Confirmation bias in the utilization of others' opinion strength

Humans tend to discount information that undermines past choices and judgments. This confirmation bias has significant impact on domains ranging from politics to science and education. Little is known about the mechanisms underlying this fundamental characteristic of belief formation. Here we report a mechanism underlying the confirmation bias. Specifically, we provide evidence for a failure to use the strength of others' disconfirming opinions to alter confidence in judgments, but adequate use when opinions are confirmatory. This bias is related to reduced neural sensitivity to the strength of others' opinions in the posterior medial prefrontal cortex when opinions are disconfirming. Our results demonstrate that existing judgments alter the neural representation of information strength, leaving the individual less likely to alter opinions in the face of disagreement

A Context-Specific Role for Retinoblastoma Protein-Dependent Negative Growth Control in Suppressing Mammary Tumorigenesis

The ability to respond to anti-growth signals is critical to maintain tissue homeostasis and loss of this negative growth control safeguard is considered a hallmark of cancer. Negative growth regulation generally occurs during the G0/G1 phase of the cell cycle, yet the redundancy and complexity among components of this regulatory network has made it difficult to discern how negative growth cues protect cells from aberrant proliferation.The retinoblastoma protein (pRB) acts as the final barrier to prevent cells from entering into the cell cycle. By introducing subtle changes in the endogenous mouse Rb1 gene (Rb1(ΔL)), we have previously shown that interactions at the LXCXE binding cleft are necessary for the proper response to anti-growth signals such as DNA damage and TGF-β, with minimal effects on overall development. This disrupts the balance of pro- and anti-growth signals in mammary epithelium of Rb1(ΔL/ΔL) mice. Here we show that Rb1(ΔL/ΔL) mice are more prone to mammary tumors in the Wap-p53(R172H) transgenic background indicating that negative growth regulation is important for tumor suppression in these mice. In contrast, the same defect in anti-growth control has no impact on Neu-induced mammary tumorigenesis.Our work demonstrates that negative growth control by pRB acts as a crucial barrier against oncogenic transformation. Strikingly, our data also reveals that this tumor suppressive effect is context-dependent

Structure of S. aureus HPPK and the Discovery of a New Substrate Site Inhibitor

The first structural and biophysical data on the folate biosynthesis pathway enzyme and drug target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), from the pathogen Staphylococcus aureus is presented. HPPK is the second essential enzyme in the pathway catalysing the pyrophosphoryl transfer from cofactor (ATP) to the substrate (6-hydroxymethyl-7,8-dihydropterin, HMDP). In-silico screening identified 8-mercaptoguanine which was shown to bind with an equilibrium dissociation constant, Kd, of ∼13 µM as measured by isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR). An IC50 of ∼41 µM was determined by means of a luminescent kinase assay. In contrast to the biological substrate, the inhibitor has no requirement for magnesium or the ATP cofactor for competitive binding to the substrate site. The 1.65 Å resolution crystal structure of the inhibited complex showed that it binds in the pterin site and shares many of the key intermolecular interactions of the substrate. Chemical shift and 15N heteronuclear NMR measurements reveal that the fast motion of the pterin-binding loop (L2) is partially dampened in the SaHPPK/HMDP/α,β-methylene adenosine 5′-triphosphate (AMPCPP) ternary complex, but the ATP loop (L3) remains mobile on the µs-ms timescale. In contrast, for the SaHPPK/8-mercaptoguanine/AMPCPP ternary complex, the loop L2 becomes rigid on the fast timescale and the L3 loop also becomes more ordered – an observation that correlates with the large entropic penalty associated with inhibitor binding as revealed by ITC. NMR data, including 15N-1H residual dipolar coupling measurements, indicate that the sulfur atom in the inhibitor is important for stabilizing and restricting important motions of the L2 and L3 catalytic loops in the inhibited ternary complex. This work describes a comprehensive analysis of a new HPPK inhibitor, and may provide a foundation for the development of novel antimicrobials targeting the folate biosynthetic pathway

VPS29 Is Not an Active Metallo-Phosphatase but Is a Rigid Scaffold Required for Retromer Interaction with Accessory Proteins

VPS29 is a key component of the cargo-binding core complex of retromer, a protein assembly with diverse roles in transport of receptors within the endosomal system. VPS29 has a fold related to metal-binding phosphatases and mediates interactions between retromer and other regulatory proteins. In this study we examine the functional interactions of mammalian VPS29, using X-ray crystallography and NMR spectroscopy. We find that although VPS29 can coordinate metal ions Mn2+ and Zn2+ in both the putative active site and at other locations, the affinity for metals is low, and lack of activity in phosphatase assays using a putative peptide substrate support the conclusion that VPS29 is not a functional metalloenzyme. There is evidence that structural elements of VPS29 critical for binding the retromer subunit VPS35 may undergo both metal-dependent and independent conformational changes regulating complex formation, however studies using ITC and NMR residual dipolar coupling (RDC) measurements show that this is not the case. Finally, NMR chemical shift mapping indicates that VPS29 is able to associate with SNX1 via a conserved hydrophobic surface, but with a low affinity that suggests additional interactions will be required to stabilise the complex in vivo. Our conclusion is that VPS29 is a metal ion-independent, rigid scaffolding domain, which is essential but not sufficient for incorporation of retromer into functional endosomal transport assemblies

The Stimulatory Gαs Protein Is Involved in Olfactory Signal Transduction in Drosophila

Seven-transmembrane receptors typically mediate olfactory signal transduction by coupling to G-proteins. Although insect odorant receptors have seven transmembrane domains like G-protein coupled receptors, they have an inverted membrane topology, constituting a key difference between the olfactory systems of insects and other animals. While heteromeric insect ORs form ligand-activated non-selective cation channels in recombinant expression systems, the evidence for an involvement of cyclic nucleotides and G-proteins in odor reception is inconsistent. We addressed this question in vivo by analyzing the role of G-proteins in olfactory signaling using electrophysiological recordings. We found that Gαs plays a crucial role for odorant induced signal transduction in OR83b expressing olfactory sensory neurons, but not in neurons expressing CO2 responsive proteins GR21a/GR63a. Moreover, signaling of Drosophila ORs involved Gαs also in a heterologous expression system. In agreement with these observations was the finding that elevated levels of cAMP result in increased firing rates, demonstrating the existence of a cAMP dependent excitatory signaling pathway in the sensory neurons. Together, we provide evidence that Gαs plays a role in the OR mediated signaling cascade in Drosophila

Comparing reinforcement learning approaches for solving game theoretic models: a dynamic airline pricing game example

Due to the difficulty in solving game theoretic models, there is a tendency to focus on the overly simplistic dynamic airline pricing games or to even ignore competition completely. Recent changes to the industry mean that airlines can no longer ignore competitors in their model. This paper adds more complex customer model aspects; i.e., customer choice using a Logit model, customer demand using a linear probabilistic demand model, and market size using a binary random function; into an existing solvable game that only had a simple customer model. A reinforcement learning method was used to solve the newly formed games with mixed results.<br/