Conflict and competition between model-based and model-free control

A large literature has accumulated suggesting that human and animal decision making is driven by at least two systems, and that important functions of these systems can be captured by reinforcement learning algorithms. The “model-free” system caches and uses stimulus–value or stimulus–response associations, and the “model-based” system implements more flexible planning using a model of the world. However, it is not clear how the two systems interact during deliberation and how a single decision emerges from this process, especially when they disagree. Most previous work has assumed that while the systems operate in parallel, they do so independently, and they combine linearly to influence decisions. Using an integrated reinforcement learning/drift-diffusion model, we tested the hypothesis that the two systems interact in a non-linear fashion similar to other situations with cognitive conflict. We differentiated two forms of conflict: action conflict, a binary state representing whether the systems disagreed on the best action, and value conflict, a continuous measure of the extent to which the two systems disagreed on the difference in value between the available options. We found that decisions with greater value conflict were characterized by reduced model-based control and increased caution both with and without action conflict. Action conflict itself (the binary state) acted in the opposite direction, although its effects were less prominent. We also found that between-system conflict was highly correlated with within-system conflict, and although it is less clear a priori why the latter might influence the strength of each system above its standard linear contribution, we could not rule it out. Our work highlights the importance of non-linear conflict effects, and provides new constraints for more detailed process models of decision making. It also presents new avenues to explore with relation to disorders of compulsivity, where an imbalance between systems has been implicated.     

OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance

Mitochondrial dynamics is a conserved process by which mitochondria undergo repeated cycles of fusion and fission, leading to exchange of mitochondrial genetic content, ions, metabolites, and proteins. Here, we examine the role of the mitochondrial fusion protein optic atrophy 1 (OPA1) in differentiated skeletal muscle by reducing OPA1 gene expression in an inducible manner. OPA1 deficiency in young mice results in non‐lethal progressive mitochondrial dysfunction and loss of muscle mass. Mutant mice are resistant to age‐ and diet‐induced weight gain and insulin resistance, by mechanisms that involve activation of ER stress and secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle, resulting in increased metabolic rates and improved whole‐body insulin sensitivity. OPA1‐elicited mitochondrial dysfunction activates an integrated stress response that locally induces muscle atrophy, but via secretion of FGF21 acts distally to modulate whole‐body metabolism.     

Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines

Efficient differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to a variety of lineages requires step-wise approaches replicating the key commitment stages found during embryonic development. Here we show that expression of PdgfR-α segregates mouse ESC-derived Flk-1 mesoderm into Flk-1(+)PdgfR-α(+) cardiac and Flk-1(+)PdgfR-α(-) hematopoietic subpopulations. By monitoring Flk-1 and PdgfR-α expression, we found that specification of cardiac mesoderm and cardiomyocytes is determined by remarkably small changes in levels of Activin/Nodal and BMP signaling. Translation to human ESCs and iPSCs revealed that the emergence of cardiac mesoderm could also be monitored by coexpression of KDR and PDGFR-α and that this process was similarly dependent on optimal levels of Activin/Nodal and BMP signaling. Importantly, we found that individual mouse and human pluripotent stem cell lines require optimization of these signaling pathways for efficient cardiac differentiation, illustrating a principle that may well apply in other contexts.     

Analysis of neutralizing antigenic sites on the surface of type A12 foot-and-mouth disease virus.

A series of seven neutralizing monoclonal antibodies (nMAbs) directed against type A12 foot-and-mouth disease virus was used to generate neutralization-resistant variants. Both plaque reduction neutralization and microneutralization assays showed that the variants were no longer neutralized by the nMAbs used to generate them, although some of the variants still reacted with the nMAbs at high antibody concentrations. Results of cross-neutralization studies by both plaque reduction neutralization and microneutralization assays suggested the presence of at least one immunodominant antigenic site on the surface of type A12 foot-and-mouth disease virus, along with evidence of a second antigenic site on the viral surface. Two of the variants had reduced virulence in tissue culture as evidenced by their inability to inhibit cellular protein synthesis and a marked reduction in virus-induced cellular morphological alterations. Nucleotide sequencing of the variant genomes placed three epitopes of the major antigenic site on VP1 and the fourth epitope on VP3 and VP1. The one epitope of the minor site appears to reside only on VP1.     

Use of cloned populations of mouse lymphocytes to analyze cellular differentiation

We describe a method for generation of homogeneous cell populations that each arise from clonal expansion of cells at a discrete stage of differentiation within a single lineage. We have used this to produce continuously propagatable lymphocyte clones. Each clone represents a cell at a progressive stage of thymus-dependent cellular differentiation. These cloned cells bear stable surface membrane glycoproteins characteristic of precursor cells and mature progeny; conditions allowing maximal cloning efficiencies for each cell type (10–85%) have been established. Mature lymphocyte clones continue to express specialized function and provide material for biochemical analysis of T lymphocyte functions; one fully differentiated clone from the “inducer” lymphocyte set synthesizes a molecule that activates other lymphocytes to secrete immunoglobulin. This activity is associated with a highly purified molecule having a molecular weight of 45,000 daltons and an isoelectric point of approximately 6.0. This molecule, together with clones of precursor and mature T lymphocytes, may provide a system to further study the mechanisms of gene activation during cellular differentiation.     

Composition,structure and phase transition in yeast fatty acid auxotroph membranes: Spin labels and freeze-fracture

• 1 Fatty acid desaturase mutant yeast cells have been enriched with 2 fatty acids having substantially different physical properties.
• 2 Differences in fatty acid composition are reflected in the ESR determined phase transitions and the freeze-fracture morphology of the tonoplast.
• 3 In these cells, fatty acid composition, rather than the position of the phase transition relative to growth temperature, appears to be the more important variable in determining membrane morphology.
• 4 The freezing process used in the freeze-fracture technique does not appear to cause a demixing of the lipid components of the membrane.