The Ugly Sequestosome1:the role of p62/SQSTM1 in autophagy and multisystem proteinopathy

Multisystem proteinopathy (MSP) defines a spectrum of degenerative diseases unified by TDP-43 pathology that affect muscle, brain and bone. Mutations in several proteins (VCP, p62/SQSTM1, HNRNPA2B1, HNRNPA1) can all cause MSP via impairments in autophagic protein degradation (VCP and SQSTM1) or RNA granule dynamics (HNRNPA2B1 and HNRNPA1). Phenotypically, MSP mutations lead to variable penetrance of several phenotypes: Paget’s disease of the bone (PDB), rimmed vacuolar inclusion body myopathy (RV-IBM), amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). However, how a same mutation of a protein can develop different diseases remains unclear. Understanding of p62/SQSTM1 (SQSTM1) function is critical to answer this question. In this dissertation, we provide evidence that SQSTM1 is regulated via its UBA domain ubiquitination. We find that Keap1/Cullin3 ubiquitinates SQSTM1 at lysine 420 within its UBA domain. Substitution of lysine 420 with arginine or disease-associated mutation of SQSTM1 disrupts its ubiquitination, sequestering activity, and degradation. In contrast, overexpression of Keap1/Cullin3 in SQSTM1-WT expressing cells increases ubiquitinated inclusion formation, SQSTM1’s association with autophagosomes and rescues proteotoxicity. We also provide evidence that the oligogenic inheritance of a disease associated SQSTM1 mutation with a rare coding variant in the low-complexity domain (LCD) of the RNA-binding protein, TIA1 (p.N357S) can dictate a myodegenerative phenotypes. Deletion or mutation of SQSTM1 along with TIA1 disease mutants synergistically impairs RNA stress granules clearance and their dynamics. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin mediated autophagic degradation that defines the penetrance of a MSP phenotype

Effective Cost Allocation for Deterrence of Terrorists

The attacks on the World Trade Center in New York, the subway and bus bombings in London, and the suicide bombings in Casablanca are only a few of the examples in which in recent years, terrorists have opted to attack multiple targets at once. Often, their strong determination to attack makes it impossible to completely deter terrorists from attacking altogether, and instead, counterterrorist units must consider how to defend targets effectively to minimize damages. We attempt to model a version of this scenario by presenting a two target sequential game where two players try to attack and defend the targets respectively. The probability of successfully destroying a target is a function of resource allocations from both players, who are also subject to budget constraints. We attempt to find the defender’s strategy that will minimize expected damages by first exploring the attacker’s optimal strategy. We show that the attacker’s decision to attack only one or both targets is dependent on the size of the attacker’s allowed budget relative to other game parameters, and use that information to evaluate the defender’s strategy. We also numerically determine the optimal defender security investment, as well its sensitivity to other game parameters. We conjecture that as the damage and expected reward at a target increases, the defender’s allocation towards that target tends to increase, while an increase in the punishment results in the opposite effect. Such conjectures allow for the creation of a flexible defense policy in the more applicable bigger picture

Comparative Analysis of Factors Related to College Selection by High Academic Ability Students Attending Mississippi\u27s Public Community Colleges in 2003 and 2011

Studies have been conducted about high academic ability students in postsecondary institutions, but rarely has research explored the college choice factors involving high academic ability students who chose to attend a community college. The purpose of this study was to determine the factors related to why high academic ability students chose to attend Mississippi public community colleges. The study also examined the differences in perception of college choice factors among students according to the variables of age, gender, race, full-time or part-time enrollment status, attendance for first-generation students to college, if one or both parents or legal guardians attended the respective community college, if a sibling attended the respective community college, and if the student was a commuter or on-campus resident. The participants were freshmen students who had scored 26 and above on the ACT composite score and who were enrolled in Mississippi public community colleges during the spring semesters of 2003 or 2011. There were 240 participants in 2003 and 247 participants in 2011. The study found that females considered academic preparation, entrance requirements, availability of specific programs of study, and contact with college representatives more highly than males; first-generation students considered community in which the college was located as more important; and on-campus students rated the following variables higher than commuters: varsity sports opportunities, racial/ethnic makeup, type of housing, extracurricular activities, social climate and activities, and male/female ratio