Three essays in regional growth, distribution, and resilience

2019 Summer.Includes bibliographical references.This work delves into two significant but less understood topics in regional labor economics. The first contribution is to growing literature examining the effects of business dynamism on regional resilience. Significant attention has, understandably, been paid to understanding why the impact of and recovery from the 2008 recession has varied across regions. Chapters 1 and 2 extend to the question of regional resilience a hypothesis that gross rates of local establishment openings, or "churn," may affect local economic performance over a business cycle. In the US, higher-churn areas are found to experience faster average employment growth over the decade spanning the recession, but with more cyclical volatility. Churn is not positively correlated with median household income growth or poverty reduction at a county level. A novel cross-country analysis reveals that in the UK, local authorities with higher churn prior to the recession did weather the financial crisis slightly better, although data limitations restrict the direct comparability between the US and UK cases. Chapter 3 turns to the growth of self-employment in the US, motivated by two observations: first, that growth in the self-employment share has been regionally heterogeneous; and second, that theory suggests workers in wage-and-salary occupations exert limited agency over their working hours. This paper investigates whether average local working hours influence subsequent changes in the county self-employment share. I find a U-shaped relationship between working hours and self-employment growth: counties with working hours furthest from the mean experienced the fastest growth in local self-employment share, adding a new wrinkle to the running debate over whether the "gig economy" is driven by opportunity or necessity

Sequential Adaptive Detection for In-Situ Transmission Electron Microscopy (TEM)

We develop new efficient online algorithms for detecting transient sparse signals in TEM video sequences, by adopting the recently developed framework for sequential detection jointly with online convex optimization [1]. We cast the problem as detecting an unknown sparse mean shift of Gaussian observations, and develop adaptive CUSUM and adaptive SSRS procedures, which are based on likelihood ratio statistics with post-change mean vector being online maximum likelihood estimators with $\ell_1$. We demonstrate the meritorious performance of our algorithms for TEM imaging using real data

Characterization of gene-activated human acid-β-glucosidase: Crystal structure, glycan composition, and internalization into macrophages

Gaucher disease, the most common lysosomal storage disease, can be treated with enzyme replacement therapy (ERT), in which defective acid-β-glucosidase (GlcCerase) is supplemented by a recombinant, active enzyme. The X-ray structures of recombinant GlcCerase produced in Chinese hamster ovary cells (imiglucerase, Cerezyme®) and in transgenic carrot cells (prGCD) have been previously solved. We now describe the structure and characteristics of a novel form of GlcCerase under investigation for the treatment of Gaucher disease, Gene-ActivatedTM human GlcCerase (velaglucerase alfa). In contrast to imiglucerase and prGCD, velaglucerase alfa contains the native human enzyme sequence. All three GlcCerases consist of three domains, with the active site located in domain III. The distances between the carboxylic oxygens of the catalytic residues, E340 and E235, are consistent with distances proposed for acid–base hydrolysis. Kinetic parameters (Km and Vmax) of velaglucerase alfa and imiglucerase, as well as their specific activities, are similar. However, analysis of glycosylation patterns shows that velaglucerase alfa displays distinctly different structures from imiglucerase and prGCD. The predominant glycan on velaglucerase alfa is a high-mannose type, with nine mannose units, while imiglucerase contains a chitobiose tri-mannosyl core glycan with fucosylation. These differences in glycosylation affect cellular internalization; the rate of velaglucerase alfa internalization into human macrophages is at least 2-fold greater than that of imiglucerase

Comparative Therapeutic Effects of Velaglucerase Alfa and Imiglucerase in a Gaucher Disease Mouse Model

Gaucher disease type 1 is caused by the defective activity of the lysosomal enzyme, acid β-glucosidase (GCase). Regular infusions of purified recombinant GCase are the standard of care for reversing hematologic, hepatic, splenic, and bony manifestations. Here, similar in vitro enzymatic properties, and in vivo pharmacokinetics and pharmacodynamics (PK/PD) and therapeutic efficacy of GCase were found with two human GCases, recombinant GCase (CHO cell, imiglucerase, Imig) and gene-activated GCase (human fibrosarcoma cells, velaglucerase alfa, Vela), in a Gaucher mouse, D409V/null. About 80+% of either enzyme localized to the liver interstitial cells and <5% was recovered in spleens and lungs after bolus i.v. injections. Glucosylceramide (GC) levels and storage cell numbers were reduced in a dose (5, 15 or 60 U/kg/wk) dependent manner in livers (60–95%) and in spleens (∼10–30%). Compared to Vela, Imig (60 U/kg/wk) had lesser effects at reducing hepatic GC (p = 0.0199) by 4 wks; this difference disappeared by 8 wks when nearly WT levels were achieved by Imig. Anti-GCase IgG was detected in GCase treated mice at 60 U/kg/wk, and IgE mediated acute hypersensitivity and death occurred after several injections of 60 U/kg/wk (21% with Vela and 34% with Imig). The responses of GC levels and storage cell numbers in Vela- and Imig-treated Gaucher mice at various doses provide a backdrop for clinical applications and decisions

Three Essays in Regional Growth, Distribution, and Resilience

This work delves into two significant but less understood topics in regional labor economics. The first contribution is to growing literature examining the effects of business dynamism on regional resilience. Significant attention has, understandably, been paid to understanding why the impact of and recovery from the 2008 recession has varied across regions. Chapters 1 and 2 extend to the question of regional resilience a hypothesis that gross rates of local establishment openings, or “churn,” may affect local economic performance over a business cycle. In the US, higher-churn areas are found to experience faster average employment growth over the decade spanning the recession, but with more cyclical volatility. Churn is not positively correlated with median household income growth or poverty reduction at a county level. A novel cross-country analysis reveals that in the UK, local authorities with higher churn prior to the recession did weather the financial crisis slightly better, although data limitations restrict the direct comparability between the US and UK cases. Chapter 3 turns to the growth of self-employment in the US, motivated by two observations: first, that growth in the self-employment share has been regionally heterogeneous; and second, that theory suggests workers in wage-and-salary occupations exert limited agency over their working hours. This paper investigates whether average local working hours influence subsequent changes in the county self-employment share. I find a U-shaped relationship between working hours and self-employment growth: counties with working hours furthest from the mean experienced the fastest growth in local self-employment share, adding a new wrinkle to the running debate over whether the “gig economy” is driven by opportunity or necessity