Posted by JenniferP

Dear Captain,

A few months ago, I met a cute new person and we clicked pretty well from the start. We both had another primary partner at the time and we often talked about those relationships as well as (of course) many other things. After a while, he and his primary broke up, and he was pretty devastated by it. I didn’t mind that he was a bit more “down” when we spent time together, and it seemed only natural to me that he talked about his break-up feelings sometimes. I still don’t mind those things.

Now here comes the difficult part: I feel like this relationship is getting more and more asymmetrical. I’m busy with a demanding job and an active social life (and I like it that way), and he has a lot of time on his hands. He has made it clear that he’d prefer to spend much more time together than we currently do (including weekend trips and the like), while from my perspective we’re close to “too much”. He is way ahead of me with things like “I love you” (WAY too early for me!). I feel like I have to be “on” at all times when we’re together, because he always seems worried that I’m not being enthusiastic enough and something must be wrong and don’t you like me anymore?

He’s had a bunch of personal issues come up lately, and he’s generally pretty unhappy right now. I find it really hard to find a balance between being kind to a person I like, and setting some “don’t make me responsible for your happiness!”-boundaries. I understand anxiety and sadness and insecurity, because I deal with plenty of that in my own life, but it feels like he’s subconsciously weaponizing these things to demand my time and attention. He often says things like:

  • “you’re the only good thing in my life right now”
  • “I feel like everyone is rejecting/leaving me lately”
  • “I’m not doing so well,
    Please view this post in your web browser to complete the quiz.
    , can I come by tonight? I need comfort”
  • “I’m dealing with so much shit that I can’t carry it on my own”
  • “You give me so much strength when we spend time together”

I really like this guy! We have a lot in common and we’ve had fun times together. I would love to see him once or twice a month for many moons to come, and for us to grow closer over time, but right now I feel like I’m under siege and I have to focus on setting boundaries and finding new ways to say “no” all the time and it’s starting to suck the joy out of what (I hope) could be a genuinely fun and rewarding relationship – through good times and bad.

Can I salvage this? How can I communicate with him in a way that does NOT say “I can’t handle people who have negative emotions ever”, but rather “it feels like you’re using your emotions against me and that’s not cool”?

Thank you!

You’re absolutely right to see a litany of “you’re the only good thing in my life” and “everyone else is rejecting me (so you won’t, won’t you?)” statements as being red flags of codependence. I’m not sure the end result of my advice is “fun new relationship is salvaged!” but I think you do have a good opening here to have an honest talk with him about getting help in handling hard life stuff and the reciprocity & seriousness of your relationship.

There are two separate conversations to be had here. I’m not sure in which order, so, use your judgment.

Conversation #1:

[Partner], I can see that you’re really suffering right now as you [grieve the loss of primary relationship][handle this recent raft of difficult life stuff]. I’m feeling overwhelmed by it all and I think it’s time to find some more support for this stuff. Maybe a trained sounding board – like a therapist or counselor – can help you process all of this.

There is a 99.99% chance he will feel insulted and hurt that you are fobbing him off on other people instead of investing deeply in his emotional well-being yourself. Get ready for some intenso responses involving “You are tired of me and you are going to reject me like everyone else” + 1,000 reasons that therapy/counseling is impossible/useless/too hard for him. This is because:

  • He is primed to feel rejected right now. Everything that isn’t “I love you come over right now and let me comfort you my dear boy” = rejection.
  • You are sending him to other people instead of wanting to deal with it yourself. (That’s okay! Just, acknowledge the truth of that so you don’t fall for the negging when it comes).
  • Mental health system is imperfect and it does take a lot of resources and energy to find a good fit and treatment that can work for you. It’s a hard thing to do when you’re feeling great, never mind when you’re feeling terrible. It’s okay to acknowledge the imperfections in the mental health system and also remind yourself that those difficulties don’t automatically make his emotional well-being your sole problem to deal with on demand in real time.

Follow-up script:

I know this sucks and that’s not what you wanted to hear. You’re right, I am telling you that you need to find other people besides me to lean on, and you’re right, the mental health system can be really difficult/annoying/expensive. But I am not comfortable or prepared to continue being your main sounding board about this stuff. I think your problems are real and serious and that taking them seriously might involve bringing in a trained listening person for a little while. Think of it as giving yourself the gift of a safe space to unload and process all of this that’s 100% focused on you, a little time in your week where you have permission to feel as sad and lost as you need to feel and get all the feelings out so you can start to heal and deal with them.

Get ready for a question like “So I guess I’m not allowed to talk about serious stuff or feelings with you anymore?” (It’s 99.99% coming)

Your script: “That’s not what I’m saying, but I am saying that I don’t want the time we spend together to be all about [Serious Feelings Stuff and Comfort]. I am asking you to find and take advantage of some alternate avenues for support and comfort, so things with us can be a little more balanced than they have been.

Chances are he will not like it. He likes his comfort to come with a side of romance/sexytimes and whyyyyy should he make an effort to find a therapist when he has youuuu? But you’re doing a kind thing by being honest about your limits and directing him toward something that actually has a chance of making him feel better.

Conversation #2 

Sometimes the answer to “I had a terrible day, can I come over and be comforted” is simply “Sorry, not tonight.” And then you put your phone away and focus on what you originally planned to do and he finds a way to self-soothe somehow. If he deals with that well, then maybe it can get better.

That doesn’t mean there is no big conversation to be had. He wants to say “I love you” and plan weekends away and remind you that you’re the only great thing in his life and it’s making you feel crowded and overwhelmed. Time to talk about that. Maybe time to also talk honestly about the way you do polyamory, like the fact that you have someone in your life that you consider to be a primary partner and that there is a hierarchy there maybe not of feelings but in terms of how you allocate time/vacation days/long-term relationship planning, etc. It seems like your relationship really worked when he had that in place too but now things have become unbalanced. This conversation might mean that y’all create something new together over time or it might mean that he and you find out that are unsuited to each other.

The thing where he wants you to be “on” and show that you are sufficiently enthusiastic seems to be the best entry point for this conversation, as in, the next time he makes you you feel that way it’s time to talk about what’s up: “Listen, I like you a lot, and I like you enough that I can make space for you to be sad and grieving right now but that also means that you make space for me being tired or having an off night or for not exactly mirroring your enthusiasm back to you. For example, we’ve only known each other a short time and I’m not ready for ‘I love you’ yet. I would love to get there someday but I need more time. When you say ‘I’m the only good thing in your life’ I know you mean it as a compliment but it feels like pressure. Also time we spend together is already about the maximum time I have to spend with you in a given week. Like of course it would be nice to spend ‘more time’ together, but I can’t do that without breaking other commitments that are pleasurable and important to me. I need you to understand that and focus on enjoying the time we do spend together.

Then, say the thing that’s the elephant in the room: “I feel like you want me to take the place of [Former Primary Partner] in your life, and that’s an okay thing for you to want on an emotional level, I get it, but it’s too much/not the right fit for me/not what I signed up for/making things unbalanced between us. I care about you a lot and I want to find a way to keep this going, so, how do we build something that is enjoyable and true and emotionally supportive without me feeling so pressured and you feeling so rejected?

He’s not going to like hearing this because it’s going to feed into the story he is telling himself about how everyone rejects him. Also there maybe is no balance between “Ideally we’d hang out once or twice a month, forever” and “LOVE ME!!!!!” But if you can’t talk honestly about this stuff and you keep feeling suffocated and overwhelmed, the thing is not going to work. “I’m at the limit of what I have to give you in terms of time and affection” isn’t what any romantic partner really wants to hear, but it’s important information if it’s the truth. The truth can hurt but it can also help us make good decisions about how to take care of ourselves. He may decide that what you have to offer is not enough for him. You may decide that what he wants is just not compatible with what you want and need. That would be painful, but I have to think that it’s better than letting him continue to build this fortress of need around you while you’re looking for the escape hatch.

Reminder for commenters: Spell out the whole word “polyamory” please.


Posted by Derek Lowe

Let’s talk about enzyme envy. That’s what we organic chemists experience when we stop to think about how every complex natural product in the world is synthesized so much more quickly and efficiently than we can do it. All those crazy multiple rings systems, those bizarre heterocycles, huge macrolides, and dense arrays of stereochemistry are cranked out at ambient temperature, under aqueous conditions, on a time scale of minutes to hours. Oh, and they’re made offhand, in the background, as time permits, while the cells and organisms themselves are otherwise occupied with the even more startling business of being living chemical systems. Envy? It’s more like enzyme terror, when you really think about what’s going on.

Now let’s talk about nanotechnology. Not the press-release stuff, I mean hard-core nanotech. The dream of assembling molecules and materials to order, atom by atom, has been around for some years now, and it largely remains just that: a dream. Eric Drexler and others have taken a lot of grief for maintaining that such things are possible, and to be sure, I have trouble myself with the real atomic scale this-carbon-goes-right-here level of the idea. But what about “this acetyl group goes right here?” That is, small-molecular scale versus atomic scale? That is exactly what every living cell on the planet is doing right now – that’s enzymatic chemistry, and I see no reason why we can’t get smart and capable enough to do the same sorts of things ourselves, and more.

That leads up to this new paper, which is a big (but small) example of just that sort of thing. A group from the University of Manchester reports the system shown above, which is basically a molecular-sized stereoselective synthesis machine. You put that unsaturated ester together on the left-hand side, and the first step is an olefin cross-coupling with it and acrolein dimethyl acetal. Now comes that “rotary switch” in the middle. If you treat the molecule with trifluoroacetic acid, it deprotects the acetal, and the acrolein now is set up to do a tandem nucleophile/electrophile addition under the influence of the chiral prolinol group. That reaction is done in solution, as stereoselective synthesis fans will know, but you only really get the syn isomers.

This system will give you both, and both enantiomers, depending on the reaction conditions. Depending on the conditions (time spent treating with trifluoroacetic acid, or with triethylamine afterwards), that hydrazone in the middle can go from E to Z putting the acrolein aldehyde in range of either the (S) or the (R) prolinol, at your choice. That forms a chiral iminium, whereupon you add a thiol nucleophile. The iminium is now released, and you have your choice again of whether you want the hydrazone in the middle to be E or Z. Whichever one you choose, you now form an enamine intermediate and bring in the electrophile (a highly activated Michael acceptor, 1,1 phenylsulfonylethylene). That does the second bond formation, and reduction with LAH releases the ester linkage and frees the product as a primary alcohol. You end up with two chiral centers, and you can choose which of the four diastereomers you want by moving the hydrazone switch around during the reaction sequence.

OK, we’re not all going to be making compounds like this next week – fine. This system is set up with every bias possible to make it succeed (such as a terrific thiol nucleophile and a terrific sulfonyl electrophile), and it doesn’t produce pure stereoisomers out the other end, even with that. Rather, you get ratios from about 80:20 to about 60:40 (although, to be sure, the solution methods to do this reaction don’t always do much better, and they can’t give you all four isomers under any conditions). The point is not that this is a wonderful new stereoselective reaction that we can use to make chiral products; the point is not the chiral products themselves at all. The point, of course, is that this thing has been designed to give you such chiral products, in a programmable fashion, and that it can indeed switch states on command to give them to you. It’s a machine – a very small machine, with limited inputs, but the first computer circuits were also very small machines with limited inputs, too.

The scientific and engineering challenges are similar – how to make these things work more reliably and how to scale them up to greater levels of complexity and utility. It’s going to be harder for chemistry than it was for computation, since our computers, fundamentally, are all about moving 1s and 0s around (throwing on/off switches over and over in increasingly complicated ways). That made the development of processing circuits more straightforward, as difficult as it was in reality to get all that to work. Organic synthesis has a lot more letters in its alphabet than just A and B, and its processes are a lot more irreducibly complex than binary logic is. But that just means that it’s a trickier problem, not that it’s an insoluble one.

I think this work points to one way around the difficulties: try, whenever you can, to reduce the key steps to binary ones. The heart of this molecular machine is that hydrazone, which can point in this direction or in that one, which makes all the difference. If we develop these and other spatiotemporal switches to be faster, more responsive, more reliable, and more orthogonal to other functional groups, we can adapt them (as this paper does) to do some fairly complicated chemistry by positioning our other reagents in the appropriate places. Some of these things are already out there in the literature (azo groups or other double bonds that isomerize photochemically, pH-responsive hydrogen bonding groups, and others). We can take our cues from the biochemical world, which uses both of those just-named processes, and how, and we can design new ones that no living cell has ever gotten around to. Cells, when you get down to it, build incredible synthesis machinery, but it’s bespoke stuff: it does what it does with fantastic speed and precision, but if you don’t want exactly what it does, you’re out of luck. What we’re after is are tougher, more general solutions: machines that will make whole ranges of molecules, the way we tell them do, with (ideally) the ability to be switched around to different functions as needed.

T. Ross Kelly and Marc Snapper have a good commentary on this paper in the same issue of Nature.

It is commonplace to dismiss seemingly impossible ideas, such as Drexler’s molecular assemblers, out of hand, and the use of such devices in chemical synthesis might indeed never find favour. One could further argue that Kassem and colleagues’ “programmable molecular machine” is more contrived than ingenious. But given that the most recent chemistry Nobel prize was awarded for the design and synthesis of molecular machines, those who dismiss the concept of molecular assemblers should heed the lesson of Lord Kelvin’s infamous 1895 pronouncement that “heavier-than-air flying machines are impossible”.

As opposed to some other similar statements that get quotes, Kelvin apparently really did say that, as well as saying (in 1900) that he didn’t think there was anything new to be discovered in physics. Anyone who watched a bird knew that heavier-than-air flight was possible; the question was whether we could figure it out ourselves. The attempt to make molecular assemblers – which is, after all, the attempt to make our own enzymes, when we know that enzymes exist – is the same sort of problem. The molecular-machine folks (last year’s Nobel!), who care about rendering fundamental ideas and processes into molecular form, and the more traditional synthetic organic chemists, who care about what products any new reaction or machine can produce for them, can find common ground in building such things. Bring on the molecular machines!

 

 

Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer

minoanmiss: (Default)
Dear Carolyn: In my childhood, criticism from my parents was the constant theme. My grades were never good enough, my room was never clean enough, whatever. As a result, I feel little to no affection for my parents now that I’m an adult, and I don’t spend much time with them or talk to them much. I just don’t like them very much.

However, some people who know this say I’m going to regret distancing myself from them when they’re gone. Do you think that’s true? Should I make more of an effort to spend more time with them now so I don’t regret it later?

— Criticized


Criticized: Your friends would regret distancing themselves, if they were in your position. That doesn’t mean you will.

So, no, I don’t think that is universally true that distance equals regrets.

However, I do believe that seeing parents as people, instead of just as parents, is a more useful way to determine how to adapt your relationship with them over time.

What you describe of your parents is a child’s view of people who, apparently, thought that being a parent meant being strict and teachy all the time. I agree with you that it’s a cold way to go, and tough to forgive, but there are other aspects of parenthood that could provide a fuller and fairer picture. Were their parents that way with them? Was the culture around them one of “seen and not heard” and “spare the rod” orthodoxy? Did they tend not to question things about life in general, their parenting views among them? Was one of them softer but not strong enough to counteract the other?

And: What did they become after their active child-rearing years were over? Did they remain locked in a cold orthodoxy, or did they bloom a little when the weight of responsibility was removed? Are they trying to get to know you now, or are you still 12 to them?

Do you know them all that well as people, or did you distance yourself effectively enough that your last real impression of them was formed as you fled their home after high school?

I ask these questions entirely without judgment. People have their natural, even reflexive ways of looking out for their own health, and kids of unhappy childhoods can even have this need as their central motivation. It makes sense.

But when you get to the point where you’re asking whether this is the right way to go, my inclination is to suggest that you keep asking questions and see where your inquiry leads you. If you don’t feel up to digging all that out, that’s reasonable. Your prerogative. It might also make sense to spend a few sessions with a skilled therapist.

And it might be liberating just to try, once or twice, with no great expectations, to talk to your parents with a different image of them in mind as you do it.

They’re people. Possibly kind of stunted people who meant no harm but had no clue. People who might have interesting things to say if you asked them different questions, and/or with a different objective in mind. Not “I want them to say they’re sorry” or “I want just once for them to be warm and welcoming,” but maybe “I want to see them how their friends do,” or one of my favorite suggestions from a long-ago chatter, “I want to approach them as an anthropologist would and see what I find out.”

Fitbit goal check

September 24th, 2017 11:19 pm[personal profile] rmc28
rmc28: Rachel smiling against background of trees, with newly-cut short hair (Default)
numbers )




Reading: Autumn

September 24th, 2017 06:19 pm[personal profile] white_hart
white_hart: (Default)
I bought a copy of Ali Smith's Autumn in the Oxfam bookshop in York last week, because they were playing Leonard Cohen and I ended up browsing the contemporary fiction section much more closely than I often do because I wanted to keep listening to it. It was the day the Booker shortlist had been announced so someone had been talking about the book on the radio as I was driving up; it sounded interesting so I thought I might as well buy it when I saw a copy there.

It's a strange book. Essentially, it's the story of a friendship between an elderly man and little girl, growing and developing across the space of years, but it's also a complicated web of allusions through which Smith considers questions of time, memory, love and art; key influences are Dickens (the opening sentence is "It was the worst of times, it was the worst of times") and Ovid's Metamorphoses although there are many others. Its time-hopping, non-linear format jumps between the aftermath of the Brexit vote (the novel was published last October and it was clearly written, fast, after the referendum), the 1990s, the Profumo scandal of the 1960s and World War 2 and the years immediately preceding it. It's funny and thought-provoking, melancholy and angry and also somehow hopeful. And the prose is beautiful and poetic. It's a short book, and a quick read, but I think it will stay with me.

Reading: St Mungo's Robin

September 24th, 2017 10:23 am[personal profile] white_hart
white_hart: (Default)
I wasn't quite ready to get my head out of fifteenth-century Scotland after finishing Gemini, so I thought I'd read the fourth of Pat McIntosh's Gil Cunningham mysteries. Set in Glasgow, about ten years after the end of Gemini, these books feel a bit like a extension of the world of the Niccolò series; some of the same historical characters appear in both and I like to imagine Dunnett's characters living their lives just off-screen. (Accidentally or on purpose, there are also a couple of cases where character names and nicknames end up being minor spoilers for points in Dunnett where knowing a character's full name rather than just their nickname would have given too much away, so if you're reading your way through Dunnett and care about remaining unspoilered I'd recommend leaving McIntosh until afterwards; I also enjoy McIntosh more for having read all of the Niccolò books now and understanding the historical background.)

In this book, Gil (now officially charged with investigating murders, after his earlier successes on an amateur basis) is called to a Glasgow almshouse where the unpopular Deacon has been found stabbed with no shortage of people who might have had a motive to kill him. He's also due to be married in a week's time and his investigations are both helped and hindered by family and friends arriving in town for the wedding, while he and his fiancée, Alys, are both suffering from pre-wedding nerves.

I enjoyed this a lot - the series really seems to be hitting its stride by this stage, with the core characters established enough to feel like old friends now; Gil's investigations manage not to feel out of place in the historical setting while still allowing him to do things like estimate times of death from the condition of a corpse. I did spot a couple of clues well ahead of Gil, and had worked out the identity of the murderer by about two-thirds of the way through the book, but then it's always nice to feel cleverer than the detective!

Five things make a post

September 24th, 2017 01:13 pm[personal profile] rmc28
rmc28: Rachel smiling against background of trees, with newly-cut short hair (Default)
1. I was just saying to my boss this week that I was quite proud of keeping my migraines under control more lately; guess what I got yesterday? So annoying, especially as I'd been looking forward to a friend's party that I ended up missing.

2. I am very slowly beginning to tackle the backlog of Stuff I Kept Putting Off While Studying; this week has been all about the clothes / fabric. I have assorted piles of worn-out clothes and out-grown clothes accumulating around my room. I pulled out all the actually worn-out stuff, and bagged that up to go to recycling. I bagged up two sets of bedding we never use for the charity shop. I bought myself some underwear that doesn't have holes in, and added all the ones that did to the recycling bags, along with my oldest & least useful bras. I sorted through my socks, and chucked a good few pairs in the recycling bags, and a few others into the charity bag. Finally I ended up sorting through my stash of pretty scarves and wraps and kept only the ones that I really love and may actually wear more than once a year. (I sort of aspire to be someone who routinely wears pretty scarves etc but in practice I am never that put-together very often.)

3. I took the charity bag to the EACH shop, and came back with a very shiny pair of not!DMs and a metallic blue stripey hat. (Amusingly, I had been whinging this week about needing new shoes for winter, and hating shoe shopping, so that was very well timed.)

4. Last Saturday I watched Robocop with [personal profile] fanf . He was inspired by this post (linked by [personal profile] andrewducker ), and I'd never previously watched it - not on purpose, just never got round to it. It's very very Paul Verhoeven isn't it? Gratuitious mixed-sex shower scene, gory violence, horrible-future-media & horrible-future-adverts. Although my reaction to the project manager with the huge glasses was a. love those glasses b. you are really enjoying imagining watsisface having his hand broken c. please tell me watsisface dies horribly after forcing a kiss on you and taking credit for your work (spoiler - he does). Watsisface really is a walking example of the unwarranted confidence of the mediocre white man.

5. Nicholas saw Trolls at holiday/after school clubs and asked for his own copy. It's not awful, and I like the music, but after sitting through it with him three times in less than a week, I think I have had enough of it for now. The trailers on it include Home (based on The True Meaning of Smekday) which I've been meaning to watch, and Nicholas is keen to do so too, so hopefully I'll enjoy that more.

[personal profile] archangelbeth on cats

September 23rd, 2017 01:19 am[personal profile] conuly posting in [community profile] metaquotes
conuly: (Default)
Cats can reproduce by budding. Make sure to dispose of all brushed fur properly.

Context needs to comb her cat more often.

Cool Stuff Friday

September 22nd, 2017 11:41 am[personal profile] jimhines
jimhines: (Snoopy Writing)

Friday has been having trouble keeping up on the blogging lately…

Mirrored from Jim C. Hines.

Posted by JenniferP

Dear Captain,

My question today is about academia and/or job opportunities and being single. I am a PhD candidate in a Very Good University in the US, and I will be on the academic job market in a year. I have a very good publication/presentation/committee/topic situation, so I should be doing fairly fine. However, my field is totally dominated by men, mostly from quite conservative countries/cultures. It’s even worse in industry (I have work experience pre-PhD and an internship).

Now, I am absolutely sure I don’t want to get married or have a cohabiting partner or “serious” relationship of any sort. If anything, I identify with relationship anarchy. I am happy like I’ve never been, and I feel like I’m thriving and my best self arises when I am alone and free. I do have many short and long romance stories with like-minded folks who are in the same line of thought, but I don’t have or want any “boyfriend” in the sense that other people seem to want me to have (focused on dating – getting engaged – moving in – marrying).

Usually, in academic conferences, in the informal networking events, or in my department, I get asked when I will be on the market, and if I prioritize going back to my country or staying in the US, this kind of things. I think it’s all fair game and I am thrilled some Big Names in the field show interest in me! But sometimes they ask things such as “will you have a 2-body problem?” or “well, eventually you’ll want to marry, right?” or “our school is in a city with plenty of young men!”. Or more bluntly “how come you are not married yet?” (my age – early 30s – is not a secret). I know those (mostly old, mostly men, mostly conservative) professors may just be trying to be nice(?), but I can tell by the way they look that I don’t fit in what they think is “a good woman” or “a normal person”.

I have told some (younger – some younger than me) professors in my department that I don’t want to marry and they all reply condescendingly “you’ll change your mind!” But they are not the ones who’ll make my hiring decisions (although they’ll write me letters of recommendation) and so I am not that much concerned. What about those from other schools who may want to hire or not hire me a year from now when I am on the market? When I have 5-minute interactions and they ask me topic/advisor/ideal placement/marital status. Should I tell them “I don’t want to marry” and out myself immediately as not-their-idea-of-good-woman? Should I tell them “oh I haven’t found anyone yet” and then lie (or risk that someone will try to set me up – it’s happened before!)? Should I just smile awkwardly and say “I don’t know!”? I also feel that, when I say I don’t want to marry, the person in front of me thinks I am lying. What if I tell them “no, I don’t want to marry, but I do want to have kids and I am very well informed about sperm banks and adoption agencies”. Will this kill forever all my job opportunities because of the single mother stigma?

It’s all a paradox, because they don’t like women because of the whole marriage and maternity thing, but they don’t like it either when women don’t conform to their standards of womanhood (wifehood?).

How can I navigate this? I do want to have a good academic placement but I want to know who won’t be supportive of my lifestyle to avoid their departments. But also, you know, academia is sometimes hard and there isn’t much choice of placement for a candidate. So at this point I mostly want to say something that won’t close all the doors but will make my point clear enough.

Any help will be welcome! Thanks so much!

Future Professor Badass

Dear Future Professor Badass,

As tempting as it would be to say a robotic “That is a sexist question” or give a long rambling Boring Baroque Response involving your theories of Relationship Anarchy whenever this comes up, here is the strategy I actually advise:

Them:Will you have a two-body problem?” (For people outside of academia, this means will you need the university that wants to recruit you to also factor in a job for your a fellow-professor spouse) or “But surely you intend to marry someday?” (Ugh) or “Good thing there are lots of young men here!

You:Thanks for asking. I’m lucky that I don’t have to consider that right now in my search and can just look for the best fit for my work.

Them:How come you are not married yet?” (This is a weird, rude question but I too have had older people from outside the US ask me this as if it’s a normal question. Then again, we in the US ask people what they do for a job right away, for this week’s Manners Are Relative reminder).

You: Smile awkwardly and say “I don’t know!“, as you suggest! Or, “It just hasn’t been a priority!” or “Search me!” or “I love being single” or “Has my grandmother been talking to you? It’s a question under much discussion in my family, believe me” or “Haven’t felt like it, I guess!

Whatever you say, keep it light and vague. The more you can answer calmly and confidently, without apology, the more people will take your cue in how they react.

 

 

I know all of this is sexist and invasive and weird and assumes heterosexuality when it should not but the individual people who ask you this think they are being kind and even helpful, especially if they are trying to recruit you to their campus. They want you to be happy and anticipate issues that they might have to work around so that you will want to stay forever at their school. They want to figure out if they have the budget to hire you and a spouse if they want you badly enough. They don’t want you to take the job and then leave in a year because it’s a romantic and sexual wasteland or because there’s no industry in the town except for the university and your (theoretical) partner can’t find work. It can be awkward attempt to mentor you, at least in some cases, so if you can find a way to be vague but positive and deal with the intentions (rather than the effects) of the question it will help you connect.

I wish it were not so, but right now you need a job so someday you can be the colleague who doesn’t ask newcomers these questions (or asks in a way that is actually helpful).

Answer with your vague positive statement, some version of “It’s not my biggest priority right now, which makes me feel very lucky! I have the luxury to just think about finding the right fit for the work I want to do. I know not everyone has that.

Then ask them questions about their lives.

  • “When you moved to [City Where University Is Located] what was it like to get your bearings?”
  • “Any advice for settling in in [City]? Where do the people who love it here shop/eat/hike/live?”
  • “Was it a difficult adjustment moving from [Country of Origin] to [City]? What was the biggest surprise?”
  • “What are the things about [City] that really make you feel at home?”
  • “Were you married when you moved here? How does your spouse like it here? What do they do?”
  • “How did you and your spouse meet?”
  • “Did you have to deal with a two-body problem? What was that like? How does the university generally deal with those?”
  • “What do you remember most from your first year of being a professor here?”

You can turn the conversation to their research or their teaching or questions about the students or the department, too. People like to be asked questions about things they are experts on, and in my experience professors like this even more than most people. Use their weird question as an opportunity to make a human connection and find out more about them as people and the place as a place to live and what you’re getting into. Be remembered as someone pleasant to talk to, focused on her work, and someone who asks good questions and is a good listener.

You’ve got this and you don’t need to make excuses for something that isn’t actually a problem. Good luck in your search.

 

 

 


Posted by Derek Lowe

Did it have to be this way? I mean all of it – biochemistry, the molecules of life. More specifically, as proteins evolve and change, how many paths could they have taken that would have taken them to the same sorts of function?

That’s a pretty hard question to answer, since we’re looking at a billion years of evolutionary tinkering, driven by all sorts of random craziness and a willingness to run with anything at all that works. But here’s a new paper from a team at the University of Chicago that tries to address the question empirically. They’d previously worked out a plausible sequence for the ancestral steroid receptor, from whence all the others have descended. It’s selective for the estrogen-response-element in DNA, so that was the original mode of action. Way back when, three particular mutations in the DNA recognition region of the protein sent some of them down the track for selectivity to the steroid-response-element (including androgen response elements and others), which is still the major divide in the mechanistic details of the whole family.

In this paper, the group systematically examines mutations at those three key sites (and one adjacent one that also varies in the superfamily). A library of all 160,000 mutants was prepared, and they used yeast fluorescent reporter assays to figure out the DNA binding and transcriptional competency of the whole shebang. As an aside, I really love modern molecular biology and chemical biology, because you can actually do experiments like this – just make every single one of the mutant proteins, test them all, sequence the ones that you find interesting, and nail down the answer. It’s not easy, and it’s not an afternoon’s work, but I well remember the days when a proposal like this would have been considered dangerously wasteful and stupid.

So starting from ancestral ERE selectivity, they found 828 variants that were specific for SRE DNA sequences, working as well as the current steroid receptors or better, with no affinity for the ERE sequences. Interestingly, they get to the selectivity in different ways, with different amino acid/DNA contacts than are seen in nature.  Graphing these out to see what the relationships were, it appears that virtually all of the functional mutants (1351 in total, including unnatural ERE selective ones) can be reached by single-point mutations from each other without going through inactive mutant proteins. The new SRE-specific protein sequences are scattered all around the graph; there’s no one bottleneck mutation that they particularly have to pass through.

And this persists under the constraints of many evolutionary models. Even if you insist that every step has to yield better affinity for SRE sequences, there are still many ways to get to them. In fact, the SRE sequences that we have now represent neither the shortest mutational path nor the highest-affinity final results. Over 90% of the SRE-selective mutants can get there by a path that’s no longer than the historical one. The evidence is that they just happened to happen that way, they worked, and here we are. It could have been many other ways, and if you reset they clock, odds are that something else would have fit instead. Another result from the graph is that if you start from different ERE-selective points, you have different paths to new SRE-selective ones. So the starting ancestral sequence we happened to have also was an influence; if you wound the clock back even further before the evolution of the ancestral receptor itself, you’d have a whole possible landscape of both forms.

There’s a further complication, though. There are eleven mutations (11P) that also differ between the ERE- and SRE-selective proteins, although they’re not directly at the DNA binding site. If you take those 11P mutations out and make the 160,000 variants again at the four mutation sites around the DNA-binding helix, things are more constrained. Now there are only 43 ERE-specific ones and 41 SRE-specific ones in the whole batch: 99.92% of the mutants are just nonfunctional, and what’s worse, the functional ones are almost entirely connected through nonfunctional nodes. So the ground had to be prepared – the relatively permissive protein landscape isn’t always there, and what we’re seeing is very likely the result of something like that being in place for the DNA-binding mutational landscape to be explored productively in the first place.

So how and why did the 11P permissive mutations take place? Looking at the mutational landscape, it fits with the hypothesis that these nonspecifically increased the affinity of the protein(s) for both ERE and SRE DNA sequences, and seem to have been part of a general improvement in the function of the steroid receptors. These general increases in affinity opened the landscape up to new functional mutations. Here’s the authors’ summary:

Our results shed light on the roles of determinism and chance in protein evolution. The primary deterministic force is natural selection, which drives the evolution of forms that optimize fitness. Chance appears in two non-exclusive ways: as historical contingency, when the accessibility of some outcome depends on prior events that cannot be driven by selection for that outcome; and as stochasticity, when there are paths to numerous possible genotypes of similar function, and which one is realized is random. . .Our results point to strong stochasticity and contingency in the many histories by which SRE specificity could have evolved. Hundreds of genotypes encoding SRE specificity were accessible from AncSR1, but selection for that function alone could not have deterministically driven evolution down any of those paths, because all were contingent on permissive mutations. . .

So the role of chance in evolution is there to see: chance built on chance, actually, with all the time in the world (well, all the time in our own world) to try things out. Things may look like they evolved deterministically, because we tell ourselves stories and our brains themselves seem to have evolved to look for them. But in reality, it’s likely that a lot of molecular-scale evolution just happened for no particular reasons at all. . .

 

Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer

Short Chemistry Topics

September 21st, 2017 04:28 pm[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

Blogging time is tight today, but there are several interesting stories and follow-ups that I wanted to mention. For starters, I wrote here about a cyclohexane analog that’s fluorinated all on one side of the molecule. That gives you very odd properties, and it and its relatives could be really useful solvents and additives, but getting such molecules has been very painful. Now, though, a route to this compound and others has been found from the far more readily available fluoroaromatic starting materials. The Glorius group at Münster reports hydrogenation using a particular rhodium catalyst that actually gives you access to all sorts of cis-fluorinated saturated rings, which is very nice to see. I would enjoy knowing if there’s a similar route that might work on fluoropyridines or fluoropyrroles to give the saturated heterocycles – any takers?

Second, here’s a neat paper for the NMR aficionados out there. It presents “supersequences” for combining a long list of useful 1D and 2D NMR experiments into single pulse sequences, importantly using only one relaxation delay (which is where the time starts to pile up). What you have, then, is an extremely efficient NMR experiment that gives you piles of data all in one run. The SI for the paper presents over 200 proposed supersequences, combinations of NMR data collection that will make your head spin. Just to give you the idea, they demonstrate one sequence that combines proton-nitrogen HMQC, proton-carbon HSQC, proton-carbon HMBC, COSY, and NOESY all at the same time, delivering pretty much everything you could want in small-molecule NMR at a substantial savings in instrument time.

While I’m on the analytical side of things, I should also note that the European X-ray laser facility (XFEL) is now open and running its first experiments. This is the fastest thing of its kind in the world – as I understand it, it can take 27,000 frames per second, which is completely new territory as far as time-resolved x-ray structure work goes, 200 times the rate of the LCLS machine out at Stanford’s SLAC facility. But there’s a free-electron laser arms race going on – the good kind, not the we’re-all-going-to-die kind. The LCLS is planning an upgrade that would take it up to millions of pulses per second, which will reveal things about protein structure alone that I can’t even imagine. I recall writing a blog post nine years ago anticipating these machines coming on line, and by golly, here they are. Time flies!

Courtesy of Angewandte Chemie/Wiley

Moving back to a much smaller scale (anything is smaller scale than a free-electron laser), do you know about Janus filters? These are membranes whose two sides are functionalized differently, and they can be great at separating out oil/water mixtures and breaking up emulsified messes. The problem with the current ones is that they haven’t been able to deal with emulsions that have non-ionic surfactants in them, and that’s a large category. But now there’s a new system that can handle pretty much the whole range. One side of the filter has polydimethylsiloxane on it, and the other has a polysoap, ethylene glycol spacers with laurate groups on the end. When an emulsion hits the polysoap side, that’s the emulsion breaker. The surfactant gets pulled away from the oil droplets, which then start to coalesce and move down the membrane material until they hit the PDMS side of things, where they happily dive through. The results is that you have a milky mass of emulsion on one side, while the oil/organic component slowly drains out the other while you go do something else (see illustration at right). I want one.

Piled Higher & Deeper by Jorge Cham
www.phdcomics.com
Click on the title below to read the comic
title: "Your Social Parabola" - originally published 9/20/2017

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Reading Wednesday

September 20th, 2017 10:35 pm[personal profile] rmc28
rmc28: Rachel smiling against background of trees, with newly-cut short hair (Default)
What I've read: short fiction
Actually read this week:Some of the backlog (all DSF):

What I've read: long fiction

Banishment by M.C. Beaton, which is the first of six apparently-fluffy Regency romances about six beautiful sisters and a malevolent stately home, recommended as a Yuletide fandom (thanks [personal profile] ceb for the pointer!)  This one was indeed the promised fast, lighthearted read, in which the family lose their beautiful stately home and much of their wealth, and (some of them) begin to learn Important Lessons About Not Being Awful To Other People.  And the first of the beautiful daughters finds true love, etc.  The remaining five in the series are now on their way so I can find out just how malevolent the house gets ...

Reading: Gemini

September 20th, 2017 09:18 pm[personal profile] white_hart
white_hart: (Default)
In the final book in Dorothy Dunnett's House of Niccolò series, Nicholas de Fleury returns to Scotland to try to make amends for the damage caused by his earlier actions and to safeguard his family from the enemies who have tried to kill both him and them so many times. For a while, I thought that Gemini was going to be a bit of an anticlimax to the series; several plot threads were resolved at the end of Caprice and Rondo, and Gemini is almost entirely set in Scotland, lacking the exotic locations of the earlier books. Nicholas has also changed and grown, and in Gemini is tackling the task of learning to care for people, and not just for the outcomes of his schemes. However, after a slow start, the novel gathers pace and the psychological drama is more than a match for the drama of any of Dunnett's other novels; there were just as many twists and edge-of-the-seat moments, and I found it just as hard to put down. It's a fitting end to the series, and like the ending of Checkmate leaves me wanting to go back and re-read key moments from earlier in the series in the light of the final revelations.

Fittingly, having started reading The Game of Kings on my 40th-birthday trip to Scotland, because I wanted to read something set in Scotland while I was there, I read Gemini while on holiday in Scotland once again. Three and a bit years, 14 books, at least 7,000 pages and an amazing sweep of European and Middle Eastern history in the early modern and late Middle Ages later, I can safely say that it has been one of the most intense reading experiences I've ever had. I can't actually remember who it was who made Dunnett sound intriguing enough for me to give her a try (I suspect it may have been a gestalt entity of friends and acquaintances), but it's been incredible, and in many ways I'm sorry to have come to the end. (I do still have King Hereafter to read, and will probably give the Johnson Johnson novels a try at least, but neither is going to be the same.)

This Week in Nazi-Punching

September 20th, 2017 04:15 pm[personal profile] jimhines
jimhines: (Snoopy Writing)

A video of a Nazi in Seattle getting punched and knocked out has been making the rounds. Responses range from satisfaction and celebration to the predictable cries of “So much for the tolerant left” and the related “Violence makes us as bad as them and plays right into their hands.”

A few things to consider…

1. According to one witness, the punch happened after the Nazi called a man an “ape” and threw a banana at him. With the disclaimer that I’m not a lawyer, that sounds like assault to me. I’m guessing Assault in the Fourth Degree. In other words, the punching was a response to an assault by the Nazi.

The witness who talks about the banana-throwing also says he was high on THC. I haven’t seen anyone disputing his account, but I haven’t seen corroboration, either.

2.Remember when George Zimmerman murdered Trayvon Martin, and people like Geraldo Rivera said it was because Martin was wearing a hoodie, and that made Martin a potentially dangerous “suspicious character”? Utter bullshit, I know. But if our legal system let Zimmerman plead self-defense, saying he was afraid because Martin was wearing a hoodie, doesn’t that same argument apply against someone wearing a fucking swastika?

We’re talking about a symbol that announces, “I support genocide of those who aren’t white, aren’t straight, aren’t able-bodied…”

3. Buzzfeed presents this as anti-fascists tracking a Neo-Nazi to beat him up. While antifa Twitter appears to have been talking about this guy, there’s no evidence that the punch was thrown by someone who’s part of that movement. And even if he was, the guy didn’t throw a punch until after the Nazi committed assault (see point #1).

Those Tweets quoted on Buzzfeed also suggest the Nazi was armed, which could add to the self-defense argument in point #2.

Is Nazi-punching right? Is it legal? As any role-player will tell you, there’s a difference between whether something is lawful and whether it’s good.

The “victim” has every right to press charges. But for some reason, he didn’t want to talk to police about the incident.

Was punching this guy a good thing? I mean, there’s a difference between comic books and real life. The Nazi was standing in front of some sort of tile wall. He could have struck his head on the corner after being punched, or when he fell to the ground. In other words, there’s a chance–albeit probably a slim one–that this could have killed him.

My country and culture glorify violence. I’d much rather avoid violence when possible. I think most rational people would. But there are times it’s necessary to fight, to choose to defend yourself and others. I think it’s important to understand the potential consequences of that choice.

Multiple accounts agree this man was harassing people on the bus, and later on the street. He was a self-proclaimed Nazi. Police say they received calls that he was instigating fights, and it sounds like he escalated from verbal harassment to physical assault … at which point another man put him down, halting any further escalation.

I don’t know exactly what I would have done in that situation, but I see nothing to make me condemn or second-guess this man’s choice in the face of a dangerous Nazi.

Mirrored from Jim C. Hines.

Posted by JenniferP

Dear Captain,

Over the last year, a once close friend of mine and I have been experiencing the African Violet of broken friendship. We had been through a very intense multi-year creative work project together, and after the project finished and she moved onto another job, we kind of drifted apart. For my part, I felt that sometimes she could say very unkind or cruel things. I noticed about two years ago that I was working very hard to win her approval, and felt very anxious if I didn’t get it and recognized that this friendship had become a bit unhealthy. I still valued many things about my friend, and thought that by setting some boundaries I could change the dynamic. After any incident where she said something unkind (for example, that half of the work on my part of the project was not my own work, which really hurt my feelings) or been judgmental (for example, negatively commenting on the dynamics of my relationship with my partner or how much I was eating and snacking during the intense project), I would take some space. Over the last couple of years my confidence has grown, not just in this area but in many other areas of my life, and I have been able to deal with some anxiety issues I had and learn how to set boundaries.

She started mainly hanging out with some different friends, and although we were still in touch, our conversation was becoming more and more surface-level. Anytime I suggested meeting up she would be really vague or say no. I was quite hurt at the time that she didn’t seem to want to hang out with me anymore, but I knew that we had just been through a really intense period in our lives and maybe she needed her space. There was always room for our friendship to get renewed further down the line. Before yesterday, we hadn’t been in contact for about four months. There wasn’t anything particularly negative about our last contact, it just tailed off.

I recently got a new job that I am very excited about and yesterday, in a whatsapp group she is also part of, someone congratulated me on my new job. About an hour later I got an feelingsemail from my friend. It’s not a nice email. It’s basically a bitter rant about how I have changed as a person. She said she didn’t recognize me anymore and how she had become fed up of what she perceives as my faults, and me being distant, over the last two years. She said that she didn’t deserve this kind of behavior from me and that she had never thought I would cut her off like this, although she had seen me do it to others (I don’t know where this comes from, I haven’t cut any one off apart from one girl back in high school which was 15 years ago!). In her mind, I am the bad guy, and it doesn’t sound like she is open to listening to anything else. She did say congratulations about the new job at the end.

I want to reply in a kind and compassionate way, because there were many things I valued about our friendship. We were so close, and I miss her. However, I don’t know what to say or how to respond to this email. I understand she sent it in a fit of overwhelming feelings, and underneath the accusations and manipulative statements, really she’s just sad about the loss of our friendship. I am open to being friends again, and rebuilding our relationship but it can’t be like this. I want to acknowledge the email, but I don’t want to get caught up in back and forth about who did what, or act in a way that says I think this email is acceptable, or apologize for things I haven’t done. How should I respond to this feelingsbomb? Should I even respond? How can people respond kindly and compassionately to feelingsmail in general?

Best wishes,
I’ve got feelingsmail

Dear Feelingsmail Receiver,

Your friend is projecting all over the place and all over you, a behavior where you take the stuff you are doing (especially stuff that you feel guilty about or ashamed of or upset about) and assign that behavior and the blame for it to someone else. Like the thing where you kept trying to make plans and she rebuffed you is now all about how you’ve abandoned her. Interesting.

Also Interesting: The less time you spend with her, the happier and more confident you’ve become over time.

Interesting Indeed: A really happy moment for you (congratulations on your new job!) has become the catalyst for her to criticize and accuse you of being a bad person and a bad friend. Not cool.

I don’t know how you repair that. It sounds like the way you’ve been drifting away from each other has been organic, with you taking care of yourself by taking space when you need it, and her choosing the company of other friends over you when she needs that.

Now she wants you to apologize and accept all the blame for the fact that your friendship isn’t as close as it was, and she also wants you to chase her. Do you want to do any of those things?

In your shoes I might just write back “Wow, okay??? Thanks for the good wishes at least. As for the rest, I miss spending time with you, too,” and just ignore the steaming pile of Feelings and Accusations. And then I’d let the ball be in her court to follow up, either to apologize or to suggest a time to get together.

I predict she will find this answer from you somewhat maddening and not see it as the face-saving mercy that it actually is, but that’s not your fault or your work to do to deal with. You don’t owe her a point-by-point response to her projection or the emotional catharsis she sought at your expense. (Note: You don’t actually owe friendship or any response at all to someone who sends you such a mean, rude message!) If she comes back with an apology or invitation to grab lunch or coffee, that will give you some useful information and if she comes back with renewed vitriol about what a terrible friend and person you are that will also give you some useful information.

If you do eventually sit down and address the issues in the friendship someday, you could say “Well, I’d been feeling like you didn’t want to hang out with me, so I stopped pushing and gave you space. I guess we’ve been mirroring each other.” It’s true and is neither an accusation nor an apology.

You can also ask her “Well, in a perfect world, where we have exactly the kind of friendship you want, how would you like this to work out?” and see what she says. In a difficult conversation where there’s a risk of getting stuck in a back-and-forth “It’s your fault”/”No it isn’t” about the past, this question can prompt people to stop and articulate a positive vision for the future. What’s the best case scenario where you get to recover a friendship that works for both of you? This “workable” version may be a very tiny, small-doses thing or no friendship at all, but I think this is your best chance for finding out if anything here can be saved.


Annie's Mailbox: Man only half there

September 20th, 2017 09:20 am[personal profile] cereta posting in [community profile] agonyaunt
cereta: Laura Cereta (cereta)
Dear Annie: I am 23 years old and have been dating "Tom" for two years. He works in a demanding job that requires an extensive amount of travel. He's away almost six months of the year.

When Tom isn't traveling, he's with me during the week, but spends most weekends going places with his fraternity or visiting his parents. This means for the six months he's in town, I get perhaps one weekend.

We are saving for a house, and Tom's constant recreational travel is cutting into our budget. I want our couple time back, as well as time to take care of things at home. I've suggested compromises (such as two weekends away and two weekends home), but things always come up that he "has to do." Two months ago, I was let go from my job. That same afternoon, Tom left on a trip with friends that could have easily been cancelled. I can't use those same weekends to visit my family because they are too far away, so I spend a lot of time sitting home alone.

I know nothing unsavory is going on. Tom is a wonderful guy. I have no intention of leaving him. I knew when we met that his job would require a lot of travel, but these personal weekends are difficult for me. I know he hates being inactive or staying home, but it seems excessive. How can we come up with a workable solution? -- Home Alone

Dear Home: Tom thinks he already has a workable solution and has no incentive to compromise. After all, he sees you all week. Right now, his schedule is a minor hardship for you, but if you marry and have children, it will be a major problem. You'll have to revisit this issue then.

Meanwhile, we are never in favor of sitting home alone moping. Please find things to occupy yourself during the weekends when Tom is absent. Look for part-time work. Take classes to bone up on your skills. Go biking. Accompany him when he visits his family, and get to know them better.

Alnylam Breaks Through

September 20th, 2017 12:35 pm[syndicated profile] in_the_pipeline_feed

Posted by Derek Lowe

As a pioneer in RNAi therapeutics, Alnylam has really had some ups and downs over the years (some of them chronicled on this blog). Today would be one of the “up” moments, for sure. The company (in collaboration with Sanofi) has just announced positive Phase 3 data on their therapy for hereditary ATTR amyloidosis – the RNAi, patisiran, met the primary and secondary endpoints with what look like solid numbers. This is the first time that an RNA interference therapy has made it all the way through clinical trials, so that’s a landmark. The company plans to file for FDA approval early next year.

It’s worth thinking back a bit to the earlier days of both Alnylam and RNAi. At one point about fifteen years ago, this was the hottest area in biotech, with everyone piling into it. Then came the backlash – several backlashes, actually, with some of the larger companies pulling out of the field completely and writing off their investments in it. Alnylam has stuck with it the whole way, and in light of this recent discussion of drug development costs, Andy Biotech on Twitter estimates that they’ve spend at least $1.9 billion along the way (and I think that’s not including opportunity costs/cost of capital, either).

Alnylam’s most recent Phase III trial also ended suddenly just last month, when an RNAi for hemophilia had to be dropped (update: put on hold) after a patient death. The company’s previous attempt at ATTR amyloidosis was also disastrous – rivusiran had gone into Phase III, but was abruptly pulled due to what was memorably described as a “mortality imbalance”. (As I understand it, Patisiran is from a later chemical series (update: actually earlier!), and the data-monitoring committee for its trial recommended that it continue after the rivusiran failure). So this is not exactly a well-worked-out path through the clinic, and a lot of onlookers were holding their breath waiting for these latest results.

hATTR amyloidosis is a nasty disease, and there is (until now) absolutely nothing that can be done about it. Note that American College of Cardiology’s recommendation of “supportive therapy and clinical trials”, which can be exactly translated as “Try to make the patients comfortable while they get worse, and hope that somebody discovers something that can help”. It’s caused by mutations in the transthyretin protein, which is produced in the liver and normally carries Vitamin A, among other things. The mutant form, though, forms amyloid fibrils, as many proteins will do under the right (wrong?) conditions. This manifests as toxic deposits of bunched protein in both the heart and nervous system, leading to heart problems and neuropathy of various kinds, which get worse and worse every year until you die.

This is a natural fit for an RNAi approach, on a couple of levels. Decreasing the amount of mutant TTR protein should slow the progression of the disease, and decreasing specific protein levels is what RNAi does for you, as it goes after the relevant messenger RNA. And the liver is one of the few places that we know for sure that you can get even the most advanced RNAi molecules to show up. The problems of drug delivery and stability are some of the big reasons it’s taken so long to get to this point (the same goes for all oligonucleotide ideas), and even now they represent serious limitations. But the liver, everything goes to the liver just for circulatory and digestive plumbing reasons. Things don’t necessarily make it back out of the liver, but they do go in.

So congratulations to Alnylam! This really is a major achievement, and the amount of time, effort, money and heartbreak it’s taken to get this far should serve as a monument to how hard it is to advance something really new in drug therapy. The work continues.

 

Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer

naraht: (Default)
nothing gold can stay (2628 words) by Naraht
Chapters: 1/?
Fandom: Yuri!!! on Ice (Anime)
Rating: Teen And Up Audiences
Warnings: No Archive Warnings Apply
Relationships: Yuri Plisetsky & Victor Nikiforov, Yuri Plisetsky & Yakov Feltsman, Lilia Baranovskaya/Yakov Feltsman
Characters: Yuri Plisetsky, Victor Nikiforov, Yakov Feltsman, Lilia Baranovskaya
Additional Tags: Rivals, Post-Canon, Growing Up, Coming of Age, growth spurt, Injury, 2018 Winter Olympics, Aging
Summary: Yuri Plisetsky will never step out of Victor's shadow. Not if Victor has anything to do with it.

Or, the epic Nikiforov/Plisetsky rivalry in the run-up to the 2018 Games.



Here it is, the long one. The first chapter of the long one, at least.

A friend tells me that 'rage-filled teenage boy athlete' is not my usual aesthetic – probably an understatement! But it's a refreshing change in writing terms, and it's good to stretch yourself... right?

Posted by Derek Lowe

Since the topic of bacteria effects on human disease came up here just the other day, I wanted to point out a new article that comes at this idea from a different direction.

This research got going when cells from pancreatic and colon tumor samples were co-cultured with human dermal fibroblasts. The cancer cell lines unexpectedly became more resistant to gemcitabine under these conditions, and it turned out that just transferring the medium from such cultures to other tumor cells was enough to reproduce the effect. However, if the medium was passed through a 0.45 micron filter beforehand, it did not bring on resistance at all. That immediately sets off alarm bells about bacterial contamination, and so it proved.

The human fibroblasts, on closer inspection, contained Mycoplasma DNA (at this point, the cell culture people in the audience can groan and say “What doesn’t?”). Treating the fibroblasts with an antibiotic also abolished the resistance effect on the later tumor cell cultures, an effect that could be reversed by re-inoculation with the M. hyorhinis species that seems to be the culprit. But it’s not just that one – they tried infecting the fibroblast cultures with 27 different bacteria, and half of them led to the same problem.

The Mycoplasma problem had been noted in cell culture just a few years ago, and the real culprit is a deaminase enzyme that turns gemcitabine into the (inactive) uridine analog. But this paper goes further. The authors (a large multinational team) show that rodent tumor xenograft can be inoculated with bacteria, and this treatment also makes the tumors much less responsive to gemcitabine, an effect reversed by antibiotics. They took this experiment all the way down to an implantable device inside the tumor mass to release antibiotic locally, and showed that only around the site of release did gemcitabine have the desired effect.

The final test was to see if this is happening in human patients. The paper details how tissue samples from pancreatic ductal carcinoma patients were carefully tested for bacterial ribosomal DNA, and the results were pretty stark: 76% of the tumor samples showed up with bacterial contamination, as compared to 15% of normal tissue controls. In situ hybridization confirmed the result. Sequencing suggests that these bacteria have migrated in from the duodenum, and the species detected all produce the deaminase enzyme. Finally, adding the bacteria from the human samples to the cell culture experiments showed that they indeed confer gemcitabine resistance – Robert Koch would be proud to read this paper, for sure.

This work immediately suggests that any cancer patients receiving gemcitabine be treated with antibiotics, and I hope that this affects clinical practice quickly. You wonder how many similar stories are out there that we don’t know about yet!

 

 

Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer

full_metal_ox: (Default)
[personal profile] sasha_honeypalm's musical tribute to Barbara G. Walker's (professionally published!) novel
Amazon:


Don't know much about history
Don't know much about theology
Don't know much 'bout how to write a book
Don't know how to cite the quotes I took
But I know all that I say must be true
And I know if you believed it, too
What a wonderful world this would be

Don't know much about geography
Don't know much sociology
Don't know how to understand folklore
Don't know what a reference book is for
But I do know that one god is bad
And if we'd kept the goddess we once had
What a wonderful world this would be

Now, I don't claim to be a goddess
But I'm tryin' to be
For maybe if I'm a goddess, people
You'll all worship me.

Don't know much about history
Don't know much about technology
Don't know much...


[personal profile] rosepsyche's paean to the Power of Story is also quoteworthy:

I have to call "bull" on Antiope's reasoning that art and music are inferior because they are "not alive" for another reason. No, such creations aren't living, breathing things. However (and I apologize if this gets a bit corny), the best of them can seem as if they are alive, get us invested in their characters, have us cheering about their triumphs and crying over their tragedies. They are just as valuable in their own way for their ability to entertain, to inspire, to teach, to help us grow and develop by seeing the world from a new point of view, and I don't think anyone involved in creating them would appreciate being told that their work can never compare to something that was squeezed out of a vagina.


Context sporks the world's worst Wonder Woman fanfic.

Posted by JenniferP

Video description: The Bangles cover Big Star’s September Gurls in Pittsburgh in 1986.

It’s time for the monthly thing where we answer the things people typed into search engines as if they are actual questions. This feature is generously funded by Patreon supporters.

1 “How to stop a neighbour and hubby putting me down every time I walk past
.”

Ugh, your husband is being a giant asshole, and it’s time to tell him straight up to knock this behavior off. “Stop doing that. It’s rude, disrespectful, and it hurts my feelings.” If he won’t, you’ve got Husband-problems more than you have Neighbor-problems.

2 “What does it mean when a girl says focusing on school right now after you say your feelings
.” 

It means she did not enthusiastically say “Yes, I feel the same way, let’s definitely date each other!” It means she’d rather focus on school than go out with you. Interpret it as “No.”

3 “Anonymous STD notification letter.”

National treasure website Scarleteen recommends InSpot  for sending an anonymous e-card and has a good how-to guide on doing this kind of notification. Australia has a service called Better To Know that lets you notify partners of possible Sexually Transmitted Infections (STI) anonymously via text or email. In both cases, you enter info, the person gets a message that lets them know that they may have been exposed to an STI (+ there’s a way for you to enter which ones) and should get tested. There’s a good roundup of similar services in this article.

If you’re feeling blue and alone in this, the Netflix show formerly known as “Scrotal Recall” (now renamed Lovesick) is a romantic comedy about a man who must notify past sexual partners about possible chlamydia exposure.

If you don’t want to go anonymous, a simple text or phone call that says “Hey [Sex Friend] I recently tested positive for ________. You should get checked out, too” is a very kind and ethical thing to send. The more we all remove stigma and shame around STIs, the better job everyone can do taking care of ourselves and each other.

4 “My boyfriend mom prophesied that we are not meant to be together.”

Translation: Your boyfriend’s mom does not want you to be together.

What do you and your boyfriend want?

5 “When some knocks on door and says the Lord compelled them to stop and talk to you.”

Translation: The someone wanted to stop and talk to you.

What do you want?

6 “How to decline a neighbor asking us over

.”

“How nice of you to think of us, but no thank you.”

7 “What to do when your friend sets you up on a blind date and the guy’s interested in her.”

Acknowledge the awkwardness, have a good laugh together, tell the guy “good luck, dude, tell her how you feel and maybe we can avoid this sitcom nonsense next time” and go home with your dignity. You didn’t do anything weird.

8 “Should you invite girls of interest to your party

.”

Throwing a party is a great reason to invite someone that you might be interested in romantically over. That person can meet your friends, see your place, everyone can see how everyone gets on together, you can get to know each other better without having it be a DATE date, etc. Why not?

Now, girl(s) plural is an advanced move, but again, why not?

9 “What do you do when your daughter owes you money and is not paying you back but takes vacations and spends a lot
.”

Ugh, this is a hard one. Here are some steps for dealing with friends and family members who are not good/prompt/conscientious about paying back loans,

a) Assume that you won’t ever be repaid. Take whatever steps you need to shore up your own financial well-being so that you’re not depending on that money. If you do manage to collect it it will be a happy thing.

b) Ask the person to repay you what they owe. If you bring up fancy vacations or their other spending they will get automatically defensive, so skip that part in your request (even if it is relevant to the issue). Why skip it? You don’t need the story about how she bought the tickets long ago or how they were really a gift from a friend and you don’t want to give her a reason to feel judged and aggrieved (even if judgment is warranted). The vacation money is spent. It’s not coming back. She knows that you know that she knows that she owes you money. Just be simple and direct and ask for what you need:

Script: “Daughter, you still owe me $______. When can we expect repayment?” or “Daughter, you still owe me $_______. Can you repay me by (date)?” Brace yourself for the wave of defensiveness and excuses that is coming. Do not, I repeat, do not get into the details of her spending or her excuses or reasons. Just repeat the question. “Okay, so, when can you get the money to me?

c) Don’t lend this person any more money. You may or may not ever get the money back, but you can definitely control whether you lend them more. You now have a lot of information about how they’ll behave when you lend them money and you both have a hard, awkward lesson. Past behavior is the best predictor of future behavior here, and “I’m sorry, Daughter, I don’t feel comfortable lending you money since you didn’t pay me back” is a situation your daughter created, not you.

I hope you get a good result. Also, general thought, if you are going to lend money to friends or family, it’s a good idea to put something in writing: How much, what it’s for, when & how will it be paid back. Your script can be “Let’s just write it down so we all know what the agreement is and I never have to bug you about paying me back.

10 “Etiquette of peeing when surfing.”

We are people of action and lies do not become us: In the unlikely comedy of errors that lands me on an actual surfboard in an actual body of water, there is no way on earth my enthusiastic and prolific middle-aged bladder is gonna be able to wait until I swim to shore, find a land-based bathroom, and peel off my wetsuit in time to pee decorously in a toilet. This seems like a “it’s a big ocean” and “that’s between you and your wetsuit” issue to me, but maybe an actual surfer has insight?

11 “How to make girlfriend move out to Colorado.”

You do not make. You ask, and then she either moves or she doesn’t.

12 “I have to leave the Midwest or I will die but my husband thinks it’s all in my head.”

Ok, this seems like a REALLY specific situation and we are DEFINITELY missing context here but what if I said “Even if it were in your head, is your need to go so great and so urgent and so necessary that it’s worth going alone, even if that’s a difficult & sad decision?”

13 “Dating female academic awful
.”

It certainly can be, since the prospect of relocation is always hanging over the whole deal.

14 “He said he wants to do his own thing and maybe see other people.”


Translation: “I am planning to see other people and have less energy/focus/time/interest for a relationship with you.”

It’s a prelude to a breakup, possibly one where “he” either wants you to be the bad guy and actually do the breaking up or where he’d like you to stick around in his life but in background/low-priority mode.

15 “My 23 year old son looks so unattractive, but he won’t shave or cut his hair
.”

[Bad Advisor] Well, it’s definitely 100% his job to make sure his face and body look attractive and acceptable to you, his parent, at all times so definitely be sure to bring this up as often as possible! Your concern, constantly expressed, will only bring you closer together as a fellow adult human strives to please you in all things, including and especially the hair that is growing on his personal face and body where he lives and you do not.

Also, to be on the safe side, hide all of your copies of the musical about this very question, lest he get ideas about fur vests, naked dancing or protesting the Vietnam War.

It is not only your business but your duty to set this young man straight. [/Bad Advisor]

16 “What does it mean if you ask for a guy’s phone number and his response is he is antisocial
.”

He did not want to give you his phone number, or, if he does/did, he is warning you that he doesn’t want to actually hang out. Try again, another dude, another day.

17 “Fucking past due invoices.”

Fucking the worst.

18 “Girlfriend of 11 years is leaving me
.”

Wallow. Fuck Around. Do The Thing.

Repeat the Bene Gesserit Litany Against Fear to yourself.

(Or not, as it suits you).

19 “Angry that my husband allows his parents to come whenever they want
.”

This would make me angry, too. His family may have a drop-in culture or agreement and expectations, but you do not, and therefore the family that you and your husband make together does not. There are several conversations/actions that need to happen if they haven’t already (and maybe they have and need to happen again):

a) “Husband, I want your folks to feel and be welcome in our house, but to make that happen I need some advance notice. Please ask them to call first and ask if we’re free, and please check with me before you say yes.” 

b) “In-Laws, I really want you to be and feel welcome in our house, but I need more advance notice than you’re accustomed to providing. Just dropping by, even when I’m happy to see you, really stresses me out. I know this is different from how you do things in your family, but I need you to call first and ask if I’m free or if now is a good time. Thanks!” 

c) “Husband, I know I’m somewhat ‘changing the rules’ on your family, but I really need some consideration here. Back me up.” 

d) When they just drop by anyway and your husband isn’t home try: “Oh, too bad this isn’t a good time, I’m just stepping out” + LEAVE (go to the library or run errands or something, just take a drive around the block on principle). Btw if they have keys and are in the habit of just letting themselves in, put the chain on when you’re home alone. Teach them that you won’t drop everything because they came over.

e) When they just drop by anyway and your husband is home, “Oh, too bad, this isn’t a good time, I was just about to take a nap” + HIDE (in your bedroom with the door shut  – keep books handy – and let him do whatever work of entertaining them). Risk seeming unwelcoming and unfriendly. You ARE unwelcoming…to people who invite themselves over.

This didn’t start overnight and won’t go away overnight but in my opinion it’s a battle worth picking.

20 “How to agree a girl for fucking if she dislikes doing it.”

Find someone else to fuck. Someone who likes doing it. Someone who enthusiastically likes doing it with you.

What the fuck, people.

21 “Got an apology from my ex after 15 years
.”

That had to feel weird.

Whether this was welcome or unwelcome contact, there’s one important thing you should know:

It doesn’t obligate you to do anything or feel anything or re-open any kind of contact with this person. If you want to talk to them, ok? You could say “Thanks for the apology, I forgive you and wish you well” if that is true of how you feel.

But if you’d rather let the past stay in the past, you can 100% delete the weird Facebook message or whatever and go on with your life.

22 “Did the date go good or bad?”

This is a great question. You can’t control whether another person will like you, so after a date ask yourself:

  • Did I enjoy myself?
  • Was I relaxed and comfortable with this person?
  • Could I be myself around this person?
  • Did the conversation flow?
  • Did I feel like the other person was on my team, helping the date go smoothly and laughing gently at any awkward moments? Or did the awkward silences turn into awkward chasms on the edge of the awkward abyss?
  • Did the other person seem at ease and comfortable with me?
  • Was the actual time we spent together fun/enjoyable/comfortable/pleasurable?
  • Was it as good as spending time alone doing something enjoyable or with a good friend or do I wish I’d just spent the evening at home?
  • Was I bored? Checked out? Apprehensive?
  • Was it easy to make plans?
  • Do I feel like the person was listening/paying attention/engaged?
  • (If kissing is a thing you’re interested in) Can I picture myself kissing them?
  • Am I looking forward to hanging out again?
  • Were there any red flags?*

If the date went well for you, where you enjoyed yourself and felt good, ask the person for another date. The rest is up to the other person.

If you can get in the habit of checking in with yourself about your own comfort and enjoyment levels during and after dates, even a “meh” date can be useful because you’ll know more about yourself and what you’re looking for.

*Bonus list of some of my personal First Date red flags from back in the day when I bravely put on clean shirts and lip gloss and met strangers from the Internet for drinks:

  • Was the person I was meeting generally congruent with the person presented on the dating site and during any prior conversations? If you’re “single” on the dating site and suddenly “planning to get divorced btw we still live together and no one at work knows we’re separated so I’d appreciate your discretion” when we meet, if you’re 28 in all your dating site photos and 58 in person…it was not going to work.
  • Did the person monologue the whole time?
  • Did I feel like I was monologuing the whole time at someone who just shyly stared at me and nodded? (The Silent Type is a great type and it may be your type but experience tells me it was not mine).
  • Did I feel like I was an unpaid nonconsensual therapist while someone shared everything about their life?
  • Did the person constantly talk about their ex & exes?
  • Was literally everything they said a complaint about someone or something?
  • Were these complaints at least funny and entertaining?
  • In these complaints was nothing ever their responsibility? Was it just a long list of Ways I Have Been Wronged By Others with a subtext of Surely You Have A Duty To Not Disappoint Me Like Everyone Else Has (Now That You Know My Tale of Woe)?
  • Ugh, mansplaining, especially politics or philosophy, how movies get made, the “authenticity” of whatever food we were eating, the makeup & history of the neighborhood where I lived and they did not (for example when I failed to pick the “most authentic” taco place in Pilsen or Little Village), telling me why everything I liked was actually overrated.
  • Talking during movies. No.
  • Taking me to some sort of performance and then critiquing how much it sucks into my ear in real time. No.
  • Overfamiliarity, over-investment. “I can’t wait to introduce you to my son, he’s going to love you!” Ok but u just met me I am still wearing my coat slow down friend.
  • Overdoing innuendo & sex talk too soon, like, “I just got a new bed, it’s very comfortable, you’ll have to come test it out with me later heh heh.” Ok but u just met me I am still wearing my coat slow down friend.
  • Overdoing it with the touching. If dinner and a movie remind me of how my cat likes to constantly crawl all over me and make annoying biscuits everywhere it’s too much touching!
  • Negging of all sorts, especially “I don’t usually date ________, but you seem really cool.” (Bonus Nope!!!!! if the blank includes fat people, feminists, “women who seem really smart”)
  • Constant contact, expecting constant texts/calls/emails before we’ve even met in person, all up in my social media biz, “liking” every single photo/comment going back through the archives. It feels good to be seen and not so good to be surveilled.
  • Neediness  – We literally just met, so, surely there is someone else in your life who can drive you home from dental surgery or hold your hand while you put your dog to sleep or fly home with you to your father’s funeral or weigh in with you about whether you should accept this job offer? (All true stories of actual things actual men wanted me to do after a few emails and one hour-long bar or coffee date). I will move mountains to take care of people I love, when, you know, I have had a chance to figure out if love them.
  • Casual, “ironic” sexist or racist comments, dropping code sentences like “I hate all the political correctness these days, I feel like I can’t say anything.
  • Bringing your feature screenplay to the date for me to read.

Your Mileage May Vary, as the great saying goes. My list doesn’t look like anyone else’s and I may have had stuff on there that is not necessarily a problem in itself or not a problem for you, or where there are exceptions to be made (I did drive the guy home from dental surgery as a human favor for a fellow human being, I just didn’t date him more) or that are just differences in styles and interest levels. It’s not meant to be universal and it’s about compatibility with you vs. any one thing being Good or Bad.

I’m including the list because I developed it over time by paying attention to what made me feel good, comfortable, safe, relaxed, happy, excited and what made me feel the opposite.I stopped asking people “Is this normal/cool/okay thing when you date?” and started asking “Am I good with this?” and “Am I delighted by this?” Those experiences (and the decision to be picky about second and third dates) helped me avoid some entanglements that would have been fleeting at best and draining at worst, and it helped me know “Just Right” when I saw it.

We focus so much on the auditioning aspect of dating – Am I good enough? Does the other person like me back? – that our own comfort and needs and pleasure can get lost right when we need them most. It was a good date if you enjoyed yourself and felt good and did your best to be kind and considerate. It was a bad date if you didn’t enjoy yourself. Whether a good date will lead to another one is up to more than just you.

 


So much of the so much

September 18th, 2017 08:36 am[personal profile] sine_nomine
sine_nomine: (Default)
There is lots going on. Mostly good. Some not so good. I watch the news on the hurricanes and marvel at The Weather Channel's ability to make weather "news". It would be interesting to research that shift, in fact.

And I worry about the people in harm's way - especially places like Barbuda which were nearly obliterated by Irma (and not "decimated", as I heard one person describe it; yes, common parlance has gotten "decimation" to mean "in large part" versus "one in every ten - be it tithe or killing of mutinous soldiers.... but it lacks the precision and clarity and honesty that "obliterated" does, to me).

And I worry about the people in my life who are wrestling with personal hurricanes, and those challenges.

And I struggle with a bunch of stuff myself, and try to figure out how to move forward, but move forward I must.

Onwards.

Posted by Derek Lowe

Chemists love crystals. We don’t do as much recrystallization as we used to, since there are higher-throughput (and less labor-intensive) ways of purifying things these days, but I don’t think I’ve ever met an organic chemist who isn’t happy when a product crystallized out nicely. And we all know what crystals are like – straight-sided, hard, brittle, prone to fracture under stress into smaller shards, etc.

Or not. People who do grow a lot of crystals (typically for X-ray structures) can tell you that while most things fit that description, there are some oddball outliers. You see some compounds that grow long, curved crystals, for one, which makes you think that one face is behaving differently in solution than another. Some of the longer ones are surprisingly twangy, and can take a good deal of bending before shattering, and even the chunky, faceted ones vary quite a bit in how hard and friable they seem to be if you expose them to stress. There’s a lot going on in the crystalline solid state, and not all of it is well understood.

Credit: Nature Publishing Group

This paper illustrates the point, for sure. It’s looking at what you’d think would be an unremarkable coordination compound, copper (II) acetylacetonate, known to many chemists (as are its kin) as “copper ack-ack”. I would not want to guess how many (acac) metal complexes have been crystallized, alone or with other ligands, but let’s stipulate that it is a large heap, and that it’s a very well known species. But you can grow long needle-like crystals of the plain Cu(II) complex that act very weirdly indeed. They’re long and flexible, and as that photo shows, can actually be threaded into knots and then untied. What’s going on at the atomic and molecular level to allow them to bend this much without breaking?

The paper presents a careful X-ray study that figures it out. The authors (from Queensland) mounted a bent crystal in a synchrotron beam and carefully focused in on different parts of bent shape. They found that a particular crystalline axis was significantly elongated on the outside of the curve, and compressed on the inside, as you’d well imagine. It turns out that while each individual copper-acac molecule is identical as the crystals bends, the arrangement they make with each other certainly changes. The distances between the crystal planes don’t change, but the molecules themselves rotate with respect to each other (here’s a movie from the paper’s SI files illustrating that). The changes are not large at all, but when you add them up across several zillion molecules in a long crystal, it gives you some real wiggle room. A philosophical question comes up: if such a sample is not a regularly arranged array of molecules across its width (or not any more), is it still a crystal, or not? If not, do we have a word for what it is?

This is a nice piece of crystallography, of course, but people into materials science will appreciate that there are a lot of interesting features that might emerge from some changes. The optical and magnetic properties of the different sides of such a crystal could well be different (in fact, might almost have to be), and these changes could well be valuable in real-world applications. These results apparently also go against at least one theory of what sorts of crystals can undergo such deformations and how they do it, which would make you think that there could be several different mechanisms available. There’s a whole world in between crystals and amorphous matter, and there’s a lot being discovered in it.

 

 

Note: All opinions, choices of topic, etc. are strictly my own – I don’t in any way speak for my employer

Fitbit goal check

September 17th, 2017 10:26 pm[personal profile] rmc28
rmc28: Rachel smiling against background of trees, with newly-cut short hair (Default)
numbers )
Piled Higher & Deeper by Jorge Cham
www.phdcomics.com
Click on the title below to read the comic
title: "Inner Gollum" - originally published 9/15/2017

For the latest news in PHD Comics, CLICK HERE!

Question thread #56

September 16th, 2017 07:45 pm[personal profile] pauamma posting in [site community profile] dw_dev
pauamma: Cartooney crab holding drink (Default)
It's time for another question thread!

The rules:

- You may ask any dev-related question you have in a comment. (It doesn't even need to be about Dreamwidth, although if it involves a language/library/framework/database Dreamwidth doesn't use, you will probably get answers pointing that out and suggesting a better place to ask.)
- You may also answer any question, using the guidelines given in To Answer, Or Not To Answer and in this comment thread.

Profile

tinyjo: (Default)
Emptied of expectation. Relax.

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