t favorable for hippocampal function, and the degenerative effects lead to a decreased learning function in rats. in people, we clearly can’t study their hippocampi in such detail (heck, we have to study the rat’s behavior before studying its hippocampus for obvious reasons) but there is evidence in human research to parallel what we see in animals. several studies have been done in people exposed to traumatic stress, showing deficits in several different memory parameters.
so what does this all mean? should survivors just shrug their shoulders and feel sorry for themselves? absolutely not! it’s a long, hard road out of hell and into life recovery. that is something that makes us much stronger than the average person, and gets us accustomed to working hard to improve our situations. a little extra work to write things down, a little extra studying to pass that test- that’s nothing. survivors are amazingly strong people who have probably spent a lot of time doing just a little bit extra. and we have a lot more benefit to realize. survivors, keep working at it. i will if you will.
awesome review:
Bremner, JD (1999) Does Stress Damage the Brain? Biol Psychiatry 45:797-805
presenting the subject of my salivation: the lexus is-f.
boasting a 5.0L v8 engine and 8-speed automatic tranny with manual override
4.6-sec 0-60 time
awesome style, lots of luxury features
ultra-low emissions certification (surprise!)
and those wheels- they are totally hot. purrrr!
Recent Comments