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Science

Jun 24 2014 Published by under Uncategorized

Cool result! Yay!

Control verification fails inexplicably. Ugh. How can this be?

Running obvious other control....works. So first control was valid, meaning the negative result was also valid.

Scrutinizes data......AHA!

Actually explains the design flaw in our first control! YAY!

New experiment planned.

12 responses so far

Will a dual sigma receptor antagonist / dopamine transporter inhibitor treat stimulant abuse?

This post covers a platform presentation in symposium 222. Molecular Basis of Addiction: Neurocognitive Deficits and Memory (Mon, Apr 28, 9:55 AM - 12:10 PM) at the 2014 Experimental Biology meeting.

803.3/D382 - Preclinical efficacy of the dual sigma receptor antagonist dopamine uptake inhibitor, CM699, as a medication for stimulant abuse

Johnathan Katz of the NIDA Intramural Research program presented an overview of the data and findings that led up to the creation of a new molecule (CM699) that functions a both a dopamine transporter (DAT) inhibitor and a sigma receptor antagonist. As a bit of background, NIDA has spent a tremendous amount of effort trying to use dopamine transporter inhibitors as agonist therapy for stimulant abuse. The theory of agonist therapy is familiar from the nicotine patch and methadone. The outline is that if you have a drug which mimics the abused drug in effect but has different time-course of effect, you may be able to blunt the acute high of the preferred drug and/or method of use. The nicotine patch supplies the identical drug but in a more sustained, slower and less-peaky manner. Methadone is relatively long acting at endogenous opioid receptors, apparently providing relief without the acute euphoric high. A similar strategy has governed attempts to identify compounds which would confer protection against stimulant abuse.

Since the acute reinforcing effect of stimulants such as cocaine and methamphetamine is mediated through the DAT, this was the target of considerable NIDA effort over decades. It has not been a successful effort.

First off, Katz pointed out that calling sigma a "receptor" is bit of a misnomer as it functions as an intracelluar chaperone protein. This molecule hangs out in association with the endoplasmic reticulum but under ligand activation can migrate to modulate the function of membrane bound proteins. One of those is apparently the dopamine transporter.

Another background consideration for the presentation is that cocaine, as Katz noted, blocks the DAT but also has some sigma affinity. The significance of this agonist activity was not made entirely clear in the talk and we should keep in mind that any antagonism of the sigma receptor will also likely remove the sigma-mediated effects of cocaine. This part was not well explicated in the talk.

At any rate, sigma antagonist compounds block the effects of cocaine. Katz described data indicating that the acute locomotor stimulant effect of cocaine can be prevented and that sigma antagonists can attenuate lethality from an otherwise toxic dose of cocaine.

An initial study from Remi Martin-Fardon, however, found that one sigma antagonist (BD1047) did not reduce cocaine self-administration. Katz then tested several additional sigma antagonists to rigorously determine that no, sigma antagonist compounds by themselves did not reduce cocaine self-administration, even cross a wide range of cocaine doses.

Katz next presented data to remind us that the DAT inhibitor methylphenidate (aka Ritalin) not only fails to reduce cocaine self-administration but that it can increase the self-administration of lower per-infusion doses of cocaine.

However, the combination of methylphenidate with any of several sigma antagonists produced an "insurmountable antagonism" of cocaine self-administration. Meaning that across a wide range of per-infusion doses of cocaine, the rats now failed to self-administer. Importantly, these combinations had no effect on food maintained operant responding, no effect on self administration of opioids or direct dopamine D1 or D2 like receptor agonists but did work to suppress methamphetamine self-administration. This indicates the effect is specific to DAT mediated reinforcing effects.

This all led up to the creation of a compound (CM699) that had the ability to both antagonize sigma receptors and to inhibit the DAT. It was found to blunt the dopamine response to acute cocaine, as measured with intracerebral microdialysis. Furthermore, this single compound produced the "insurmountable antagonism" of cocaine self-administration that had been found for the two-drug combinations.

The talk ended with a proposal that the mechanism of action is that sigma antagonism depletes cholesterol from the membrane which promotes an inward-facing conformation of the DAT.

Obviously, Katz is optimistic that this combined-action CM699 compound proves the concept for a stimulant abuse treatment medication. The half-life of this particular compound was only about 4 and a half hours, thus their immediate goal is to get a longer acting compound which both antagonizes sigma and blocks the dopamine transporter. Nevertheless, the chance that it can completely remove the rewarding properties of cocaine supports the idea that combined activity at DAT and sigma is the route to effective agonist therapy for stimulant abuse.

No responses yet

Full disclosure to the higher education consumer

Jan 31 2014 Published by under Uncategorized

An article in Slate makes the case, a bit excitedly, that popular college/University ranking entities should present the ratio of permanent to temporary faculty more prominently. I agree wholeheartedly that this is information the consumer needs to know. The relative adjunctification is highly pertinent to the quality of education on offer.

The simple ratio of teaching bodies is not enough, though it is probably the only thing Deans and Presidents are willing to report.

Ideally the percentage of student contact hours, including labs and sections, would be reported by tenure track status of the instructor.

29 responses so far

Maybe the problem in NIH grant award is in topic diversity?

Jan 29 2014 Published by under Diversity in Science, Uncategorized

I had a thought occur to me over the past few days. It's been growing along at the back of my mind and is only partially crystallized.

What if PIs of a given class of interest, whether that be sex, ethnicity, nation of origin or whatever, are not randomly distributed across the various topic domains supported by the NIH? What if a PI of characteristic X tends to work on Topic B using Model M whereas a PI of characteristic Y tends to work on Topic A using Model H?

What if the funding rates for Topic X differed from those for Topic Y? Or if applications using Model M consistently succeeded differently compared with applications using Model H?

I didn't see any covariates for topic domain or even the funding IC in the Ginther report.

Surely someone at NIH is thinking about this. Surely?

I have two anecdotes for your consideration.

First, as with many areas of science, the ones dear to me suffer from a sex bias. There is a huge tendency to do the animal studies in male animals. Any study using female animals is very frequently a sex comparison study and is proposed explicitly or implicitly as a comparison with the default, i.e. male. I've talked about this before. The NIH also takes pains to fix the generalized reluctance via their most functional technique, the call for applications for a dedicated pool of money. In theory, the awarding of grants on sex-differences or on issues specific to women's health will then spur additional work. Perhaps create a sustained program or even a career of work on this topic.

My anecdote is that I've noticed over the years (possible confimation bias here) that women in my field have a greater representation than men in these sorts of studies. Sex-differences models and womans' health issues in my fields of interest seem to have women as the driving investigators more often than their overall representation.

If this generalizes, then we will want to know if the competitive success of such grant applications because of topic is contaminating our estimation of women PI's success.

The second anecdote is older and comes from my long history participating on the "Diversity" committees of various academic institutions. Back in the dark ages I recall an incident where a Prof in the experimental sciences had to go to war with a Dean who was in charge of undergraduate summer research funds for underrepresented individuals. The Prof had a candidate who wanted to work in the experimental science, but the awards were generally being made to kids who wanted to work on academic topics related to underrepresented groups. The Dean thought this was the most important thing to do. In this case the prof won his battle in the second year of trying, over the objections of the Dean. I keep in touch with some of my undergraduate professors and I can say that said undergrad went on to become a NIH funded investigator (who still fails to work on issues directly related to underrepresentation). I have no idea if any of the other underrepresented summer research students went on to glorious academic careers in their respective disciplines, perhaps they did. But this is not the point. The point is that perhaps I am a little too glib about the pipeline implications of Ginther. Perhaps the grooming of underrepresented minority undergrads for a career in academics is itself not topic neutral. And the shaping and shifting from that very early stage may dictate field of study and therefore the eventual success rate at the NIH game.

Assuming, of course, that Topic X enjoys differential success rate from Topic Y when the grants are under review at the NIH.

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Doctoral Degrees to African Americans by topic

36 responses so far

Thought of the Day

Jan 29 2014 Published by under Uncategorized

Should I cite my research articles "diversely"?

That is, should I give the slightest thought to whether the people I cite, the lab heads in particular, represent the full diversity of my field? Of my country? The world?

If I consider this at all, am I compromising the purity and integrity of my research manuscripts?

13 responses so far

whaddayamean hockey players are thugs? .....oh.

Jan 22 2014 Published by under Uncategorized

5 responses so far

Disallowed "Resubmissions"

Jan 14 2014 Published by under Uncategorized

Any of you fuckes who have repurposed an unfunded A1 into a new A0, I want to hear about whether your grant was accepted as a new grant or rejected as an impermissible resubmission. And I want all the motherfucken deets about what you changed etc etc etc.

14 responses so far

The ethics of carbon offsets

Dec 26 2013 Published by under Uncategorized

I have recently become aware of http://www.popoffsets.com, which apparently lets you burnish your carbon standing via support for family planning. Carbon offsets are fraught, but overall it seems a good thing to be thinking this way. Reduce the input and increase the carbon sponge. I am in favor.

Family planning to reduce the population growth rate has many obvious benefits. On a local level it improves the life of individuals and families. Population planning and control improves regional economic development in many cases. I am in support!

The organization supports projects in both developed and developing countries. So it is not only about excessive energy consuming people buying their way into feeling good via the developing world.

But it feels that way to me. It feels squicky. I'm having trouble figuring out exactly why....

18 responses so far

Merry Christmas

Dec 24 2013 Published by under Uncategorized

I wish all of you a wonderful holiday, filled with peace, family, friends and good food.

DM

8 responses so far

Thought of the day

Dec 04 2013 Published by under Uncategorized

38 responses so far

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