Monthly Archives: December 2002

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Martin Scorsese, shame on you.

You had a fantastic idea--you opened up a period of history that has been ill-served. You created a magical spectacle, a sweeping drama with superb visuals. You brought Daniel Day-Lewis back to us, and for this, we love you.

But then what did you do? You hired an incompetent editor. There are more than a dozen bad cuts--not stylistic choices--just crappy continuity and amateurish slices. What's the matter, didn't you film enough coverage? Couldn't you give up those two seconds where Diaz sweeps her skirt around and squats against the wall? Nice shot, but if you can't edit to it properly, let it go.

Then you couldn't decide what story to tell. Subplots = good. Rambling = bad. You have made enough films to know how to weave it tightly, make it flow, make it dance intricately, beautifully to the viewer's imagination. Here, you began an intimate story, then drowned it in historical action. Just one more re-write might have done the trick, but you missed this. You missed it badly.

Finally, you told us that women weren't involved. Well, there was the one with the filed teeth. And all the nice prostitutes. And Diaz, who could have disappeared completely without hurting the plot. I guarantee you that the women were as important as the men in this struggle--but you chose not to look. You don't understand women, and you certainly don't understand Irish women.

If this were your second or third film, most of these gaffes would have been perfectly forgivable. On the whole, Gangs is a gorgeous film. It may even be one of the top five or ten of the year. But this was your 35th film. It was so sloppy you didn't even bother to make Day-Lewis's glass eye believable. If you couldn't pull it off, you could have written it out. But you preferred to go sloppy. I expect more from someone of your obvious genius. You blew a fantastic premise. You wasted a unique opportunity. I left the theater angry with you. For shame.

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On Christmas at around 9:00pm, Bill answered two wrong numbers. They were both the same woman, calling for someone named Wendy*. She sounded drunk. Bill was very kind to her. Later in the evening, when we were in another room where we couldn't hear the phone, she called again. I didn't pick up the message until a few days later.

What resulted is a mix of poignant and pathetic. The woman is remarkably articulate for being so obviously inebriated (I didn't edit, except to add punctuation). I'm not sure what to think about it, but I know I want to keep it:

Uh, hello, Wendy I'm trying to reach you, I need to reach you, I know you're home. I know you go to work tomorrow. please answer your phone, honey. I'm begging you.

You're gonna get so much stuff, and that's all you care about from me, so please, answer the phone. Please, Wendy. I'll never ask you again for anything. And you're getting everything of mine. I mean everything. I made out my living will; you're getting everything. Please, Wendy, please, please, I'm begging you to call me back.

You always say you can call anytime, you can come over any time, but you know that's a lie. Please, honey, I'm begging you. Please, Wendy. I don't know how much longer I can stay awake. Please. Please. You're getting everything you've always wanted. You have been blessed with that and you are gonna be blessed again. Please Wendy, please.

I am your mom. I had a choice not to keep you or keep you and I kept you, even though it meant losing my life, I kept you. But I didn't, we both lived through it. I've loved you all my life, and I've seen you, I don't know what life was like before you. You're so cruel to me! I need you to call me. You avoid me, you lie to me. You say come over any time but you don't mean it cause you don't even have my coat, you lost it. My 23-dollar moisturizer is gone, everything, my book--my library book's gone, my stationery's gone, everything is gone.

I don't have anything any more. I don't have photos of you any more Wendy. I'm so proud of you and I don't have photos of you. I love you so much, why are you doing this to me, Wendy, why? If you'd stop doing it I wouldn't be sad all the time, don't you understand that? All you gotta do is call these doctors. I'll sign releases for you. Or all you gotta do is call Tony, he talked directly with them.

*Her name has been changed.

January 3, 2003 Addendum:

For the past two nights, a deep voiced woman (not Mom) has called asking for Wendie. Last night she was quite rude, accusing Bill of lying to her, and asking him if he was someone else--presumably Wendie's boyfriend. He was not impressed, and told her not to call again.

A guestbook. How quaint.

I can't believe that thing is still around. I took it down about a month after I put it up, I think. Somehow, someone found it and it showed up in my referrer log.

Of course I couldn't resist dinking with it a little--I updated the graphic and made it slightly less ugly. But only slightly. Maybe I should put it up again.

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Are you a thoughtful gifter? Here's the test:

Your spouse (or mother, or best friend) looooves orange paisley. They wax poetic about it, but have little as it's so rare a thing. You are shopping and find the perfect orange paisley scarf. They will absolutely love it. You, on the other hand, loathe and despise it. You will cringe a little every time you see it. You:

  1. Tell him about it, and let him get it his own darned self.

  2. Never speak of it.
  3. Take a deep breath and buy it for him.

While none of those answers is necessarily wrong (we all must defend our aesthetic comfort zone), it is naturally number three that is the sign of a good gifter. But don't feel bad if you aren't one. Gifting well is a learned behavior. That's right, I'm afraid your mother only loved the ballerina earrings because they came from you.

Buying The Right Stuff

Want to find the perfect gift? It all depends on your knowledge of the giftee. Two-thirds of gifting is observation. This may require a little stealth. Some important suggestions:

  • If you feel confident buying clothes (about the last thing I'd recommend), jot down the sizes of the garments the giftee likes the best.

  • Notice what the giftee has a lot of. A collection of turtle figurines is a good hint.
  • Go shopping with the giftee for someone else, and notice what they look at.
  • What does the giftee do? What wishes have they shared? Is there a nostalgic story from their childhood involving a favorite item?

Some things to avoid:

  • Unless you have a specific title you're sure of, and you know they'd never buy it themselves, stay away from media. Music and movies are things people casually buy for themselves, so you're likely to get scooped. If they have an Amazon wishlist, then disregard this advice--you've got a sure thing (unless they don't update it--someone stayed mad at me for a long time over just such an incident).

  • Clothes are very personal. You must have a keen sense of your target's taste before embarking on such a risky journey. The same goes for fragrance.
  • Never buy someone else something you want, disregarding their tastes. Just because you like it doesn't mean they will. This isn't about you.
  • Unless the giftee is your child or (maybe) spouse, never, ever give a pet.

Once you've got a few ideas, make a little list. If you have specifics, that's great; but also jot down ideas. My list this year looked something like this (not the real items--my giftees read me ;-):

Star Trek
Bath stuff
Dvorak
Fantasia
White chocolate

Carry your cheat sheet everywhere, and repeat it in your mind. Next, go to places your target wouldn't necessarily go. Gift shops in museums and libraries are great for unusual items. Science shops, art supply stores, toy stores, etc. Especially good: many cities have markets full of beautiful, hand crafted merchandise. Just stay away from crocheted toilet roll covers. Unless I'm gifting people I don't know all that well, I tend to stay away from general merchandise stores. Going unusual places will increase your chance of finding that perfect thing that will pleasantly blindside your giftee.

Are Gift Certificates Rude?

You betcha. Well, okay, not always. A gift certificate must be given very carefully, with a specific purpose in mind. Good certificate giving:

  • A housewarming gift of a certificate to a decor store

  • An evening out package of restaurant and movie certificates.
  • A pampering package of spa, salon, and clothing certificates

Get the idea? A generic certificate says "I'm off the hook." Is that what you want to say to someone you love?

The Best Gift...

...is almost always handmade. I have an afghan in garish red, yellow, and blue. It's the most obnoxious thing you've ever seen, but I love it because someone made it for me. A mix of favorite music, or a framed picture of you or the giftee are good for those without the crafty skills.

What About Gift Baskets?

Yes! Gift baskets are wonderful things to give and to receive. They're low-stress to put together, and a lot of fun. Here's how:

  1. Decide how big your basket will be--you can buy it first or not. Beware of over spending if you decide to buy the basket last.

  2. Find great generic things that go to everyone. Specialty foods and candy, toys, a book of humor, some holiday glassware, ornaments.
  3. Make things that go to everyone. Fudge, cookies, handmade bookmarks.
  4. Find one special thing for each person.
  5. Get decorations--garland, confetti, etc.
  6. If possible (if you're shipping, it's harder), pack the basket for attractiveness. Leave food visible--cover homemade items in clear, colored cellophane. Wrap non-food items.
  7. Decorate liberally between the items. Take a look at how professional baskets are done. Make it look packed.

But I don't know this person!

That's a toughie. First, consider closely why you are gifting this person at all. Too many times we fall into the trap of obligation--beware of it. That way lies the path of horrible, stressful holidays. In the end, we all have a few folks on our list whom we don't know well enough. There are still good generic possibilities. Of course, find out as much as you can. Ask their friends and family what they like--but be careful. Remember you're getting filtered information. Here are some ideas for giftees who aren't in your pocket:

  • Candles (always unscented--allergies!) and candle accessories

  • Plants
  • Candy or specialty food (jams from a local grower, for example)
  • Gift certificates for movies, restaurants, massage, etc. (Remember: be specific!)
  • Bath goodies (probably shouldn't get this for guys--too bad--they don't know what they're missing!)
  • Boxes--a really nice container filled with a little candy is often good.

The last tip: shop year-round, or at least get started early. What? You're not done with your holiday shopping? GET TO IT!

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Ever discover a humor site, and think to yourself that you wish you'd discovered it years earlier? Well, here's a chance to get in on the ground floor.

Izzle Pfaff! launched a few days ago. It is the blog of one of the funniest men I've ever met. It may, in fact, be the first-ever attempt at a short form comedy blog.

And before you think I'm pimping Skot just because I designed the site--I put it together because I'd been begging him to get a site for a long time. I finally decided that if I wanted it so badly, I should put up or shut up.

So consider this your engraved invitation to Izzle! Izzle pfaff!

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A quick correction to my last post: there are typically only 72 'cloves' stuck into the 'orange', and cloves are too small to make a good visualization. Golf tees stuck into a small orange might be closer. Go here to see numerous pictures of HIV-1 (scroll down to lentiviruses).

The cloves or tees are made up of a 'stem', glycoprotein (gp) 41 and a 'knob', gp120. The numbers are simply the molecular masses of the molecules, in kiloDaltons (a Dalton is the mass of a single hydrogen atom). The stem is inserted into a lipoprotein membrane (the skin of the 'orange', if you like; but stop thinking of an orange now, because the inside of the virus is nothing like that) which is derived from the host cell and surrounds a protein coat composed of the viral matrix protein. Taking up a good deal of the space inside this coat is the viral core, which is often appropriately described as 'coffin-shaped'; the primary structural component of the core is the viral capsid protein. Inside the core are two copies of the viral genome, about 9000 bases of single stranded RNA, each complexed with (inter alia) one reverse transcriptase molecule. Other viral proteins, notably integrase and protease, are also present in the core, together with molecules 'stolen' from the host cell from which the virus particle emerged. One notable 'stolen' molecule illustrates just how intimately evolution has intertwined the biology of the virus with that of the human host: HIV-1 uses human tRNA as a primer for reverse transcription. Not only is a specific tRNA required, but mutations which allow the use of an alternative primer rapidly revert to the wild type. (Transfer (t) RNAs are the 'connectors' that recruit amino acids to the site of protein synthesis in normal cellular activity.)

To be susceptible to HIV-1 infection, a host cell must express a surface protein called CD4, which is only expressed on certain cells of the immune system (note: this makes clear the reason for the virus' primary pathological effect, immune deficiency). When the virus particle encounters such a cell, interaction between CD4 and gp120 enables fusion of the viral with the cell membrane. (In so describing it I've simplified the fusion process considerably, in part because it is not fully understood.)

Now things get a bit fuzzy in terms of our understanding of the reproductive cycle (the term 'life cycle' is common, but I dislike it as the virus is not alive IMO). After fusion effectively inserts the protein coat into the host cell, stuff happens, at the end of which stuff happening the viral genome has been converted into double stranded DNA and inserted into the host cell genome. My studies over the last four years were concerned mainly with the nature of the stuff that happens, which I think is best understood as a series of events which overlap in space and time:

  • the outer and inner (matrix and capsid) protein coats essentially fall apart

  • the RNA genome is converted into DNA
  • the RNA genome together with its attendant proteins and the growing DNA copy moves from the cell membrane to the nucleus and then enter the nucleus
  • the completed DNA copy is inserted into the host cell genome (this is almost random, although I think that certain sites are favoured, probably on the basis of activity rather than sequence)

We don't know the fine structure of these events, nor precisely how they overlap. I doubt, for instance, that "fall apart" is accurate: the removal of the protein coat(s) is, IMO, much more likely to be a regulated process that occurs in concert with other events such as the initiation of reverse transcription. In fact, I suspect that membrane fusion is part of the same concerted series of events. To indulge in a brief anthropomorphism, this is not a virus that leaves things to chance. It packs a dozen genes into about 9000 base pairs, using multiple reading frames; compare that with the human genome, which carries about 30000 genes on roughly 3 thousand million base pairs! (The average, ~100kbp/gene, is misleading because only about 10% of the human genome encodes protein, but that too is a useful comparison. The HIV-1 genome contains no "junk" and relatively little regulatory DNA.) With such a compact genome, streamlined by the need to evolve so as to stay out of the way of the host's defenses, HIV is a designer particle specifically engineered to infect H. sapiens. I would be surprised to find any part of its reproduction that was not tightly regulated. That much of the regulation is achieved by subverting cellular mechanisms only increases my astonishment at the ingenuity of the damn' thing!

From integration onwards, we know a lot more about what the virus does inside the cell -- but my work did not involve post-integration steps in any detail, and this is already a long entry. Very briefly, the integrated viral genome (called a provirus) is expressed in much the same way as cellular genes, except that it is regulated by a viral protein called Tat. (Another example of the compact nature of the virus: Tat is also essential for efficient reverse transcription, a fact which underlies most of the research I was doing.) Viral proteins and RNA assemble at the cell membrane and form immature particles, and another series of concerted events results in budding of these particles from the cell (during which process they acquire their outer lipoprotein membrane). The viral protease, which will be familiar to many as the target of newer antiretroviral drugs, cleaves the proteins in the immature particle and the smaller proteins thereby formed rearrange into a mature virion capable of infecting a susceptible cell. Again, I've left an enormous amount of detail out of that thumbnail sketch, which I've only included for completeness, to round out the cycle. I haven't touched on the dynamics of infection and treatment, the epidemiology of the virus, or any of a dozen other fascinating topics; but this was more or less just a brain dump, and I hope that perhaps some of Kitty's readers and Link & Think browsers have found it interesting.

World AIDS Day and the Link&Think project seems like as good a time as any for me to look back over four years working on the molecular biology of HIV-1. I'll start with some of the questions people asked me when they learned that I was working on HIV.

1. The question of whether AIDS is caused by HIV-1 has been laid to rest and the answer is yes. Look here for detailed info.

2. No, you can't get it from a toilet seat (or a telephone; you'd be amazed at the number of people who, having dialed the HIV-1 laboratory by mistake, couldn't put the phone down fast enough!). You can only be infected by HIV-1 through contact between your bloodstream and the virus laden bodily fluids (most importantly blood, semen and anal and vaginal secretions) of an infected person. It's quite a labile virus, and does not survive long outside the protective environment of the host body. If this is a relief to you, please keep linking and thinking until you know how to protect yourself against AIDS! Here are a couple of links (AIDS basics, whatudo) to get you started.

3. What is HIV-1, anyway? Physically, it's a roughly spherical particle about 100 nm across. That's 100 thousand millionths of a meter; for comparison, the diameter of a human hair is about 50 millionths of a meter, 2000 times larger. For a rough visualization, think of an orange studded with cloves, not so closely that they touch but nearly so. Biochemically, it's an outer lipoprotein coat and an inner nucleoprotein core. Genetically, it's an RNA genome which is converted to DNA and inserted into the host cell genome in the process of infection, and then expressed in a manner similar to cellular gene expression. Viral RNA and proteins assemble at the cell membrane and form immature virions which bud off from the membrane and, after maturation, can continue the cycle. If you want to go into the natural history of HIV-1 further, the HIV InSite Gateway and the online textbook Retroviruses are good places to start.

4. There's no cure yet, and I think a vaccine is still some way off (if pressed, I'd say I wouldn't be surprised to see a vaccine in my lifetime, but it's virtually impossible to be more precise). That's the bad news; the good news is that vaccine trials are proceeding, drug discovery continues, and basic research is ongoing. I firmly believe that research will beat HIV.

It's VERY important to note at this point that infection with HIV-1 is still a death sentence. There is no cure, and if you get infected now there is not likely to be any advance in what's left of your lifetime to save you. There has been an upswing in the rate of new infections in western countries, at least in part because of the erroneous impression that "new AIDS treatments" will effectively give you back your life. No, they won't. You may live quite a long time, but it will not be all beer and skittles: antiretrovirals are vile drugs and can make you sick and miserable much of the time. To illustrate this: some portion of the failure of combinatorial chemotherapy against HIV-1 can be traced back to patient noncompliance with the drug regime, because it is so unpleasant. Recent innovations include trialling "drug holidays", brief pauses in the usual drug regime designed to protect against such noncompliance.