New Papers

Li, Y., Chow, C. C., Courville, A. B., Sumner, A. E. & Periwal, V. Modeling glucose and free fatty acid kinetics in glucose and meal tolerance test. Theoretical Biology and Medical Modelling 1–20 (2016). doi:10.1186/s12976-016-0036-3

Katan, M. B. et al. Impact of Masked Replacement of Sugar-Sweetened with Sugar-Free Beverages on Body Weight Increases with Initial BMI: Secondary Analysis of Data from an 18 Month Double–Blind Trial in Children. PLoS ONE 11, e0159771 (2016).

These two papers took painfully long times to be published, which was completely perplexing and frustrating given that they both seemed rather straightforward and noncontroversial. The first is a generalization of our previously developed minimal model of the fatty acid and glucose as a function of insulin to a response to an ingested meal, where the rate of appearance of fat and glucose in the blood was modeled by an empirically determined time dependent function. The second was a reanalysis of the effects of substituting sugar-sweetened beverages with non-sugar ones. We applied our childhood growth model to predict what the children ate to account for their growth. Interestingly, what we found is that the model predicted that children with higher BMI are less able to compensate for a reduction of calories than children with lower BMI. This could imply that children with higher BMI have a less sensitive caloric sensing system and thus could be prone to overeating but on the flip side, can also be “tricked” into eating less.

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New paper in PLoS Comp Bio

Shashaank Vattikuti , Phyllis Thangaraj, Hua W. Xie, Stephen J. Gotts, Alex Martin, Carson C. Chow. Canonical Cortical Circuit Model Explains Rivalry, Intermittent Rivalry, and Rivalry Memory. PLoS Computational Biology (2016).

Abstract

It has been shown that the same canonical cortical circuit model with mutual inhibition and a fatigue process can explain perceptual rivalry and other neurophysiological responses to a range of static stimuli. However, it has been proposed that this model cannot explain responses to dynamic inputs such as found in intermittent rivalry and rivalry memory, where maintenance of a percept when the stimulus is absent is required. This challenges the universality of the basic canonical cortical circuit. Here, we show that by including an overlooked realistic small nonspecific background neural activity, the same basic model can reproduce intermittent rivalry and rivalry memory without compromising static rivalry and other cortical phenomena. The background activity induces a mutual-inhibition mechanism for short-term memory, which is robust to noise and where fine-tuning of recurrent excitation or inclusion of sub-threshold currents or synaptic facilitation is unnecessary. We prove existence conditions for the mechanism and show that it can explain experimental results from the quartet apparent motion illusion, which is a prototypical intermittent rivalry stimulus.

Author Summary

When the brain is presented with an ambiguous stimulus like the Necker cube or what is known as the quartet illusion, the perception will alternate or rival between the possible interpretations. There are neurons in the brain whose activity is correlated with the perception and not the stimulus. Hence, perceptual rivalry provides a unique probe of cortical function and could possibly serve as a diagnostic tool for cognitive disorders such as autism. A mathematical model based on the known biology of the brain has been developed to account for perceptual rivalry when the stimulus is static. The basic model also accounts for other neural responses to stimuli that do not elicit rivalry. However, these models cannot explain illusions where the stimulus is intermittently switched on and off and the same perception returns after an off period because there is no built-in mechanism to hold the memory. Here, we show that the inclusion of experimentally observed low-level background neural activity is sufficient to explain rivalry for static inputs, and rivalry for intermittent inputs. We validate the model with new experiments.

 

This paper is the latest of a continuing series of papers outlining how a canonical cortical circuit of excitatory and inhibitory cells can explain psychophysical and electrophysiological data of perceptual and cortical dynamics under a wide range of stimuli and conditions. I’ve summarized some of the work before (e.g. see here). In this particular paper, we show how the same circuit previously shown to explain winner-take-all behavior, normalization, and oscillations at various time scales, can also possess memory in the absence of input. Previous work has shown that if you have a circuit with effective mutual inhibition between two pools representing different percepts and include some type of fatigue process such as synaptic depression or spike frequency adaptation, then the circuit exhibits various dynamics depending on the parameters and input conditions. If the inhibition strength is relatively low and the two pools receive equal inputs then the model will have a symmetric fixed point where both pools are equally active. As the inhibition strength (or input strength) increases, then there can be a bifurcation to oscillations between the two pools with a frequency that is dependent on the strengths of inhibition, recurrent excitation, input, and the time constant of the fatigue process. A further increase in inhibition leads to a bifurcation to a winner-take-all (WTA) state where one of the pools dominates the others. However, the same circuit would be expected to not possess “rivalry memory”, where the same percept returns after the stimulus is completely removed for a duration that is long compared to the average oscillation period (dominance time). The reason is that during rivalry, the dominant pool is weakened while the suppressed pool is strengthened by the fatigue process. Thus when the stimulus is removed and returned, the suppressed pool would be expected to win the competition and become dominant. This reasoning had led people, including myself, to believe that rivalry memory could not be explained by this same model.

However, one thing Shashaank observed and that I hadn’t really noticed before was that the winner-take-all state can persist for arbitrarily low input strength. We prove a little theorem in the paper showing that if the gain function (or FI curve) is concave (i.e. does not bend up), then the winner-take-all will persist for arbitrarily low input if the inhibition is strong enough. Most importantly, the input does not need to be tuned and could be provided by the natural background activity known to exist in the brain. Even zero mean noise is sufficient to maintain the WTA state. This low-activity WTA state can then serve as a memory since whatever was active during a state with strong input can remain active when the input is turned off and the neurons just receive low level background activity. It is thus a purely mutual inhibition maintained memory. We dubbed this “topological memory” because it is like a kink in the carpet that never disappears and persists over a wide range of parameter values and input strengths. Although, we only consider rivalry memory in this paper, the mechanism could also apply in other contexts such as working memory. In this paper, we also focus on a specific rivalry illusion called the quartet illusion, which makes the model slightly more complicated but we show how it naturally reduces to a two pool model. We are currently finishing a paper quantifying precisely how excitatory and inhibitory strengths affect rivalry and other cortical phenomena so watch this space. We also have submitted an abstract to neuroscience demonstrating how you can get WTA and rivalry in a balanced-state network.

 

Update: link to paper is fixed.

Two new papers

Pradhan MA1, Blackford JA Jr1, Devaiah BN2, Thompson PS2, Chow CC3, Singer DS2, Simons SS Jr4.  Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction.  J Biol Chem. 2016 Jan 1;291(1):342-54. doi: 10.1074/jbc.M115.683722. Epub 2015 Oct 26.

Abstract: Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF)-E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (Amax) and the steroid concentration required for half-maximal induction (EC50) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps. The action at two of these steps is dependent on BRD4 concentration, whereas the third step requires the association of BRD4 with P-TEFb. BRD4 is also found to bind to NELF-E, a component of the NELF complex. Unexpectedly, NELF-E modifies GR induction in a manner that is independent of the NELF complex. Several of the kinetically defined steps of BRD4 in this study are proposed to be related to its known biochemical actions. However, novel actions of BRD4 and of NELF-E in GR-controlled gene induction have been uncovered. The model-based competition assay is also unique in being able to order, for the first time, the sites of action of the various reaction components: GR < Cdk9 < BRD4 ≤ induced gene < NELF-E. This ability to order factor actions will assist efforts to reduce the side effects of steroid treatments.

Li Y, Chow CC, Courville AB, Sumner AE, Periwal V. Modeling glucose and free fatty acid kinetics in glucose and meal tolerance test. Theor Biol Med Model. 2016 Mar 2;13:8. doi: 10.1186/s12976-016-0036-3.

Abstract:
BACKGROUND:
Quantitative evaluation of insulin regulation on plasma glucose and free fatty acid (FFA) in response to external glucose challenge is clinically important to assess the development of insulin resistance (World J Diabetes 1:36-47, 2010). Mathematical minimal models (MMs) based on insulin modified frequently-sampled intravenous glucose tolerance tests (IM-FSIGT) are widely applied to ascertain an insulin sensitivity index (IEEE Rev Biomed Eng 2:54-96, 2009). Furthermore, it is important to investigate insulin regulation on glucose and FFA in postprandial state as a normal physiological condition. A simple way to calculate the appearance rate (Ra) of glucose and FFA would be especially helpful to evaluate glucose and FFA kinetics for clinical applications.
METHODS:
A new MM is developed to simulate the insulin modulation of plasma glucose and FFA, combining IM-FSIGT with a mixed meal tolerance test (MT). A novel simple functional form for the appearance rate (Ra) of glucose or FFA in the MT is developed. Model results are compared with two other models for data obtained from 28 non-diabetic women (13 African American, 15 white).
RESULTS:
The new functional form for Ra of glucose is an acceptable empirical approximation to the experimental Ra for a subset of individuals. When both glucose and FFA are included in FSIGT and MT, the new model is preferred using the Bayes Information Criterion (BIC).
CONCLUSIONS:
Model simulations show that the new MM allows consistent application to both IM-FSIGT and MT data, balancing model complexity and data fitting. While the appearance of glucose in the circulation has an important effect on FFA kinetics in MT, the rate of appearance of FFA can be neglected for the time-period modeled.

New review paper on GWAS

Comput Struct Biotechnol J. 2015 Nov 23;14:28-34
Uncovering the Genetic Architectures of Quantitative Traits.
Lee JJ, Vattikuti S, Chow CC.

Abstract
The aim of a genome-wide association study (GWAS) is to identify loci in the human genome affecting a phenotype of interest. This review summarizes some recent work on conceptual and methodological aspects of GWAS. The average effect of gene substitution at a given causal site in the genome is the key estimand in GWAS, and we argue for its fundamental importance. Implicit in the definition of average effect is a linear model relating genotype to phenotype. The fraction of the phenotypic variance ascribable to polymorphic sites with nonzero average effects in this linear model is called the heritability, and we describe methods for estimating this quantity from GWAS data. Finally, we show that the theory of compressed sensing can be used to provide a sharp estimate of the sample size required to identify essentially all sites contributing to the heritability of a given phenotype.
KEYWORDS:
Average effect of gene substitution; Compressed sensing; GWAS; Heritability; Population genetics; Quantitative genetics; Review; Statistical genetics

New Papers

I have been negligent about posting new papers but here is a list.  I’ll expound on them in the future.

Lee, J. J., Vattikuti, S. & Chow, C. C. Uncovering the Genetic Architectures of Quantitative Traits. Computational and Structural Biotechnology Journal 14, 28–34 (2016).

Lenstra, T. L., Coulon, A., Chow, C. C. & Larson, D. R. Single-Molecule Imaging Reveals a Switch between Spurious and Functional ncRNA Transcription. MOLCEL 60, 597–610 (2015).

Stavreva, D. A. et al. Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing. Genome Res 25, 845–857 (2015).

Paper on the effect of food intake fluctuations on body weight

Chow, C. C. & Hall, K. D. Short and long-term energy intake patterns and their implications for human body weight regulation. Physiology & Behavior 134:60–65 (2014). doi:10.1016/j.physbeh.2014.02.044

Abstract: Adults consume millions of kilocalories over the course of a few years, but the typical weight gain amounts to only a few thousand kilocalories of stored energy. Furthermore, food intake is highly variable from day to day and yet body weight is remarkably stable. These facts have been used as evidence to support the hypothesis that human body weight is regulated by active control of food intake operating on both short and long time scales. Here, we demonstrate that active control of human food intake on short time scales is not required for body weight stability and that the current evidence for long term control of food intake is equivocal. To provide more data on this issue, we emphasize the urgent need for developing new methods for accurately measuring energy intake changes over long time scales. We propose that repeated body weight measurements can be used along with mathematical modeling to calculate long-term changes in energy intake and thereby quantify adherence to a diet intervention and provide dynamic feedback to individuals that seek to control their body weight.

New paper on global obesity

We have a new paper out in the World Health Organization Bulletin looking at the association between an increase in food supply and average weight gain:

Stefanie Vandevijvere, Carson C Chow, Kevin D Hall, Elaine Umali & Boyd A Swinburn. Increased food energy supply as a major driver of the obesity epidemic: a global analysis, Bulletin of the WHO 2015;93:446–456.

This paper extends the analysis we did in our paper on the US food supply to the rest of the world. In the US paper, we showed that an increase in food supply more than explains the increase in average body weight over the duration of the obesity epidemic, as predicted by our experimentally validated body weight model. I had been hoping to do the analysis on the rest of the world and was very happy that my colleagues in Australia and New Zealand were able to collate the global data, which was not a simple undertaking.

What we found was almost completely consistent with the hypothesis that food is the main driver of obesity everywhere. In more than half of the countries (45/83), the increase in food supply more than explains the increase in weight. In other mostly less developed nations (11/83), an increase in food was associated with an increase in body weight although it was not sufficient to explain all of the weight gain. Five countries had a decrease in both food and body weight. Five countries had decreases in food supply and an increase in body weight and finally three countries (Iran, Rwanda, and South Africa) had an increase in food but a decrease in body weight.

Now by formal logic, only one of these observations is inconsistent with the food push hypothesis. Recall that if A implies B then the only logical conclusion you can draw is that not B implies not A. Hence, if we hypothesize that increased food causes increased obesity then that means if we see no obesity then that implies no increase in food. Thus only three countries defied our hypothesis and they were Iran, Rwanda, and South Africa where obtaining accurate data is difficult.

The five countries that had a decrease in food but an increase in body weight do not dispute our hypothesis. They just show that increased food is not necessary, which we know is true. Decreased activity could also lead to increased weight and it is possible that this played a role in these countries and the 11 others where food was not sufficient to explain all of the weight increase.

I was already pretty convinced that food was the main driver of the obesity epidemic and this result puts it to rest for me. This is the main reason that I don’t believe that the obesity epidemic is a health problem per se. It is a social and economic problem.