Journal Club

Here’s the paper I will be covering in Journal Club tomorrow:

Neurons for hunger and thirst transmit a negative-valence teaching signal

Abstract

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

New paper on steroid-regulated gene expression

I am extremely pleased that the third leg of our theory on steroid-regulated gene expression is finally published.

Theory of partial agonist activity of steroid hormones
Abstract: The different amounts of residual partial agonist activity (PAA) of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS), which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

Steroids are crucial hormones in the body, which are involved in development and homeostasis. They regulate gene expression by first binding to nuclear receptors that freely float in the cytosol. The receptor-steroid complex is activated somehow and transported to the nucleus, where it binds to a hormone response element and initiates transcription. Steroids can either induce or repress genes in a dose dependent way and the dose-response function is generally a linear-fractional function. In our work, we modeled the whole sequence of events as a complex-building biochemical reaction sequence and showed that a linear-fractional dose response could only arise under some specific but biophysically plausible conditions. See herehere, and here for more background.

Given the importance of steroids and hormones, several important drugs target these receptors. They include tamoxifen and raloxifene, and RU486. These drugs are partial agonists in that bind to nuclear receptors and either, block, reduce, or even increase gene expression. However, it was not really known how partial agonists or antagonists work. In this paper, we show that they work by altering the affinity of some reaction downstream of receptor-ligand binding and thus they can do this in a gene specific way. We show that the activity of a given partial agonist can be reversed by some other downstream transcription factor provided it act after this reaction. The theory also explains why receptor-ligand binding affinity has no affect on the partial agonist activity. The theory makes specific predictions on the mechanisms of partial agonists based on how the maximal activity and the EC50 of the dose response change as you add various transcription factors.

The big problem with these drugs is that nuclear receptors act all over the body and thus the possibility of side effects is high. I think our theory could be used as a guide for developing new drugs or combinations of drugs that can target specific genes and reduce side effects.

The Ebola response

The real failure of the Ebola response is not that a physician went bowling after returning from West Africa but that there are not more doctors over there containing the epidemic where it is needed. Infected patients do not shed virus particles until they become symptomatic and it is emitted in bodily fluids. The New York physician monitored his temperature daily and reported immediately to a designated Ebola hospital the moment he detected high fever. We should not be scape goating physicians who are trying to make a real difference in containing this outbreak and really protecting the rest of the world. This current outbreak was identified in the spring of 2014 but there was no international response until late summer. We know how to contain Ebola – identify patients and isolate them and this is what we should be doing instead of making  emotional and unhelpful policy decisions.

The ultimate pathogen vector

If civilization succumbs to a deadly pandemic, we will all know what the vector was. Every physician, nurse, dentist, hygienist, and health care worker is bound to check their smartphone sometime during the day before, during, or after seeing a patient and they are not sterilizing it afterwards.  The fully hands free smartphone could be the most important invention of the 21st century.

Optimizing food delivery

This Econtalk podcast with Frito-Lay executive Brendan O’Donohoe from 2011 gives a great account of how optimized the production and marketing system for potato chips and other salty snacks has become. The industry has a lot of very smart people trying to figure out how to ensure that you maximize food consumption from how to peel potatoes to how to stack store shelves with bags of chips. This increased efficiency is our hypothesis (e.g. see here) for the obesity epidemic. However, unlike before where I attributed the increase in food production to changes in agricultural policy, I now believe it is mostly due to the vastly increased efficiency of food production. This podcast shows the extent of the optimization after the produce leaves the farm but the efficiency improvements on the farm are just as dramatic. For example, farmers now use GPS to optimally line up their crops.

The Stephanie Event

You should read this article in Esquire about the advent of personalized cancer treatment for a heroic patient named Stephanie Lee.  Here is Steve Hsu’s blog post. The cost of sequencing is almost at the point where everyone can have their normal and tumor cells completely sequenced to look for mutations like Stephanie. The team at Mt.  Sinai Hospital in New York described in the article inserted some of the mutations into a fruit fly and then checked to see what drugs killed it. The Stephanie Event was the oncology board meeting at Sinai where the treatment for Stephanie Lee’s colon cancer, which had spread to the liver, was discussed. They decided on a standard protocol but would use the individualized therapy based on the fly experiments if the standard treatments failed.  The article was beautifully written, combining a compelling human story with science.