Physical reasoning in complex scenes is sensitive to mass

Thesis (M. Eng. and S.B.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2012.Cataloged from PDF version of thesis.Includes bibliographical references (p. 57-58).Many human activities require precise judgments about the dynamics and physical properties - for example, mass - of multiple objects. Classic work suggests that people's intuitive models of physics in mass-sensitive situations are relatively poor and error-prone, based on highly simplified heuristics that apply only in special cases. These conclusions seem at odds with the breadth and sophistication of naive physical reasoning in real-world situations. Our work measures the boundaries of people's physical reasoning in mass-sensitive scenarios and tests the richness of intuitive physics knowledge in more complex scenes. We asked participants to make quantitative judgments about stability and other physical properties of virtual 3D towers composed of heavy and light blocks. We found their judgments correlated highly with a model observer that uses simulations based on realistic physical dynamics and sampling-based approximate probabilistic inference to efficiently and accurately estimate these properties. Several alternative heuristic accounts provide substantially worse fits. In a separate task, participants observed virtual 3D billiards-like movies and judged which balls were lighter. In contrast to the previous experiments, we found their judgments to be more consistent with simple, visual heuristics than a simulation-based model that updates its beliefs about mass in response to prediction errors. We conclude that rich internal physics models are likely to play a key role in guiding human common-sense reasoning in prediction-based tasks and emphasize the need for further investigation in inference-based tasks.by Jessica B. Hamrick.M.Eng.and S.B

Age-related increase of kynurenine enhances miR29b-1-5p to decrease both CXCL12 signaling and the epigenetic enzyme Hdac3 in bone marrow stromal cells

Mechanisms leading to age-related reductions in bone formation and subsequent osteoporosis are still incompletely understood. We recently demonstrated that kynurenine (KYN), a tryptophan metabolite, accumulates in serum of aged mice and induces bone loss. Here, we report on novel mechanisms underlying KYN's detrimental effect on bone aging. We show that KYN is increased with aging in murine bone marrow mesenchymal stem cells (BMSCs). KYN reduces bone formation via modulating levels of CXCL12 and its receptors as well as histone deacetylase 3 (Hdac3). BMSCs responded to KYN by significantly decreasing mRNA expression levels of CXCL12 and its cognate receptors, CXCR4 and ACKR3, as well as downregulating osteogenic gene RUNX2 expression, resulting in a significant inhibition in BMSCs osteogenic differentiation. KYN's effects on these targets occur by increasing regulatory miRNAs that target osteogenesis, specifically miR29b-1-5p. Thus, KYN significantly upregulated the anti-osteogenic miRNA miR29b-1-5p in BMSCs, mimicking the up-regulation of miR-29b-1-5p in human and murine BMSCs with age. Direct inhibition of miR29b-1-5p by antagomirs rescued CXCL12 protein levels downregulated by KYN, while a miR29b-1-5p mimic further decreased CXCL12 levels. KYN also significantly downregulated mRNA levels of Hdac3, a target of miR-29b-1-5p, as well as its cofactor NCoR1. KYN is a ligand for the aryl hydrocarbon receptor (AhR). We hypothesized that AhR mediates KYN's effects in BMSCs. Indeed, AhR inhibitors (CH-223191 and 3',4'-dimethoxyflavone [DMF]) partially rescued secreted CXCL12 protein levels in BMSCs treated with KYN. Importantly, we found that treatment with CXCL12, or transfection with an miR29b-1-5p antagomir, downregulated the AhR mRNA level, while transfection with miR29b-1-5p mimic significantly upregulated its level. Further, CXCL12 treatment downregulated IDO, an enzyme responsible for generating KYN. Our findings reveal novel molecular pathways involved in KYN's age-associated effects in the bone microenvironment that may be useful translational targets for treating osteoporosis