Protein aggregation into amyloid fibrils is associated with multiple neurodegenerative diseases, including Parkinson’s disease. Kinetic data and biophysical characterization have shown that the secondary nucleation pathway highly accelerates aggregation via the absorption of monomeric protein on the surface of amyloid fibrils. Here, we used NMR and electron paramagnetic resonance spectroscopy to investigate the interaction of monomeric α-synuclein (α-Syn) with its fibrillar form. We demonstrate that α-Syn monomers interact transiently via their positively charged N terminus with the negatively charged flexible C-terminal ends of the fibrils. These intermolecular interactions reduce intramolecular contacts in monomeric α-Syn, yielding further unfolding of the partially collapsed intrinsically disordered states of α-Syn along with a possible increase in the local concentration of soluble α-Syn and alignment of individual monomers on the fibril surface. Our data indicate that intramolecular unfolding critically contributes to the aggregation kinetics of α-Syn during secondary nucleation.Does stunted upward mobility in an educational system impede beneficial psychological processes of learning? We predicted that growth mindsets of intelligence, a well-established psychological stimulant to learning, would be less potent in low-mobility, as compared to high-mobility, learning environments. An analysis of a large cross-national dataset and a longitudinal experiment accumulated converging evidence for this hypothesis. Study 1 examined data from 15-y-old students across 30 countries (n = 235,141 persons). Replicating past findings, growth mindsets positively predicted students’ math, science, and reading literacy. More importantly, the country-level indicator of educational mobility (i.e., the percentage of children from low-education households to graduate from tertiary education) moderated the effect of growth mindsets. Depending on the subject, the gain in predicted academic performance from a one-unit increase in growth mindsets was reduced by 42 to 45% from a high-mobility to a low-mobility country. Results were robust with or without important covariates. Study 2 experimentally manipulated people’s perception of mobility in a carefully constructed learning environment. The moderating role of educational mobility was replicated and extended to learning behavior, which subsequently predicted performance. Evidence further suggests that in high-mobility environments, both advantaged and disadvantaged learners benefited from growth mindsets, albeit likely through diverging mechanisms; when the effect of growth mindsets was attenuated in low-mobility environments, the potential for the disadvantaged to overcome the performance gap was also limited. Implications for galvanizing the upward mobility of the disadvantaged, evaluating the effectiveness of mindset interventions, and conceptualizing social mobility from a psychological perspective are discussed.Do conversations end when people want them to? Surprisingly, behavioral science provides no answer to this fundamental question about the most ubiquitous of all human social activities. In two studies of 932 conversations, we asked conversants to report when they had wanted a conversation to end and to estimate when their partner (who was an intimate in Study 1 and a stranger in Study 2) had wanted it to end. Results showed that conversations almost never ended when both conversants wanted them to and rarely ended when even one conversant wanted them to and that the average discrepancy between desired and actual durations was roughly half the duration of the conversation. Conversants had little idea when their partners wanted to end and underestimated how discrepant their partners’ desires were from their own. These studies suggest that ending conversations is a classic “coordination problem” that humans are unable to solve because doing so requires information that they normally keep from each other. As a result, most conversations appear to end when no one wants them to.Vaccine-based elicitation of broadly neutralizing antibodies holds great promise for preventing HIV-1 transmission. However, the key biophysical markers of improved antibody recognition remain uncertain in the diverse landscape of potential antibody mutation pathways, and a more complete understanding of anti-HIV-1 fusion peptide (FP) antibody development will accelerate rational vaccine designs. Here we survey the mutational landscape of the vaccine-elicited anti-FP antibody, vFP16.02, to determine the genetic, structural, and functional features associated with antibody improvement or fitness. Using site-saturation mutagenesis and yeast display functional screening, we found that 1% of possible single mutations improved HIV-1 envelope trimer (Env) affinity, but generally comprised rare somatic hypermutations that may not arise frequently in vivo. We observed that many single mutations in the vFP16.02 Fab could enhance affinity >1,000-fold against soluble FP, although affinity improvements against the HIV-1 trimer were more measured and rare. The most potent variants enhanced affinity to both soluble FP and Env, had mutations concentrated in antibody framework regions, and achieved up to 37% neutralization breadth compared to 28% neutralization of the template antibody. Altered heavy- and light-chain interface angles and conformational dynamics, as well as reduced Fab thermal stability, were associated with improved HIV-1 neutralization breadth and potency. Selleckchem P110δ-IN-1 We also observed parallel sets of mutations that enhanced viral neutralization through similar structural mechanisms. These data provide a quantitative understanding of the mutational landscape for vaccine-elicited FP-directed broadly neutralizing antibody and demonstrate that numerous antigen-distal framework mutations can improve antibody function by enhancing affinity simultaneously toward HIV-1 Env and FP.Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1-/- Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts.