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Posted by Derek
One of the comments to yesterday's post turned the topic around by asking me how I like to be interviewed. That's a fair question, and I'm going to resist a quick answer of "In as fawning a way as possible". I have to say that I haven't been out on the conference-room trail in a few years - I'm not one of those people who goes out and interviews every couple of years just to keep their hand in. But I have been on the other side of the table a few times.
I think that one thing I look for is the quality of the questions I get asked. You want to join a company with good people, and what a person is curious about is a good window into how they think. That's one reason I'm not a fan of the mechanism-quiz technique, because at its worst it embodies some personality traits (bet-I-can-find-things-you-don't-know, test-until-destruction) that I find unappealing and counterproductive.
And that's why I don't necessarily mind getting questions that I don't know the answer to (as long as they're not questions that I obviously should know the answer to, naturally). It's good to be able to recognize anomalies and potentially interesting clues in a mass of data, so when someone picks out an oddity from a presentation of mine, I'm pleased (again, as long as it's one that I already knew about!) Many times, the answer to such questions is "Well, we don't actually know why that happens, but here are some possibilities. . ." The part of that answer after the comma needs to be included every time the first part is used, by the way.
I like seeing that the place I'm interviewing at is run in a reasonably organized manner. I'm not talking synchronized watches (which would make me run the other way), but if no one seems to have any idea of what my schedule is or where anyone can be found, it might be a bad sign for the way that projects are being run as well. (The flip side is that some apparent disorganization might be from everyone doing productive work instead, which isn't so bad).
And most of all, it's good to get the impression that people are doing things that they're interested in. At a small company, that's usually not a problem. But large companies have all sorts of people, and most places have some disgruntled time-servers taking up office space here and there. Any recruiting committee should know not to put these folks on an interview schedule. I've been on such committees myself, and you really do think about these things. So if I visit a place and end up talking to Wally out of the "Dilbert" strip, it's at best a mark against the people who made up my schedule, and at worst a bad sign for the whole department.
Comments (16)
+ TrackBacks (0) | Category: How To Get a Pharma Job
My "How to Get A Pharma Job" category over on the right has taken on a whole new meaning these days, what with me (and all my co-workers) scrambling around for new positions. You run into all kinds of interviewing styles out there, most of them fairly benign - but there are a few techniques that (to me, anyway) are warning signs.
The "Let's Go to the Board" folks can be in this category. (I've spoken about this before). While it's true that you want to make sure that a prospective candidate understands the science of what they're doing, a dissertation-defense blackboard grilling may not be the best way to do that. A medicinal chemists's job does not, to a first approximation, revolve around solving mechanism problems. It's a useful skill, and can be used as a surrogate for general mental acuity, but it's not the absolute first requirement.
At the other end of the scale, you have the HR-department "If you were a tree, what kind of tree would you be?" interviewers. I should point out that the people who ask these sorts of questions generally aren't the shining stars of the HR office themselves. And yes, I actually have heard of someone getting the tree question. I live for the day that someone tries it out on me.
People who have been through a lot of training courses may also try out a technique called "Behavioral Event Interviewing". That's when they ask you about some situation you found yourself it - "Tell me about a time when you had to meet a tight deadline", or the like. There's nothing wrong with this in principle, but if it's the centerpiece of the whole interview process, I think that it turns into a moral hazard for the interviewee. That is, it's an incentive to bring out the makeup crew and the special effects team, for a new, improved, version of the past. Everyone does this to a degree, of course, but the BEI style almost encourages it.
And it should go without saying that if you're treated in a disrespectful manner during an interview, and it seems like part of the company culture rather than the work of a random fool, then you should keep on walking. This is rare, but it happens. I knew an associate a few years ago who got a call for a Saturday morning interview at a small company, which was done by several of the lab heads who sat around eating breakfast in front of her. Do you really want to work for a company that thinks that this is acceptable behavior? Exactly.
Comments (31)
+ TrackBacks (0) | Category: How To Get a Pharma Job
So, what actually happens, down at the molecular and cellular level, when a person is exposed to alpha radiation? If it's coming from outside the body, not all that much. The outer layer of dead skin cells is enough to soak up most of the damage, and it's not like alpha particles can make it that far through the air, anyway. This is good news for Londoners worried about exposure (I note that reports have at least three sites there showing traces of radioactivity). I strongly discourage anyone from standing around next to an alpha source, but there are a lot worse things that you can stand next to - a gamma or fast neutron source, for example, either of which will penetrate your tan and keep on going.
But inside the body, that's a different story. Alexander Litvinenko was given polonium in his food or drink, and from there the stuff distributes fairly widely across many tissues. At lower radioactive doses, that pattern is probably a good thing. When you have a radionuclide that concentrates in a particular tissue, like iodine in the thyroid, a dose that would be bearable across the entire body can cause a lot of local damage when it piles up. At higher doses, though, the situation can flip around. People can survive with damaged thyroid glands, or after total bone marrow transplants or the like. But general tissue damage is much harder to deal with.
Polonium ends up concentrating in the kidneys, to the extent that it concentrates anywhere, and attempts have been made to minimize radiation damage there. But by then an awful lot of destruction has occurred elsewhere – the blood-forming tissues, the linings of the gastrointestinal tract and the blood vessels themselves, and others. Note that these are all fast-dividing cell populations.
Zooming in, the mechanisms for all that mayhem are complex, and they're still not completely understood. The first thing you can imagine is the alpha particle smacking into something, which to a first approximation is exactly what happens. They don't get far – less than 100 micrometers. But along the way they can bash into quite a few things, losing some energy each time, which shows up as flung-off electrons, various strengths of photons, and doubtless some good old kinetic bouncing around. Eventually, when the particle slows down enough, it drags off a couple of electrons in passing and settles down as a peaceful atom of helium. That leaves some positive charges to account for, though, since those electrons were otherwise employed before being press-ganged, and this ionization (along with that caused by those stray electrons along the way) is one of the major sources of cellular damage.
All this can take place either in the nucleus or out in the cytoplasm, with different effects. This sort of thing can damage the cell's outer membrane, for one thing, which can lead to trouble. In the nucleus, one of the more dramatic events is sudden double-strand DNA breakage. That's never a good thing, since the strands don't always get put back together correctly. A couple of years ago, a group from the Netherlands was able to come up with dramatic images of chromosome breakage along the tracks made by alpha particles in living cells.
Then there's also the complication of the "bystander effect". Untouched cells in the vicinity of one that has taken an ionizing radiation hit also show changes, which seem to be at least partly related to an inflammation response. This seems to happen mostly after damage to the nucleus.
All this focused destruction has long since drawn the attention of people who actually want to kill off cells, namely oncology researchers. Alpha sources conjugated to antibodies are a very big deal in cancer treatment, and a huge amount of work is going on in the area. The antibodies can, in theory, deliver the radiation source specifically to certain cell types, which soak up most of the exposure.
So there's a use for everything. But one of those uses, this time, was assassination. Alexander Litvinenko's killers knew exactly what they were doing, and exactly what would happen to him. I hope that they're eventually found and dealt with proportionately.
Comments (9)
+ TrackBacks (0) | Category: Chem/Bio Warfare | Current Events | Toxicology
I was going to write up a piece on thallium poisoning, until word came out over the long weekend that the Russian spy case was instead an instance of polonium poisoning. That's a very different matter indeed.
For starters, polonium isotopes (like most radioactive substances) are much more hazardous as radiological agents than as chemical ones. Unraveling the two isn't always easy, but this case is pretty clear. It's likely that polonium is chemically toxic, since it's in the same series as selenium and tellurium (which both are), but it's also likely that any reasonable dose would kill a person from alpha radiation rather than from whatever enzyme inhibition, etc., that might also ensue. People have been dosed with fairly robust amounts of tellurium and survived, albeit uncomfortably, but I can't imagine that anyone has been exposed to a systemic dose of a hard alpha emitter and pulled through.
This takes us into the long-standing arguments about the toxicity of such isotopes. Readers who remember the anti-nuke days of the 1970s and 80s may recall the statements about plutonium's incredible toxicity, generally expressed in terms of how miniscule an amount would be needed to kill every human being on the planet. Left unsaid in those calculations was that said plutonium would have to be dosed intermally in some bioavailable form. More Pu was surely vaporized in the atmospheric bomb tests of the 1950s, without depopulating the Earth to any noticeable extent. (See the arguments here, for example).
Here, though, we have a case of that exact bioavailable dosing of a strong radioisotope, with the unfortunate effects that you'd predict. There were some experiments early in the atomic research era where patients were dosed with radioactive isotopes. Oddly, the polonium experiments may have been the only ones that stand up to ethical scrutiny. A good review of what's known about polonium exposure, at least as of 1988, can be found here.
One thing that many people may not realize is that every person on the planet has some polonium exposure. There are many people who equate "radioactive" with "man-made", but those categories don't completely overlap. Polonium is a naturally occurring element, although certainly not in high abundance, but there's enough for Marie Curie to have isolated it. It's part of the radioactive decay series of U-238, and as a daughter radionuclide is a contributor to the toxicity of radium and radon exposure. You've had it - but not like this.
Comments (17)
+ TrackBacks (0) | Category: Current Events | Toxicology
Another thing a large research site has, and in mighty impressive quantities, is paper. Something's got to be done with it, but not all laboratory paper is created equal.
Of course, a lot of the mass represents hard copies of files that exist in digital form. Non-proprietary stuff (journal articles that are no longer needed, etc.) will go into big recycling bins to be handled by guys who really have some long days ahead of them. A serious office move (and this is about as serious as it gets) is a good chance to toss ancient literature folders whose contents have become outdated. I just heaved out a pile of that stuff the other day, since I don't thing that 1991 reviews of Alzheimer's pathology are going to come back into fashion. I also had a bunch of miscellaneous hard copies of the Journal of Organic Chemistry from the early 1990s stuffed into a file cabinet - out they went. They were joined by old copies of C&E News, local phone books, 3-ring binder contents of short courses whose contents I don't expect to ever need, and a pile of chemical company and lab equipment catalogs.
Pages with proprietary data on them are a different matter. They're to be tossed in a special shredder box, to be picked up later by some other guys who are also going to earn their money. There are trailer-size portable shredder operations that you can hire for occasions like this. Compound lists, graphs of in vivo activity, photocopies of notebook procedures, handouts from project meetings - all that stuff is headed down this path. Different people save different amounts of this material. I save all the computer files, but heave most of the paper when a project finishes up, so I don't have as much in this category.
Things like printed NMR spectra used to be in a special category, because back in the days of expensive digital storage the hard copy was all you had. I guarded my NMR spectra pile fiercely in grad school, since I was going to need that data to get out of there. And in my first years in the industry, digital archiving was spotty. Now that gigabytes are carried around on key chains, all spectral data are automatically archived, so hard copies are just a convenience.
At the top of the paper mountain are lab notebooks. We switched over to an electronic notebook system a few years ago, but it didn't relieve us of the obligation of keeping a hard copy. Printouts are to be taped into the good ol' notebooks, and signed and witnesses just like the handwritten pages of yore. That's a legal requirement, and scientists at research sites across this great nation are regularly harangued about keeping up to date on it. It does little good. Researchers are just not wired to get things countersigned on a regular basis.
That can lead to some real problems for US patents in particular. We're still a "first to invent" country, while the rest of the world is mostly "first to file". And if you get in an argument about the date of an invention, well, lab notebooks are probably where you're going to end up. An invention that isn't signed and witnessed until a year or so later isn't going to help much in that situation. Admittedly, it's rare that things get to that point, but when they do it means that serious money is at stake.
So no one's throwing away any notebooks, that's for sure. And we're all getting them up to date, signed off on, etc. Companies keep track of every extant lab notebook - they're all numbered, and completed ones no longer in immediate use are kept under lock and key. Nothing's going to be allowed to slide.
Comments (4)
+ TrackBacks (0) | Category: Closing Time | Closing Time | Drug Industry History | Patents and IP
Since I mentioned a little while ago that I'd gone short Imclone stock (at $29 and change), it was heartening to see Gretchen Morgensen make the exact same case against them in the New York Times on Sunday. (Subscriber link). The article makes much of the company's recent patent troubles, and the competition for their lone drug, Erbitux:
But neither the new competition from Amgen nor the legal ruling on the Yeda matter seems to worry the hopefuls who have bid up ImClone shares in recent weeks. These speculators also appear undaunted by results earlier this month from a drug trial in patients with midstage colorectal cancer. ImClone had hoped that the trial would show a survival benefit; it did not.
Two analysts, at Merrill Lynch and Citigroup, predicted that the trial results would mean stagnant market share for Erbitux and growth prospects for Vectibix. Both analysts rate ImClone a "sell." Bristol-Myers Squibb, which owns 17 percent of ImClone, said in its most recent quarterly filing that Yeda might seek damages for infringement on past Erbitux sales and royalties on future sales of the drug. If Yeda licenses its patent to other companies, Bristol-Myers acknowledged that new competition for Erbitux would arise, but added that it was too early to tell what impact such a development would have on its business.
Investors are going to have to catch up with therapeutic reality here: Erbitux is a drug of limited utility. All cancer drugs are, unfortunately. "Cancer" is a catch-all term for hundreds of distinct disorders of cell division and growth, and no one drug is likely to be efficacious across much of that range. Even in its best applications, though, Imclone's drug is only fair-to-good. Meanwhile, progress in the field (though incremental) is very real, and every slightly better compound that comes along is going to capture a lot of market share.
So when I hear Carl Icahn going on about how he wants the company to step up its marketing efforts, I have to roll my eyes. The thing is, to some extent cancer drugs market themselves. They already sell much more than a purely rational calculation would predict. That's because many clinicians try them all, against all sorts of things, no matter what the label says. And it's not like no one's heard of Imclone or Erbitux, so there's only so much that a whiz-bang selling campaign can accomplish. Icahn is trying to apply the lessons he's learned from other industries to pharmaceuticals, a tempting idea that has sent more than one R&D-based organization rolling off the edge of the table.
I know that I've linked to this post of mine several times - it's the one where I talk about all the times I've told people to sell Imclone. But you know, it's been good advice. After all, I took it myself, and I didn't even own the stock. . .
Comments (6)
+ TrackBacks (0) | Category: Business and Markets | Cancer
OK, here's a stumper: are there any anti-inflammatory medications that don't have cardiovascular side effects? Aspirin's GI bleeding effects have been known for decades, various NSAIDs have had warnings turn up over the years, the COX-2 drugs are somewhere over there in that huge cloud of legal and statistical dust, and now a study says that one of the last left standing, naproxen, may have cardiac effects as well.
Or does it? This is an attempt to get some useful data out of a large Celebrex trial, looking to see if it had protective effects against Alzheimer's disease, and the whole thing was stopped early when all the COX-2 cardiovascular risks became an issue. As this article makes clear, Steve Nissen isn't convinced, and he's not a person who keeps his worries about drug safety all bottled up inside. His point is that the trial's statistical validity was ruined by the early halt, and that larger epidemiological studies don't back up its conclusion. I should note that he's now running a massive trial addressing this issue as well.
Contrast that with this quote from one of the new paper's authors:
"Particularly for safety data, 'truth' may come in small doses. We firmly believe that results from trials should be published regardless of the direction, magnitude, or statistical significance of the observed results," said Barbara Martin of the John Hopkins University School of Public Health, who worked on the study.
Let me tell you, that kind of thing makes me very nervous. Regardless of the magnitude or statistical significance? That's not a way to arrive at the truth. That's a tornado passing over a pig farm
Comments (14)
+ TrackBacks (0) | Category: Cardiovascular Disease | Toxicology
As I mentioned the other day, I'm sprinting to finish some last experiments on my side project. These are all on the "vial thirty-three" system that I first described here and finally got to work reproducibly here. Looking back, I remember how surprised I was earlier in the year when I first saw this experiment work. Figuring it out has been like building an invisible ladder and then climbing up it, watching the rungs become solid under my feet.
Now, of course, I'm pulling out all the stops there are to pull. There are so many other experiments that I've been planning for and trying to do, but they won't get done, at least not here. I have to do everything I can with what I have on hand, because there's no time to make anything new. The publication that comes from this won't be as sweeping a story as I'd like for it to be, but it'll do.
But I'm accomplishing more in a few days than I have in months, because, sadly, there's no one competing for any of resources I need. Compounds from the repository? They're ready inside of an hour. More biological materials from the labs in the next building? They're giving me whatever I want, because all the projects that had first call have been stopped. The mass spectrometer downstairs, an essential piece of equipment for me and the largest single bottleneck I've faced? It's wide open as of tomorrow. I don't have to get in line any more; there is no line.
I went downstairs and loaded up one of the NMR machines with a day-long queue of proton and carbon spectra - in fact, they're still going and they'll be running all night. If I'd pulled that a month ago, someone probably would have gone out to the parking lot and slashed my tires. Now I'm the only person using the machine at all. No one cares. This brief, strange interval has been like having my own research institute, and I doubt if I'll ever see anything quite like it again. Everything's going perfectly, because everything's going away.
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+ TrackBacks (0) | Category: Birth of an Idea | Closing Time
When a bunch of chemistry projects suddenly stop in their tracks, you're faced with a real waste disposal problem. What do you do with all the blasted chemicals? First off, there are reactions going in people's fume hoods, some of which probably aren't going to be worked up. Into the red waste can they go. Then there are all the opened bottles of solvent, which aren't going to be shipped off anywhere like that. Unless there's a local university that's not very picky, those are going to end up hauled off for waste, too. (I wouldn't trust a solvent bottle that someone unknown to me has opened and left around, personally, especially if I have no way of tracking down its previous owner).
Solid commercial reagents are a bit different, since they're generally more stable and less likely to be contaminated (and often easier to spot if they've gone bad). Everything unopened - and every lab has plenty of unopened stuff in it, for one reason or another - will either be moved to the sites that are still running, or have several chances at donation or sale before being treated as waste. Opened commercial reagents will be subject to the same calculations, but on a steeper curve. Is the stuff still commercially available? Do the folks on the other end have enough of it already? If no, is anyone likely to want it? Is it worth shipping a long distance? Any "no" answers send the bottle to the "donate" pile, and that much closer to a waste pickup.
My guess is that very few of the commercial reagents will stay within the company. Compounds and intermediates that were made in-house, though, will get much more deferential treatment. These are almost certainly not commercially available, and have (be definition) been used to make something that was thought to have some value and to have some chance of being proprietary. Everything in this category will probably make the cut for being shipped, unless it's obviously turned to black tar on storage.
The mother lode of these compounds is, of course, the repository. Every drug company has one, full of racks and rows of vials and small bottles, every one of them containing something that someone thought was worth making and worth testing. Some of these have been dissolved in small quantities of DMSO, for liquid handling machines to dispense them, and these may or may not be worthwhile. But all the stock solids will be carefully packed and shipped off, no questions asked. They represent a huge investment in man-hours and money. Tossing them would be like a coal company setting its mines on fire.
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+ TrackBacks (0) | Category: Closing Time
Just a few days after I commented on the troubles that Isis Pharmaceuticals has had developing antisense DNA therapies, they've popped up with impressive clinical cardiovascular clinical data. Their latest hope, ISIS 301302, has shown some strong LDL-lowering effects, both as a single agent and in combination with statin therapy.
It's aimed at the production of a key LDL-transporting lipoprotein, apoB-100, which target the company correctly describes as "undruggable" through standard med-chem approaches. Of course, the RNA people are hot on its trail, too (these guys, for example). It's a good opportunity for these approaches, since the protein is of clear biochemical importance, and the site of its synthesis is in the liver and gut wall. Those, of course, are the first tissues that an oral drug sees, and (in the case of many antisense and RNAi attempts) the last ones, too. Going after something that lives there is a good strategy.
On a different topic, welcome more additions to the blogroll, such as Totally Medicinal, a med-chem blogger who's concentrating on the synthetic chemistry end of things. And there's Xcovery, a good kinase-o-centric site for those who can't get enough of 'em.
We now return you to our regularly scheduled site closure, already in progress. I've started a new category, "Closing Time", where my posts on that topic will go. There are a lot of odd blogworthy issues and loose ends associated with shutting down an operation like this. I'll be writing on them in the coming weeks, since many people will (fortunately) not have experienced the process firsthand.
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+ TrackBacks (0) | Category: Blog Housekeeping | Cardiovascular Disease
Friday afternoon was quite strange. There had been another meeting to explain to people what the timetable would be to close down the site, but I left during its question-and-answer period. . .to go and set up an experiment. A half an hour later, colleagues of mine from down the hall were coming back from the main auditorium, talking among themselves about job searching and severance, and staring at me in disbelief as they walked past my lab bench.
You see, if I'm going to get a good publication out of my idea, I'm going to need some more data. For one thing, I need to go back and run some of the things I've already done, but this time at least in triplicate, so I can plot the data with error bars. Before I was running in duplicate, trying to save some of the harder-to-obtain reagents for later experiments, but that's not going to be an issue now. Inside of a couple of weeks, there aren't going to be any more experiments to run, because we're going to be shutting down the labs.
In addition to the repeats, I'm going back to my main sequence and setting up some new experiments which will help support my conclusions in a paper. Friday afternoon's run was a large one in that category, and (needless to say) it had better work. I'm not going to get much time to troubleshoot. I had been working on a different series of compounds, but there's not going to be time to finish that area, so it has to be thrown over the side.
So there I was, using some pipets that were left over when the company laid off a hallway full of biologists two years ago. I have no idea who the equipment I'm using belonged to, but I knew everyone over there. And the vials I set up went into a plastic rack, which is still labeled with the name of a lab associate who was let go about a year ago when another hallway was cleared out. I'm using reagents from projects that have been told to stop, trying to generate data before the analytical lab has to shut down. No wonder people were looking at me as if I'd lost my mind - if I had the time, I'd stop and stare, too.
Comments (13)
+ TrackBacks (0) | Category: Birth of an Idea | Closing Time
It's not my intention to turn the site into a Saga of the Job Hunt, although that will be a recurring subject for a while. (I'd like to thank everyone for their expressions of support in yesterday's post, by the way. Much appreciated). The immediate future is fine - I'll still be at the workplace into December, and my lovely-parting-gifts package from the Wonder Drug Factory looks like it can take me a good way into next year if needed.
One interesting side effect of all this has to do with the side project described (elliptically) in the Birth of an Idea posts. Weirdly, the rapid end of normal research work at my site has opened a window of opportunity to get some of my off-the-radar samples looked at, and I plan to take advantage of that. I'm setting up a good-sized run of experiments to go over this weekend, for example.
I also hope to write up these results as quickly as possible, and for a better journal than I've appeared in to date. So here's a question: which journal? I think that this has a good shot at Angewandte Chemie or JACS, but I'm also considering really going for broke and sending it somewhere like Science or Nature. Can anyone speak to the reception that organic/medicinal chemistry manuscripts get in these venues? And are there other places I should consider (PNAS, for instance)? I realize that it's hard to judge this sort of thing without knowing quite what the manuscript is about. . .
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+ TrackBacks (0) | Category: Birth of an Idea
Well, here's a post I didn't think I'd be writing, although the possibility (given my industry) has always been there. The Wonder Drug Factory has decided to totally rearrange their research divisions, and we've been informed that our site is slated to close. Several hundred people will be losing their jobs, and I'm one of them. I don't agree with the decision (hey, I never think it's a good idea to turn me out on the street), but "out of my hands" doesn't begin to describe it. By all appearances, things will be shut down by the end of the year.
So the job search is on, and I'm going to start it by using whatever size platform I've built here. As for my background and experience, well, si curriculum vitae requiris, circumspice. I'm told by colleagues that reading my site is a pretty good simulation of having me around in person, so (for better or worse), that's what you'd be getting. I can provide a more traditional CV on request, of course, with the accompanying lists of patents, publications, and previous projects.
For family reasons, I'd prefer to stay in Connecticut, but I'll obviously start looking farther afield depending on what's out there. Industrial drug discovery is my strong point, naturally, but I'm certainly willing to listen to other ideas (academia, etc.) I can be contacted at firstname.lastname@example.com. I also want to mention that I have a number of very capable colleagues, at all levels of experience. Recruiters and search firms, give me a call - I can put you on to some excellent prospects: chemists, biologists - we've got 'em all. Or more accurately, we had them all, until today.
I'd been reasonably optimistic as the clouds gathered here over the last few months, but at the same time I've been preparing for this event, which is within error bars of the worst case. As for my attitude toward such things, I can tell you that Epictetus said it a long time ago:
Work, therefore to be able to say to every harsh appearance, "You are but an appearance, and not absolutely the thing you appear to be." And then examine it by those rules which you have, and first, and chiefly, by this: whether it concerns the things which are in our own control, or those which are not; and, if it concerns anything not in our control, be prepared to say that it is nothing to you. . .
When therefore we are hindered, or disturbed, or grieved, let us never attribute it to others, but to ourselves; that is, to our own principles. An uninstructed person will lay the fault of his own bad condition upon others. Someone just starting instruction will lay the fault on himself. Some who is perfectly instructed will place blame neither on others nor on himself.
Losing this job has not been in my control. Finding another one is. Here goes!
Comments (61)
+ TrackBacks (0) | Category: Business and Markets | Current Events | Drug Industry History
No post this evening, for reasons that should become very clear in the late morning (EST) on Thursday. I'll update then. . .
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+ TrackBacks (0) | Category: Blog Housekeeping
As many of you have noticed, there's some Movable Type construction work going on behind the scenes over here, which seems to have knocked out the commenting function for the moment. I hope that it'll be back quickly, and that the various service interruptions will diminish.
I was up late eating Indian food and following the election, with little time to post last night. No matter which side you were cheering for, I can recommend plenty of tandoori chicken and papads. My wife's home-made basmati rice, curried cauliflower, and cucumber yogurt are not (as of yet) available online, though, so you're on your own there.
So for today, I've updated the blogroll to the left. A few inactive sites have departed, but there's more than enough new linkage to make up for them. Welcome to Omics! Omics!, from longtime reader Keith Robison, Molecule of the Day (waving the chemistry flag at Scienceblogs), the clearly obsessed Kinase Pro, and the up-to-your-elbows lab details of Org Prep Daily. And there are plenty more these days: Whistling in the Wind, The Curious Wavefunction, Carbon-Based Curiosities, the Half-Decent Pharmaceutical Chemistry Blog, Dreaming Spirals, Chemical Forums, Mining Drugs, Chemical Musings (the former Interfacial Science), Atom Pusher, She Blinded Me With Science, Transition State, Chemoblog, Culture of Chemistry, and Lamentations on Chemistry.
Man, blogging does seem to have finally reached takeoff in the chemistry world over the last few months. Enjoy!
One of the things I like most about science is that you really don't know what's going to happen next. That's especially true in the areas where things have just barely settled down. Before that, when a field is new, no one knows what to expect, so in a way there aren't really any surprising results: everything's a surprise. A much more settled area, by contrast, is far less likely to produce surprises, although when one shows up it really stands out. But a field where people are just starting to exhale and think that maybe they've finally figured out what's going on - that has the best combination of high contrast and a real likelihood for craziness.
Here's a perfect example, since I was just expressing some doubts about the immediate commercial potentials of RNA interference the other day. In a paper coming out in PNAS, a group at UCSF was investigating the use of some small double-stranded RNAs, just the sort of thing that can be used for RNAi experiments. But they found (to their great surprise) that their experiments were stimulating the transcription of their targeted genes, rather than shutting them down. Needless to say, this was not what anyone expected, and I'll bet the folks involved repeated these things many, many times before they could trust their own eyes. There are plenty of other people who won't believe it until they've seen it with theirs.
On a molecular biology level, it's hard to say just what's going on. The authors, according to this news item from Science (probably subscriber-only) say that they've found some rules about which genes will be susceptible to the technique and which won't, which will be released soon. (Translation: as soon as they can be reasonably sure that they won't make fools of themselves - this paper took enough nerve as it is).
The Science article includes a good deal of if-this-holds-up language, which is appropriate for such a weird discovery. (Are the editors there wondering why they didn't get a chance to publish the article themselves, or did they have the chance and turn it down?) At any rate, if-it-holds-up this effect will simultaneously complicate the RNAi field a great deal (it was gnarly enough already, thanks) and also open a door to some really unusual experiments. Upregulating genes isn't very easy, and there are no doubt many ideas that have been waiting on a way to do it. There are therapeutic possibilities, too, naturally - but they'll have to wait on the same difficulties as the other RNA therapies.
Anyway, I'm happy to see this. It opens up some completely new biology, and it opens a door to a potential Nobel for the discoverers should everything work out. And it always cheers me up when something totally unexpected flies down like this and lands on the lawn.
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If you're one of my industrial-research readers and you're looking for a trend to get worried about, try this one: the number of large companies that are opening med-chem research sites in China. Here's the latest example, from Novartis, and it might be the biggest yet.
There's a huge expatriate Chinese research presence in the US and Europe, and has been for many years. Recently, though, some of them have been moving back to China (or, probably, not leaving at all) because of the opportunities that have opened up there. As with other industries, it started out as we'll-do-your-worst-stuff contract work, and has picked up from there. Now we're to the point where companies can consider doing serious med-chem.
To a first approximation, I guess I'm supposed to be upset about this. But (free-trader that I am), I remember that at one point the US was the offshore research location for European firms. And as China's economy develops, those low-wage jobs that attract this kind of outsourcing won't stay so low-wage. If you're a worried US or European researcher, you pretty much have to hope for China to grow and take off to that point, or you have to root for a collapse. I vote for the former.
Another reason I'm not worried is that research isn't a zero-sum game. There are more pharma ideas to work on than anyone has time, manpower, or money to investigate - there always have been, and there will be for some time to come. Now, not all of these are going to be great ideas. Most of them are going to flop. But there's not much way of knowing which ones those are, so having a chance to put more bets down is a good thing.
"Ah, but research budgets are zero-sum", I hear some of you saying. That's a better point, but I don't see (yet) any evidence that these offshore operations are being used to substitute for current operations. As far as I can tell, they're in-addition-to, on the cheap. After all, no one's sure yet how well these things will work out, especially in these early cases, and given the state of the industry, cutting your research back hard is not a very good decision.
But yes, the competition is there, and will be increasing. As I've said here before, that means that you have to try to offer something that a company can't get in Shanghai. And sitting around wringing your hands about China (and India) instead of coming up with good ideas or improving your skills isn't going to do that.
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I haven't mentioned Merck's mighty acquisition of Sirna yet - 1.1 billion dollars, eh? If anyone didn't think that RNA interference was hot, that kind of money should change their mind.
But still. . .antisense DNA was hot at one time, too, and then it cooled off considerably. It's come back in recent years, admittedly, as painful progress has been made. In fact, one of the big deals that showed that antisense was taken seriously again was made by. . .Merck, come to think of it. They had a big collaboration with ISIS for diabetes and (I believe) some other indications, but it didn't work out well. That press release has ISIS putting a brave face on having their clinical candidate thrown back over the fence, with talk of taking it on into clinical trials themselves. Four years later, it's still listed as Phase II on the company's website, which isn't a good sign, I think.
The rest of that 2002 press release is also instructive. The Phase III PKC-alpha compound they mention working on with Lilly bit the dust the next year, for one thing. And the ICAM-1 inhibitor met a similar fate in 2004. The 2002 story mentions the company having six products in Phase II, and now, according to their chart, they have five. None of those six candidate have progressed, and no doubt there's been some turnover along the way.
I'm not trying to be hard on ISIS. It's just that antisense DNA therapies have been extraordinarily hard to develop, and I see no reason why RNA interference will not have exactly the same sorts of problems. Small nucleic-acid based compounds are going to be hard, no matter what. It's interesting to note that Merck didn't just up and buy ISIS back then. But they're more desperate to fill their pipeline than they were back in the late 1990s, so out comes the checkbook. Good luck to all concerned.
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Back in 2003, I wrote about the paper that identified the natural product resveratrol as an activator of the sirtuin deacetylase pathway. This may well be the common thread between a host of studies on life-extending genes in model organisms and the much-publicized phenomenon of life extension through caloric restriction. In other words, if you want to live longer, but don't feel like taking in a third fewer calories, it's possible that activating sirtuin might do the job for you, and resveratrol is the prototype activator.
Three years ago, after first pointing out that many companies might want to run screens for sirtuin activators, I went on to speculate:
Second, there is no reason to think that resveratrol itself is an optimized molecule. It's a great starting point, but as a medicinal chemist I can see several things I'd like to do to it immediately. Hey, fellow chemists, let's talk shop here. . .(list of possible structural modifications follows - DBL). . .Believe me, thousands of folks like me are looking at this structure today and having these exact thoughts, and some of them are going to act on them (if someone hasn't already.)
Third, this compound is surely being given to higher animals as we speak. I can see no reason not to start feeding it to mice in a long-term study. Mice live around two years - let's try for three! After all, it's already been given to rodents in other studies. (And those are just papers from the last year or two!) But as far as I can tell, none of these have allowed the mice to age to their full normal lifespan under resveratrol dosing. Time to find out!
Well, in an unusual development for my predictions, all of this is coming true. This summer, David Sinclair (who leads one of the major efforts in this area - another is led by his former boss, Leonard Guarente) published an interesting review of resveratrol's in vivo effects. Now his group reports in Nature that resveratrol does indeed have effects in mice - very powerful effects indeed. When put on a high-fat diet, normal mice gain weight, develop diabetes and liver problems, and die early. But on the same diet along with resveratrol, the mice (although they do put on weight) show improved glucose and insulin levels, better liver function, and significantly increased lifespan. Their activity and motor abilities appear to mimic normal-diet mice, even into their extended old age. (Here's their press release if you don't have a Nature subscription).
And on top of this, Sinclair's company has let it be known that they have developed improved molecules based on resveratrol, and are now taking them into the clinic. The first one is called SRT501, and I'd be very interested to know its structure. But remember that compound code - you're going to be hearing about it again.
These are still early days. There may be penalties to pay for messing around with longevity (increased cancer rates are only the first thing that come to mind). But there may also be a revolution in progress here, something that will make the future quite different from what we've been imagining it will be. G. K. Chesterton would be happy - scroll down here for a discussion of the game of "Cheat The Prophet". Is anyone ready for Cheat the Reaper?
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+ TrackBacks (0) | Category: Aging and Lifespan
The German government has handed down some interesting pharmaceutical decisions recently. Although Sanofi-Aventis's Accomplia (rimonabant) is available there (in fact, that's probably the largest market it's shown up in so far), the German regulators have decided that state health care plans are not going to reimburse for it. They've put it in the "lifestyle" drug category, which they don't cover. This appears to be a cost-cutting move, and there's a 60-day window in which it can be changed.
S-A had better hope that HMOs here don't follow suit. Of course, for this to be an issue, the drug would actually have to be approved by the FDA here, and the company still has no details to offer about when they might expect that. Their quarterly report states that they've answered the FDA's concerns, which isn't much of an update, but goes no further, as far as I can see.
Meanwhile, Pfizer's inhaled insulin Exubera has also been denied reimbursement in Germany, which follows on a similar British decision earlier. I expressed doubts about the product here a while ago (I wasn't alone), and now the doubters are getting louder. Exubera hasn't been launched in the US, either, despite being approved early this year, which isn't helping sooth Pfizer's hardy investors, either. . .
Presumably both these products will debut here in 2007, and we can all see how they do in the most lucrative pharmaceutical market in the world. If anyone is thinking of making a big upside investment decision based on these compounds, though, I think they'd be well advised to sit on their money for a while.
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Back pressure problem
So, I'm out camping this weekend and while driving around (about 10 to 15 mph) my truck stops running. It had just come out of regen and the display indicated to make a safe stop or something like that and it died. I get a check eng light about every 6 to 8 weeks and every time they tell me its because of the lack of back pressure from the after market ext. I have been told it is an MBRP 5" dual ext. and Bankston Ford in Arlington, Texas wants to cancel my waranty over this. So I have 2 ?
1.Has anyone else had this kind of problem?
2.If I buy a SCT or Spartan do you think this problem will go away.
I took the truck back to where I bought it (not Banston) to see if they could help me with this since the ext. was on there when I bought it from them and they will look into it. If my warranty is going to be vioded any way I would buy the SCT or Spartan but would like some input if one of them would clear this problem up or not.
The dealer is BSing you about the back pressure due to the aftermarket exhaust. All of the backpressure is built up in the DPF. Go with the SCT or Spartan and get rid of the DPF and you'll never have this problem again.
Sounds like the EGT's are getting too high and it's going into emergency shutdown.
Yes, modifying the exhaust, even the tail pipe can cause problems with the stock system. It has been well documented and those exhaust tips are not like that just for looks. This does not mean you can't have a bad sensor though.
The aftermarket programmers that disable regeneration allow you to run an aftermarket exhaust and remove the DPF. No more problems unless there is already a real problem. In that case the problem will likely still be there. Can you put the original tail pipe on and try it?
They can always void certain parts of the warranty work if an aftermarket part causes a problem. They cannot void the entire warranty over this. When you have an unrelated problem it is still warrantied.
However there could be something that happens and it could appear to be caused by an aftermarket part when it is actually not. There is probably no way to tell for sure in some cases.
Last edited by DavidPhillips; 07-05-2009 at 03:06 AM.
No I don't have the origenal ext as I bought it with the after market one thats on there. The hits just keep on comming. Today When I went to get my trailer that I had to leave at the camp site when the truck got towed on Friday, before I got to the end of my street I hear a loud ticking sound and then started blowing white smoke out of the ext. The only thing about my 2006 F250 is it was a gasser. This 2008 is starting to make me a little crazy All my friends come to me when they need a truck so I'm not sure at the moment how I'm going to get my trailer home with out paying for a towe truck. Sorry if I'm starting to rant but just getting it out I fell a little better....
Sounds to me like there is a lot more of a problem than the exhaust tip.
You should probably try another dealer.
Mine did the same thing. It did the emergency shut down towing a gooseneck trailer back from the ranch. After setting for about 10 minutes and restarting I drove it and the trailer home. The next day took it to the dealer and they replaced the DPF, it only had about 6500 miles on it. Have had no problems since and am at 29,000 miles
Well I got my truck back today and they had to put an factory intake back into it to get it to work with out throung out cades. The place were I got my truck payed for it () but the dealr gave me the AFE back so now I have both of them. In the classifieds someone is selling an SCT I offed to buy it so I'll wait and see. The first two that I tryied to buy in the classifieds never got back to me about selling them. If this one dosen't work out I'll give up trying to buy from this classified area and save my money for a spartan like eveyone else. Thanks to all that posted info for me.
I hope it works out for you.
It is hard to believe that the intake would overheat the DPF though. Time will tell.
If your removing the DPF I would say the problem will soon be gone.
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|ASU Men's Soccer Adds Three Recruits
|Written by Paul Blascovich
|Saturday, 04 February 2012 10:57
Appalachian State University men's soccer head coach Matt Nelson has announced three recruits that have committed to join the Mountaineers next season. Alex Herbst, Matt Melton and Mason McCarter will don Black and Gold jerseys this fall, adding to the strength of the Appalachian program.
warranted a smaller-than-usual newcomer class this year. "We are only adding three players at this time, because we feel that the foundation of our team is returning, and the continuity will show in our play on the field. These three new players will bring work ethic, technical ability and a tactical awareness that will help our program improve."
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text: http://techcrunch.com – This week's Ask A VC series features a slew of awesome guests in the investment world. Tomorrow, we have True Ventures' partners Tony Conrad and Puneet Agarwal in the studio, and Thursday, Shasta Ventures' co-founder Rob Coneybeer will be in the hot seat. Remember, you ask questions either in the comments or here and we'll ask them of our VC guests. Coming off True Ventures' new $205 million third fund, there's a lot to talk about with Conrad and Agarwal. And the firm now has $600 million under management. Conrad is the Founding Venture Partner at True Ventures (IT news)


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Welcome to this week's Christian Carnival! As always, it is lovely to have you here and I hope you enjoy the wide variety of posts that you will find here today. Without further ado, let's begin.
First cab off the rank, Engelbert Hudson gives us a great resource in 20 Useful Specialty Search Engines for Bible Scholars posted at A Blog of Biblical Proportions.
Courtney Kleppinger presents simple yet compelling argument from design, showing that an argument doesn't have to be overly complex to hold weight, in Kindergarten Apologetics posted at In His ocean I'm ankle deep.
In a lovely post that examines what is truly valuable, Marisa presents My Prized Possessions posted at Me, You, and Creamed Corn.
One of the things that amazes me about good Christian teaching is that it is as relevant to our lives today in the 21st century as it was to the lives of those who have gone before us, whether it be two thousand or two hundred years ago. We see this timelessness of the Bible's teachings when Joe Plemon presents 5 Bible Verses John Wesley Used For His Money Decisions posted at Personal Finance By The Book.
Jason Price talks about discontent as a motivating force in When Discontent is a GOOD Thing posted at One Money Design.
Josh presents an extremely comprehensive roundup of Bible verses relating to stregth in Bible Verses About Strength- 25 Encouraging Scripture Quotes posted at What Christians Want To Know.
Timothy Yordy presents a hilarious post about some of the excuses people used to get out of trouble in Old Testament times. Check out An Old Testament Guide to Getting Out of a Jam – Timothy Yordy posted at Timothy Yordy. Number 5 is my preferred method, what's yours?
Ong Seng Aun presents some useful tips on identifying cults in Cult Checklist – Tipskey posted at Tipskey – Unlock Practicality.
Looking at the last Christian Carnival I was amazed at the beautiful presentation of the post, and of the blog that hosted it. It really is one of the best presented blogs I have ever seen. But, it is not just style, there is substance as Fadi shows in Love your Neighbor as Yourself – Part 1 posted at INSPIKS.
Kaleb shows us that there is no such thing as a harmless sin in The Progression of Sin posted at W2W Soul.
"Reflections on beauty as seen in a dream: Why was I living in this shack when under my very feet was a mansion?" Jennifer in OR presents My Reflection part 2 posted at Diary of 1.
Maryann Spikes (Ichthus77) takes a very comprehensive look at "The Reason for God", including sermon links, when she presents Blog Discussion and Sermon Ideas for Tim Keller's "The Reason for God" posted at Ichthus77.
Rey Reynoso takes a look at the topic of the moment when he presents Should Christians Rejoice Over The Death of the Wicked? posted at The Bible Archive.
michelle gives us an admirably honest insight into what she is thinking and feeling in what are you thinking? posted at finding God's way….
Ridge Burns reflects on the recent Royal Wedding in The Royal Wedding posted at Ridge's Blog.
A truly lovely post from Paige Carter who presents Paigerific: Even if you fall posted at Paigerific.
The always erudite Jeremy Pierce presents Hezekiah's post-mature death posted at Parableman. Man, that guy is SMART.
Forgiveness is tough, as Weekend Fisher finds in Problems in forgiveness posted at Heart, Mind, Soul, and Strength.
And finally, my rambling thoughts as I try and come to grips with the celebrations at the death of Osama Bin Laden.
If you have any questions about the Christian Carnival, please visit here.
Thanks for popping by!


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I admit to some bias in the matter of packs. I am not keen on many of the more extreme American variations with huge mesh pockets across the outside and no lids. I prefer a more traditional clean design with some sort of frame - something that the Europeans seem to have mastered.
However, this pack does deviate slightly from that 'clean' concept, but in acceptable ways. It has two compartments, with the lower one accessible from the outside. It has a back pocket a bit like the huge mesh ones found on some American packs, but this one is a lot more robust and has not all that much capacity when the main bag is full. It is held up by the buckle in the middle of the back. The harness is adjustable for length by means of some heavy webbing straps across the back and some heavy hook and loop tape wrapped around them. This is visible in the right-hand photo above. There is a rather large pocket in the lid. The pack is 'hydration-compatible', although I don't think that is worth anything. There is a sleeve inside the pack for a bladder, but it functions much better as a map sleeve. It has the usual loops for ice axes and so on. And there is a marginally hidden pocket under the lid for storing valuables such as money, passports etc.
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It only makes sense that the story of a man with knife-fists spans across 8 movies.
Much as you should be avoiding Japan and Libya right now, it is highly recommended that you avoid San Francisco May 3- May 15.
Darren Aronofsky discussed some of his plans for the Wolverine sequel, and it sounds like this could be a really good movie about a guy who has knives jutting out of his metacarpus.
The Darren Doppler is tweakin' again. Aronofsky's deal to direct Wolverine 2 is so close to being a real thing that Fox is already talking about concessions of the un-Sour Patch Kids variety. The studio will allow Aronofsky to shoot the sound stage portions of the film in New York so the filmmaker and Hugh Jackman can still go home to their families at night. Production will begin in March, after Aronofsky has had time to pimp Black Swan to the press. After the New York scenes have been shot, the production will move to Japan, far, far away from any wives and kids. You know what that means… Both guys will finally have time to finish The Girl Who Kicked the Hornet's Nest novel. They can't wait to see how the Millenium Trilogy ends. (Deadline)
In further Awesome Directors Making Batsh*t Decisions news, Darren Aronofsky is one step closer to directing Wolverine 2, the sequel to a movie that starred Will.I.Am and featured a guy causing a tank to explode by punching it in the cannon.
There was some debate online whether he would choose the comic book movie, or go with Tales From The Gangster Squad late last week. He's reportedly passed on Gangster Squad, leaving his schedule wide-open for Wolvie. Though, no deal is in place and we've heard no official word from his reps, it's likely he'll parlay Black Swan's Oscar buzz into instructing Hugh Jackman to growl. Or he could choose to do a good movie. We'll keep you posted. In the meantime, Nikki Minaj should probably practice surfing on nuclear warheads. (Deadline)
Yesterday, everyone on the Internet was reporting that Darren Aronofsky was taking on the Wolverine sequel. Well hold your damn horses. Now, Empire Online is reporting that Warner Bros. has made a counter offer that might just land the director in their camp: a 40's era period piece called Tales from the Gangster Squad.
Tales from the Gangster Squad follows the exploits of Sergeant John O'Mara's off-the-books team of police mercenaries, who targeted mob-linked gangster Mickey Cohen and his attempts to bring East Coast organised crime firmly into LA. Originally chronicled in a series of LA Times articles by Paul Lieberman, the script has been penned by cop-turned-writer Will Beall.
That's a tough call. Both films sound like a good fit for Aronofsky. It reminds me a little of Sophie's Choice, except for this I'm going to stay tuned to find out what happens instead of switching over to "Real World/Road Rules Challenge" (Sorry, Sophie).
We'd heard the rumors but they sounded too crazy to even qualify. Yet somehow, against all laws of nature, Darren Aronofsky is in talks to direct Wolverine 2. Aronofsky surpassed rumored shoe-in David Slade to win the honor of directing the second film in this so far pretty sh*tty franchise, just days after it was announced that Zack Snyder won the Superman directing duties.
May be a case of Justin Bieber punk'n us all, but if not, at least we have a director who can artfully convey Wolverine's frustration with the world that won't accept him as he surfs on a missile or whatever ridiculous action set-piece makes its way into this film.
Where this leaves Preacher or movies that are a good idea for Aronofsky to do, we do not know. But if you ask me, this move is in direct reaction to the failure of The Wrestler action-figure line. Apart from the Marisa Tomei Lapdancer dolls, those things just didn't sell. (Deadline)
David Slade would be wise not to decorate his home office with Wolverine action figures just yet. Though it was believed that the helmer of Hard Candy and assorted vampire movies was a shoe-in for the Wolverine Goes To Japan directing gig, a new contendor has emerged. Granted, he's a highly-unlikely candidate, but Darren Aronofsky's hat has somehow been thrown into the ring. Whether he threw that hat himself, or some neighbor kid bully threw it in the ring just to be a jerk remains to be seen.
Given Aronofsky's body of work, I'm going to go ahead and rule him out. The X-Men films have been twisted into goofy, popcorn wannabe-action films, and Wolverine is no exception. Though if anyone could lend some gravity to the material, it's Aronofsky. Look what he did for Marlon Wayans. (Deadline)
David Slade, director of Twilight Eclipse, 30 Days of Night, and Hard Candy, is the lead contender to helm the sequel to the X-Men Wolverine spin-off, the aptly titled, Wolverine 2. His sole competition is Robert Schwentke, who last directed The Time Traveler's Wife, and has the upcoming Bruce Willis vehicle, Red. Hugh Jackman himself will pick the winner, so let the ass-kissing begin. According to Vulture, "A well-placed source inside the production insists: 'It's going to be Slade.'" Looks like someone already sent a fruit bouquet to someone else's house.
I suppose I'd prefer Slade to Schwentke since I'm a big fan of Hard Candy and he made the least sh*ttiest Twilight movie, but I feel strongly that the sequel to Wolverine couldn't be any worse than the original no matter who's directing.
Oh no. I've gone and done it again. I've said the words that release the evil genie who travels on a bed of Cheetos dust.


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City Councilwoman Teresa M. Macaluso will fill up her last cup of joe at her Coffeen Street business on Friday.
Long before she became a councilwoman, Ms. Macaluso opened a drive-through coffee shop called Brew Ha Ha.
After more than 12 years, she will close the business on Friday, saying that she wants to devote more time to her family, the community and City Council business. She put the business on the market last year and still hopes to sell it.
Its just time for me to move on, she said Monday.
Ms. Macaluso said she recently paid off her mortgage on the building and all her vendors, so the business is debt-free.
She and her sister, Karen E. Mikos, worked as baristas at Brew Ha Ha.
The business woman-turned councilwoman said she will miss her many regular customers, including Mayor Jeffrey E. Graham and Donald C. Alexander, the CEO of the Jefferson County Local Development Corp., making daily appearances.
Her sister said they became close to some customers, who told the women about what was going on in their lives. They watched their customers children grow up and get married.
I had a ton of customers who kept it going for years and would have kept it going for another 100 years, she said.
With temperatures hitting well below zero on many days and so much snow this winter, it was more difficult to get up at 3:30 a.m., make sure the Coffeen Street property was plowed and open at 5:30 every morning, Since she opened in 2001, Ms. Macaluso has not been able to go on vacation, she said.
Even on the day of her father Carmen J. Macalusos funeral in 2010, Ms. Macaluso recalled that she and her sister had to be there.
It just got to be too much, she said.
Regular customer Rachel A. Ulrick said shes pretty sad after seeing a sign that was taped on the drive-up window a few days ago.
Its the best coffee in town, she said.
Buying a white mocha ice, even on the coldest days of the winter, was a part of her daily routine, said Adria S. Amaral.
They call me the crazy girl for getting it in the winter, she said.
Ms. Macaluso, a former registered nurse, plans to return to that profession part-time.
When she ran for re-election to a second term, Ms. Macaluso stayed comfortably in the confines of Brew Ha Ha to campaign, often speaking to voters who drove up to the coffee shops drive-up window to gain support for her.
During her stint on the council, customers also knew where to find her when they wanted to talk to her about city issues. But now that shes closing the business, shell be able to spend more time on city business.
On Monday, Megan J. Kimple placed her order at the drive-up window and pulled away, initially forgetting to wait for her coffee and then turned around to get it.
Literally, weve had to chase people down the street when that happens, Ms. Macaluso said.
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Play our fun game and find out if the one you like likes you back. Confide in us if you think you'd hit it off by clicking: Yes, No, or Maybe. We'll anonymously find out and let you know if the feeling is mutual. You have nothing to lose!
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You both said YES! The feeling is mutual. Now the rest is up to you! Say Hi and get the conversation started.
I recently relocated here for work, and to be closer to family. I brought my 4 year old Shiba Inu with me and he is loving having real grass to sniff and lay out in! On my off time, Buko and I can often be seen at a dog park, on random walks and trying to find a place to hike. I enjoy snowboarding in the winter when I can, which has been more difficult since moving from Colorado. I also like to read, travel and am trying to expand my cooking skills. I grew up riding horses, playing volleyball, tennis and golf, and am looking forward to getting back into these activities as I settle into the community. Hopefully I will be able to travel more frequently and enjoy working less and having more fun now that I'm not having to work and study so much! I am pretty easy to please- I enjoy most all music, although I like techno and really heavy metal the least. The only movies I try to stay clear of are the super gory and bloody ones. I have traveled abroad quite often, and I lived in Italy when I was in high school. Eventually I would like to live abroad again if my life allows. I enjoy plays, concerts, and pretty much anything that gets me out and about!
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The latest in the Elm Creek Series. Several of the Elm Creek Quilters are moving on, Gwen's daughter Sommer who has been working before heading back to university and Gwen's friend Judy who moves out of town with her family. Despite Sarah and Sylvia being sad, Sarah has some news of her own.....an addition or two to the residents of Elm Creek.
The ramblings & obsessions of a fisherman's wife! ~ a potpourri of history, genealogy and books. Also some general ramblings if they take my fancy!
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Sunday, 10 August 2008
The Winding Ways Quilt: An Elm Creek Quilts Novel by Jennifer Chiaverini
Posted by Julie Goucher at 11:07 p.m.
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Audio Samples
Track List
Album Notes
Liner Note Authors: Richard Armitage; Norman Newell; John O'Regan.
This set collects four of Peter & Gordon's British LPs on two discs, 1964's Peter & Gordon and In Touch with Peter & Gordon, 1965's Hurtin 'N' Lovin' and 1966's Peter & Gordon (yep -- the same title as the duo's first album but with different songs). Peter & Gordon called it quits as an act in 1968, so the balance of their recorded work is here. ~ Steve Leggett


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Mabel Dress
Style: 31031958
This classic lace from Tadashi Shoji takes new shape in a sleek, belted silhouette! The soft tonal colors, paired with a peplum accent and eyelash trim make this dress a standout. Neatly pressed into a bow, a grosgrain belt ties together Tadashi Shoji's sophisticated and unique floor-skimmer. Side zip. Polyester lace; polyester satin lining. Dry clean. Imported.
- Falls 45" from natural waist
Contact a BHLDN Stylist for style advice, reassurance, second opinions


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Salacious mom putting aside her phone getting lured into frantic fucking
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Mr Elliott says "a number of community police officers" were taken from their regular duty in the weeks leading up to, and during the summit, with many of them tasked to focus on G8-related work.
"I am conscious that crime levels have risen in a number of areas and I am obviously worried that some police officers haven't had the opportunity to work in their own area during the long period of the overall G8 operation.
"It is important that even though this was a very important event the wider community of Fermanagh require the services of police, I trust that they will now have the time and opportunity to devote to those local communities that may not have had the level of police attention they would expect during the past four months," said Mr Elliott.
The PSNI has confirmed that crime in Irvinestown has shown a "slight increase" and attribute it primarily to a series of burglaries of unoccupied properties during late May. "This series is the subject of a live and focused investigation," said a PSNI spokesperson.
The police say that during the G8 Summit and the run up to it they took steps to ensure that local core policing responsibilities were met.
"There was an increased profile of PSNI patrolling across Fermanagh for a number of months prior to G8, this was gradually increased on the approach to the event. This increase was possible due to the provision of officers from across the service into Fermanagh. Some local officers were redeployed within the last two weeks prior to G8. A lot of these officers maintained involvement in their normal duties but assisted with the G8 operation, during which time there was not an increase in crime," said a PSNI spokesperson.
The police state that maintaining normal service delivery and meeting the ongoing needs of the community was a "key consideration" in selecting the officers that remained at their normal duty location prior to and during the summit in Enniskillen.
The PSNI spokesperson added: "Our primary aim was to ensure the G8 Summit was a safe and secure event for all concerned - primarily for our local community but also for visitors, delegates and campaigners. This included ensuring the community was protected from opportunist criminals, whilst a lot of attention was focused on the G8 and related activities."
Meanwhile, Tom Elliott wants to know why initial figures for hosting the G8 summit were "so wrong and inaccurate" after it was revealed this week that it cost £80 million.
"It is not that long ago since we were informed that the G8 would cost in the region of £50 million, then just a few weeks ago it was estimated at £60 million, now we hear the cost has been £80 million. This is over a 60 per cent increase in projections over what were very large sums of money to begin with," said Mr Elliott.
"Given this significant increase in costs many people will be asking if that is the final figure, or indeed if there will be further financial costs and if the £20 million that is required from the Northern Ireland Executive will be added to. We don't want to be informed of further finances required over the forthcoming months and years. While many people agree that the G8 was a very successful event, an £80 million bill is massive for an event that essentially lasted just over one day," he said.


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Harlem Globetrotters return to the Blaisdell Areana
2 shows on Saturday with special military discount
After nearly 20 years, the Harlem Globetrotters will return to the Neal Blaisdell Arena for two shows, this Saturday, May 12 at 2 p.m. and 7:30 p.m., as part of their 2012 Championship Tour.
The Harlem Globetrotters are led by "Big Easy" Lofton, a 6-foot-9-inches-tall superstar from New Orleans. He will be joined on the court by dribbling sensations Handles Franklin and Scooter Christensen; 4-point sharp shooter Buckets Blakes; high-flying dunkers Bones Millien, Bull Bullard and the 2011 College Slam Dunk Champion who sports a 50-inch vertical leap, Hops Tucker; 7-foot rookie Stretch Middleton; and TNT Maddox, the team's first female player since 1993.
Reserved tickets, priced at $35, $25 and $20, are now on sale at the Blaisdell Box Office and all Ticketmaster outlets.
Special military discount of $7.00 off the price of admission in the $25 and $20 sections.
Tickets can be ordered online at ticketmaster.com or by phone at (800) 745-3000.
Copyright 2012 by KITV All rights reserved. This material may not be published, broadcast, rewritten or redistributed.


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Capital Markets
Company Overview of Forward Management, LLC
BOARD MEMBERS AFFILIATED WITH Jerome Alan Reid Jr., CIMA*
Chief Executive Officer
*Data is at least as current as the most recent Definitive Proxy.
MOST CONNECTED PEOPLE TO Jerome Alan Reid Jr., CIMA
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Antique Edwardian 14K White Gold Filigree Diamond Bow Shell Pin Brooch
Click thumbnails for expanded view.
- $299.95
- Or Best Offer
- Quantity Available: 1
Weighs 2.2 g / 1.41 dwt / 0.07 ozt Measures High: .75" Measures Long: 1.25" Metal: 14K White Gold Hallmark: 14K Condition: Pre Owned Design: Filigree Good Ole Tom's is pleased to offer this beautifully designed Pin. Around the rim there is a filigree design which makes the pin even more unique. In the top left corner there is a solitaire bow which makes the pin cute and ties together well. with the filigree design. The diamond accents on the bow make the bow stand out as it shines. This pin is made up out of 14K White Gold which makes this vintage sterling silver pin that much more lovely. Own a piece of history by claiming this pin as your own today! Notice in the picture the United States quarter. It measures exactly one inch in diameter. This will give you an idea of the size of the pin. Do not miss out on the opportunity to own this pin. You will not be disappointed.
GoodOleToms Antiques
- East Hartford, Connecticut
- Seller Since 5
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Item Details:
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- Weight: 0 pound
- Condition
- Pre-owned


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Chicago Soft Red Winter (SRW) and KC Hard Red Winter (HRW) are the global industry standards for wheat. Chicago SRW Wheat is the most liquid Wheat futures contract in the world, trading the equivalent of more than 15 million tons each day in 2013--9 ½ times more than the largest European contract. Producers, processors, millers and exporters continue to look to Chicago SRW and KC HRW Wheat for the liquidity that is critical for any risk management solution.
Liquidity means that you can execute positions quickly, effectively and efficiently.
Liquidity offers more flexibility in structuring hedging strategies to meet your
timing and market needs. And when the world is facing new challenges
in Wheat risk management, liquidity provides the security you need in
order to respond with confidence.
News and Highlights
Product Information


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We had a good crowd at the concert. The new compositions were very interesting too and in different styles. From Germany we had a more baroque influenced piece. There has been talk since last year of recording some of the music and we are hoping we can find some funds to do this in a near future. If anyone knows of grants that apply to recording that would be helpful. We also did a small presentation for Harvard Student at the Lamont Library on Saturday and had a lot fo interesting questions from students and a lot of interest some students even doing some paper on muisc buisness.
Taikoza Tickets for 9/26 & 27
for Taikoza NYC concerts
9/26 & 27
Great gift of Music CD for you or a friend
Pay for your classes here
Upcoming shows
01/27/2016Gillette, WY - Gillette, WY
01/30/2016Lincoln Center - Ft Collins, CO
Mailing List
Marco Lienhard's music from his CD
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Markinch Heritage Group
Markinch Heritage Group
Welcome to our organisation...
Interested in local History and Heritage?
Markinch Parish once stretched from the modern town of Glenrothes to the lost village of Innerleven. The history of this stretch of land is only partially written and there are many mysteries and historical puzzles to unravel. If you are interested in revealing the past or in preserving it for the future this could be the organisation for you. Annual membership (October to October) is currently only £10.
For those that require it, please use the various accessibility options along the top of each page. You can change the text size, typeface and colour as well as listen to the page contents.
Braes Loan
A new (18th Oct 2013) Braes Loan page has been created dedicated to information on the history of the Braes Loan. It includes extended history, a downloadable leaflet and links to the iOS and Android app.
Useful links
|Researching the past for our future......


text: More from SI Report: Dodgers release pitcher Freddy Garcia Report: Dodgers release pitcher Freddy Garcia Marshawn Lynch sports gold cleats for Super Bowl Marshawn Lynch sports gold cleats for Super Bowl Louisville vs. FIU: Game time, live stream, TV coverage Louisville vs. FIU: Game time, live stream, TV coverage Pittsburgh-area high school football player dies after... Pittsburgh-area high school football player dies after... Close Tweet0 Share0 Comment0 Share0 Share0 Stumble It0 Print0 More SI Wire Report: Bulls guard Nate Robinson unlikely to return to team next season by Scooby Axson Email Posted: Sun May. 19, 2013 Bulls guard Nate Robinson will be a free agent this summer. (Issac Baldizon/NBA/Getty Images)Chicago Bulls guard Nate Robinson was forced into action during this postseason because of numerous injuries to three starters.He responded well, averaging 16.3 points in 33.7 minutes in 12 playoff games.It might be his last appearance with the team, according to Comcast SportsNet Chicago. Robinson will be an unrestricted free agent this offseason after making $1,146,337 this past season. Robinson has indicated that he would like to return to the team but knows there is "limited space."From CSN Chicago:However, with Rose's expected return next season, Hinrich having another deal on his contract and rookie point guard Marquis Teague needing at least the opportunity to develop in game situations, it's unlikely that next season will be in Chicago for the instant-offense scorer and fan favorite.If it was up to Robinson, though, the little man with the big heart would be back in the Windy City. "I would love to. Honestly, I really would, but knowing the guys we have here, I know it's probably limited space for me. But we'll see how it goes. Talk to my agent and stuff like that and figure out what's the best plan for me," the loquacious speedster said. "I love this team, I love these guys and if I could stay here, it would be wonderful." Promoted Stories Comments


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Mmm. Doesn't that fudge look melt-in-your-mouth delicious? I swear I can almost taste it. LivingSocial has a great deal right now for one pound of chocolate or chocolate walnut fudge Emil's Fudge for $8 (regularly $16)! Emil's Fudge is located in Kaysville, but you can order online.
Buy as many as you'd like (think Christmas!), but limit 1 per person per visit. Only 2 days left to buy! This deal expires September 8, 2012.


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Sunday nights are usually easy dinner nights and tonight was no exception. A Ceasar Salad sandwich followed by Sticky Date Pudding with Caramel Sauce. I can't even remember if I've ever made a Sticky Date Pudding. Plenty of cakes and muffins with dates but not ever a pudding. The Sticky Date made a huge comeback there a couple years ago, appearing on menus everywhere but it wasn't something that I usually went for. This recipe is from my Country Women's Association (CWA) Cookbook "Country Classics" and it's as easy as to throw together at the last minute.
Easy Sticky Date Pudding with Caramel Sauce
1 cup chopped dates
1.1/4 cups water
1 tsp bicarbonate of soda
60g butter
3/4 cup caster sugar
1/4 tsp vanilla
2 eggs
1 cup self raising flour
1 cup soft brown sugar
125g butter
150ml cream
1/2 tsp vanilla
- Preheat oven to 180 deg C and grease an ovenproof pan or dish.
- Cook dates in water, until combined.
- Beat in remaining ingredients and mix well.
- Pour into prepared tin and bake for 25 mins or until cooked.
- For sauce, combine all ingredients in a saucepan and boil for 5 minutes.
- Pour over pudding to serve. Serve with cream or ice cream.


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I was unfair to Simmons twice. He gave a specific example of what I was talking about and al I noticed was that he had started by saying who we should get after first.
I HATE being unfair. But let me give you a smell of what the other extreme looks like.
Every congressional staffer is desperately sick of congressmen using committee time to flatter each other. You are working a hundred-hour week, you have fourteen balls in the air, and the Member you need to see FINALLY drops by the Committee. He says, "I want to start by saying something to my friend Mr. Bovine, from the third district of Pennsylvania. He and I worked together on the Lice Farmer Subcommittee on legislation …" and on and on and on.
Or, as we staffers would privately say to each other, "He's a great guy, I've known him for years, and we just spent a wonderful half hour in the Men's Room together."
Translation: We were SICK of that crap.
I apologize a lot. But every time I do somebody belated justice I am not doing what you are here for. Believe me, nothing would be more boring than a seminar in which I was scrupulous about this.
Being fair can get ENDLESS.
I am serious. There is an advantage to having a tired old man here. It cuts the crap.
And believe me, gang, it is crap you do NOT want.


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plus it might take a lot of mana, and he has to recharge
...god DOES take mana, right?i kid, i kid...
and are the trolls here yet?
btw slugs - New Jerusalem = pearly gates. Not heaven, sadly.
Skullgrin, you started good but fell off at the end... sorry
God made the sun and moon which made day and night. He didn't have to "make something up". It created itself when these were made.
God used the frame of 7 days with the last one to "rest" to give us an example on how we should live. 6 days should be used for work and the last to devote to resting and focusing on God and the life He's given us.
Then God said, Let there be light, and there was light... God divided the light from the darkness. God called the light Day, and the darkness He called Night. So the evening and the morning were the first day.
The "Day" is quite clearly defined there.
Another pretentious question solved by The Good Doctorâ"¢
I want my ticket to heaven now. Make it quick. Make it two tickets. Just so I can take someone there with me.
I can goez to heaven nowz?
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Great product!
High-quality leather, clean design, and good craftsmanship. Padded inside and especially around the edges to protect from zipper scratches. I'm using it for the Lenovo X1 Carbon, which has a larger 14-inch screen but very slim and a mere 0.2 inch wider than the 13.3-inch MacBook Air this product was designed to fit (and honestly blows the MacBook Air out of the water). The fit is a bit snug, as one would expect, but that'll become comfortable after a bit of breaking in. I presume that for a MacBook Air the sleeve would fit like a glove.
Review of 13" Macbook Air Laptop Sleeve
This is a very well made sleeve. It is cushioned on the inside, and the leather is a very good quality on the exterior,
I would recommend this highly.
High Quality, Inexpensive Case
I purchased a new MacBook Air and was looking for a sophisticated leather case that wasn't covered with designer logos. This case is perfect. The leather is high quality and the color is accurately represented in the picture. My MacBook Air fits securely in the case, unlike cases not specifically designed for the Air. I had it embossed with my initials and am very happy with the professional, finishing touch.
3 Item(s)


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Atualy i dint know what fs was and i was doing it anyways. so thats pritty easy.
anyways Nice guide
Atualy i dint know what fs was and i was doing it anyways. so thats pritty easy.
anyways Nice guide
a question about SSing, when you are trying to switch weapons, (in your opinion) is it better to use keys or the mouse wheel?
Thanks, but what was windstep?
nice guide thanks dude
Arent those all Basic Techinques? -->.>-- My portion of my guide.
Doublefly/Daggerstep/Dan Step
Jump>Slash>Block>Slash>Block>Jump>Dash>Slash>Block >Slash>Block
this techinque is like the easiest one in the world :D
Uppercut>Block>Jump>Slash(Hold)>Switch to gun>Release to shoot> Switch guns> Shoot> Cycle when person is on ground or if person is countered from this, just fight them or repeat the process again.
these are two variations of instafall, both are easy, just timing is needed.
Reload Shot/ Fast Shot/ Fast Swap
Shoot> Reload > Swap> Shoot
very easy, trust me x]
Uppercut> Aim> Shoot while person is in midair > Walk almost right under the person and uppercut> then pretty much repeat.
only timing is needed... otherwise this is really easy to do, the way i do it though is glitchy because my uppercut is pro :O and they dont flip in the air instead they are gltiched and just are frozen while they fly in the air, then when i shoot thye automaticall cant safe fall, in stead it looks like they land but they end up on the floor :]
My Combo that is really cheap.
Uppercut> Block> Slash (hold) > Swap > Shoot > Reload> Swap > Shoot > Swap > Shoot.
once again another easy techinque all that is needed is timing. But this one is especially fun to do. Because even if they safe fall the insta fall you pb them twice before they hit the ground and all that is need is another swap from shotgun and their dead :D
Please note most of these techinques are Massive Techniques except doublefly. Also Please note that most of these only apply with Dual Shotguns :P. Also Please note that you not to steal this.
IGN: meluvsugar lvl 41
-nomimono lvl 19
My main got banned for false accusation of hacking :[ caution use doublefly at your own risk people might kick you for thinking that you are using fast actions as well as every other techiqnue i posted. Also please note if you suck, please dont attempt and complain.