ABSTRACT
Many scholars suggest that visa restrictions push individuals who would have otherwise migrated legally toward illegal channels. This expectation is difficult to test empirically for three reasons. First, unauthorized migration is clandestine and often unobservable. Second, interpersonal ties between migrants and would-be migrants form a self-perpetuating system, which adapts in ways that are difficult to observe or predict. Third, empirical evaluations of immigration policy are vulnerable to endogeneity and other issues of causal inference. In this paper, we pair tailor-made empirical designs with an agent-based computational model (ABM) to capture the dynamics of a migration system that often elude empirical analysis, while grounding agent rules and characteristics with primary data collected in Jamaica, an origin country. We find that some government-imposed restrictions on migrants can deter total migration, but others are ineffective. Relative to a system of free movement, the minimal eligibility conditions required to classify migrants into visa categories alone make migration inaccessible for many. Restrictive policies imposed on student and high-skilled visa categories have little added effect because eligible individuals are likely able to migrate through alternative legal categories. Meanwhile, restrictions on family-based visas result in significant reductions in total migration. However, they also produce the largest reorientation toward unauthorized channels-an unintended consequence that even the highest rates of apprehension do not effectively eliminate.
ABSTRACT
The pathologic self-assembly of proteins is associated with typically late-onset disorders such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. Important mechanistic details of the self-assembly are unknown, but there is increasing evidence supporting the role of transient α-helices in the early events. Islet amyloid polypeptide (IAPP) is a 37-residue polypeptide that self-assembles into aggregates that are toxic to the insulin-producing ß cells. To elucidate early events in the self-assembly of IAPP, we used limited proteolysis to identify an exposed and flexible region in IAPP monomer. This region includes position 20 where a serine-to-glycine substitution (S20G) is associated with enhanced formation of amyloid fibrils and early onset type 2 diabetes. To perform detailed biophysical studies of the exposed and flexible region, we synthesized three peptides including IAPP(11-25)WT (wild type), IAPP(11-25)S20G, and IAPP(11-25)S20P. Solution-state NMR shows that all three peptides transiently populate the α-helical conformational space, but the S20P peptide, which does not self-assemble, transiently samples a broken helix. Under similar sample conditions, the WT and S20G peptides populate the α-helical intermediate state and ß-sheet end state, respectively, of fibril formation. Our results suggest a mechanism for self-assembly that includes the stabilization of transient α-helices through the formation of NMR-invisible helical intermediates followed by an α-helix to ß-sheet conformational rearrangement. Furthermore, our results suggest that reducing intermolecular helix-helix contacts as in the S20P peptide is an attractive strategy for the design of blockers of peptide self-assembly.
