Doctor of Philosophy

dissertationThis dissertation is to characterize two evolutionarily conserved but uncharacterized mitochondrial proteins using yeast and mammalian cells. The first protein, which we named respiratory supercomplex factor 1 (Rcf1), is required for the assembly of respiratory supercomplexes. Deletion of the RCF1 gene causes destabilization of respiratory supercomplexes, impaires respiration and elevates mitochondrial oxidative stress. We also show that HIG2A, a mammalian homolog of RCF1, performs the same function in mammalian cells. Therefore, we suggest that Rcf1 and HIG2A are members of a conserved protein family that acts to maintain the homeostasis of mitochondrial metabolism by promoting respiratory supercomplex assembly. The second protein on which my dissertation research was based, originally annotated as mitochondrial sorting of protein 1 (Msp1), performs multiple tasks. The first function is its role in facilitating the removal of tail-anchored (TA) proteins that are mislocalized to mitochondria. Disruption of the guided entry of tail-anchored protein (GET) system was shown to cause a subset of TA proteins to mislocalize to mitochondria. The AAA+ ATPase Msp1 can limit the accumulation of mislocalized TA proteins on mitochondria. The human homolog of Msp1, ATAD1, also limits the mitochondrial mislocalization of TA proteins in mammalian cells. Therefore, Msp1 and ATAD1 are conserved members of a mitochondrial protein quality control system that iv functions to promote the extraction and degradation of mislocalized TA proteins to maintain mitochondrial integrity. The second role of Msp1 and ATAD1 is in a novel vesicular trafficking system from mitochondria to peroxisomes in an ATPase activitydependent manner. Impaired peroxisome biogenesis and mislocalization of peroxins (peroxisomal biogenesis factors) to the mitochondria has been observed in cells from Zellweger patients. Overexpression of ATAD1 facilitates the removal of these peroxins from mitochondria and the accumulation in vesicle-like structures of unknown character and function. We speculate that these vesicles might sort the peroxins to peroxisomes for peroxisomal biogenesis. Therefore, we propose that Msp1 and ATAD1 participate in a novel vesicular trafficking pathway, which is likely associated with protein sorting from mitochondria to peroxisomes. In conclusion, our findings provide a better understanding of mitochondrial biology, which further sheds light on the etiology of human mitochondrial diseases

The Effects of Firm-Initiated Clawback Provisions on Earnings Quality and Auditor Behavior

While firm-initiated compensation recovery (or clawback) provisions are gaining popularity and the recently enacted Dodd-Frank Act seeks to make the clawback of erroneously awarded compensation mandatory for all listed companies, little is known about their effectiveness. We find that the incidence of accounting restatements declines after firms initiate such provisions. In addition, we show that investors and auditors view such provisions as associated with increased accounting quality and lower audit risk. Specifically, we find that firms' earnings response coefficients increase after the adoption of clawback provisions. Further, for firms that adopt clawbacks, auditors are less likely to report material internal control weaknesses, charge lower audit fees, and issue audit reports with a shorter lag

Optimal Allocation of Water and Sanitation Facilities To Prevent Communicable Diarrheal Diseases in Senegal Under Partial Interference

For several decades, Senegal has faced inadequate water, sanitation, and hygiene (WASH) facilities in households, contributing to persistent, high levels of communicable diarrheal diseases. Unfortunately, the ideal WASH policy where every household in Senegal installs WASH facilities is impossible due to logistical and budgetary concerns. This work proposes to estimate an optimal allocation rule of WASH facilities in Senegal by combining recent advances in personalized medicine and partial interference in causal inference. Our allocation rule helps public health officials in Senegal decide what fraction of total households in a region should get WASH facilities based on block-level and household-level characteristics. We characterize the excess risk of the allocation rule and show that our rule outperforms other allocation policies in Senegal

Late Cenozoic metamorphic evolution and exhumation of Taiwan

The Taiwan mountain belt is composed of a Cenozoic slate belt (Hsuehshan Range units, HR, and Backbone Slates, BS) and of accreted polymetamorphic basement rocks (Tananao Complex, TC). Ongoing crustal shortening has resulted from the collision between the Chinese continental margin and the Luzon volcanic arc, which initiated ~6.5 Ma ago. The grade and age of metamorphism and exhumation are a key record of the development of the orogenic wedge. Because the Taiwan mountain belt is mostly composed by accreted sediments lacking metamorphic index minerals, quantitative constraints on metamorphism are sparse. By contrast, these rocks are rich in carbonaceaous material (CM) and are therefore particularly appropriate for RSCM (Raman Spectroscopy of CM) thermometry. We apply this technique in addition to (U-Th)/He thermochronology on detrital zircons to assess peak metamorphic temperatures (T) and the late exhumational history respectively, along different transects in central and southern Taiwan. In the case of the HR units, we find evidence for high metamorphic T of at least 340°–350°C and locally up to 475°C, and for relative rapid exhumation with zircon (U-Th)/He ages in the range of 1.5–2 Ma. Farther east, the BS were only slightly metamorphosed (T < 330 °C), and zircons are not reset for (U-Th)/He. From the eastern BS to the inner TC schists, T gradually increases from ~350°C up to ~500°C following an inverted metamorphic gradient. Available geochronological constraints and the continuous thermal gradient from the BS to the basement rocks of the TC suggest that the high RSCM T of the TC were most probably acquired during the last orogeny, and were not inherited from a previous thermal event. Zircons yield (U-Th)/He ages of ~0.5–1.2 Ma. Peak metamorphic T and the timing of exhumation do not show along-strike variations over the TC in the studied area. In contrast, exhumation is laterally diachronous and decreases southward in the case of the HR units. In particular, our data imply that the HR units have been exhumed by a minimum of 15 km over the last few Ma. In the case of the BS, they show far less cumulated exhumation and much slower cooling rates. We propose that most of the deformation and exhumation of the Taiwan mountain belt is sustained through two underplating windows located beneath the Hsuehshan Range and the TC. Our data show significant departures from the predictions of the prevailing model in Taiwan, which assumes a homogeneous critical wedge with dominant frontal accretion. Our study sheds new light on how the mountain belt has grown as a possible result of underplating mostly

Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate.

Type IIA topoisomerases (Top2s) manipulate the handedness of DNA crossovers by introducing a transient and protein-linked double-strand break in one DNA duplex, termed the DNA-gate, whose opening allows another DNA segment to be transported through to change the DNA topology. Despite the central importance of this gate-opening event to Top2 function, the DNA-gate in all reported structures of Top2-DNA complexes is in the closed state. Here we present the crystal structure of a human Top2 DNA-gate in an open conformation, which not only reveals structural characteristics of its DNA-conducting path, but also uncovers unexpected yet functionally significant conformational changes associated with gate-opening. This structure further implicates Top2's preference for a left-handed DNA braid and allows the construction of a model representing the initial entry of another DNA duplex into the DNA-gate. Steered molecular dynamics calculations suggests the Top2-catalyzed DNA passage may be achieved by a rocker-switch-type movement of the DNA-gate

Acupuncture for the Treatment of Opiate Addiction

Acupuncture is an accepted treatment worldwide for various clinical conditions, and the effects of acupuncture on opiate addiction have been investigated in many clinical trials. The present review systematically analyzed data from randomized clinical trials published in Chinese and English since 1970. We found that the majority agreed on the efficacy of acupuncture as a strategy for the treatment of opiate addiction. However, some of the methods in several included trials have been criticized for their poor quality. This review summarizes the quality of the study design, the types of acupuncture applied, the commonly selected acupoints or sites of the body, the effectiveness of the treatment, and the possible mechanism underlying the effectiveness of acupuncture in these trials