Ryan Williams

The Absence of Mitochondrial Thioredoxin 2 Causes Massive Apoptosis, Exencephaly, and Early Embryonic Lethality in Homozygous Mice

ABSTRACT Thioredoxin 2 (Trx-2) is a small redox protein containing the thioredoxin active site Trp-Cys-Gly-Pro-Cys that is localized to the mitochondria by a mitochondrial leader sequence and encoded by a nuclear gene (Trx-2). Trx-2 plays an important role in cell viability and the regulation of apoptosis in vitro. To investigate the role of Trx-2 in mouse development, we studied the phenotype of mice that have the Trx-2 gene silenced by mutational insertion. Homozygous mutant embryos do not survive to birth and die after implantation at Theiler stage 15/16. The homozygous mutant embryos display an open anterior neural tube and show massively increased apoptosis at 10.5 days postcoitus and are not present by 12.5 days postcoitus. The timing of the embryonic lethality coincides with the maturation of the mitochondria, since they begin oxidative phosphorylation during this stage of embryogenesis. In addition, embryonic fibroblasts cultured from homozygous Trx-2-null embryos were not viable. Heterozygous mice are fertile and have no discernible phenotype visible by external observation, despite having decreased Trx-2 mRNA and protein. These results show that the mitochondrial redox protein Trx-2 is required for normal development of the mouse embryo and for actively respiring cells.

Stability of Phosphoprotein as a Biological Marker of Tumor Signaling

Purpose: The purpose of the study was to evaluate the stability of phosphoprotein as a marker of signaling activity in human tumors using clinical samples and xenografts. Experimental Design: The expression of phospho-Ser473-Akt (p-Akt) was assessed by immunohistochemistry in paraffin-embedded samples from patients enrolled in a Southwest Oncology Group clinical trial of gastroesophageal junction tumors and by immunohistochemistry and Western blotting in human colon tumor xenografts at various times after removal from the animal. Results: Clinical samples had evaluable p-Akt staining only when obtained as biopsies (9 of 13) and no staining was observed in tumors obtained as surgically resected samples (0 of 15). In HT-29 colon cancer xenografts, p-Akt staining was present in fresh sample but not in tissue that had been allowed to stand for 30 minutes at room temperature. Western blotting of HT-29 tumor xenografts at room temperature showed a slow decrease in total Akt with a half-life of 180 minutes and a rapid decrease in p-Akt with a half-life of 20 minutes. Conclusions: Caution should be used when using phosphoprotein levels in human tumor specimens to measure intrinsic signaling activity or drug effects because of the potential for rapid dephosphorylation. Rapid processing of biopsies is essential and postoperative surgical samples may be of limited value because of the time to fixation.

In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316.

Akt, a serine/threonine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (PtdIns)-3-phosphates formed by PtdIns-3-kinase. D-3-Deoxy-phosphatidyl-myo-inositols that cannot be phosphorylated on the 3-position of the myo-inositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositol 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (PX-316). PX-316 administered intraperitoneally to mice at 150 mg/kg inhibits Akt activation in HT-29 human tumor xenografts up to 78% at 10 h with recovery to 34% at 48 h. Phosphorylation of GSK-3beta, a downstream target of Akt, is also inhibited. There is no decrease in PtdIns(3,4,5)-trisphosphate levels by PX-316, showing it is not an inhibitor of PtdIns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the PtdIns-3-K inhibitor wortmannin, with downregulation of several ribosomal-related genes, while PX-316 uniquely increases the expression of a group of mitochondrial-related genes. PX-316 has antitumor activity against early human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice. PX-316 formulated in 20% hydroxypropyl-beta-cyclodextrin for intravenous administration is well tolerated in mice and rats with no hemolysis and no hematological toxicity. Thus, PX-316 is the lead compound of a new class of potential agents that inhibit Akt survival signaling.

Customer-Supplier Relationships and Liquidity Management: The Joint Effects of Trade Credit and Bank Lines of Credit

We examine the determinants of trade credit for a sample of U.S. public firms while controlling for supply-side and demand-side factors. Our dataset contains characteristics of suppliers and their key customers matched with data on their access to short-term financing through lines of credit. We find that suppliers that have access to a bank line of credit and a lower probability of financial distress have higher amounts of outstanding trade credit to their customers. Further, we find that supplier firms have higher amounts of outstanding trade credit when their customers lack access to a bank line of credit, have a higher probability of bankruptcy, and are more financially constrained. We also show that liquidity shocks to supplier firms influence the amount of trade credit outstanding.

The Effect of CEO’s Risk-Taking Incentives on Relationship-Specific Investments by Customers and Suppliers

A firm’s customers and suppliers make relationship-specific investments (RSI) whose value reduces if the firm undertakes risky investments. We hypothesize that the risk-taking incentives in the firm CEO’s compensation will lower the RSI by firms up and down in the vertical channel. We provide significant evidence that customer/supplier RSI declines with the risk-taking incentives of the firm’s CEO. Moreover, we find that RSI is more sensitive to the CEO’s risk-taking incentives when they are more likely to increase the firm’s cash flow volatility. Our findings are robust to correcting for endogeneity and several measures for RSI and risk taking.

Fortune Favors the Bold

Center for the Economic Analysis of Risk (CEAR) at Georgia State University; Stephen Smith Fellowship

Identifying vulnerabilities of consumer Internet of Things (IoT) devices: A scalable approach

The Internet of Things becomes more defined year after year. Companies are looking for novel ways to implement various smart capabilities into their products that increase interaction between users and other network devices. While many smart devices offer greater convenience and value, they also present new security vulnerabilities that can have a detrimental effect on consumer privacy. Given the societal impact of IoT device vulnerabilities, this study aims to perform a large-scale vulnerability assessment of consumer IoT devices exposed on the Internet. Specifically, Shodan is used to collect a large testbed of consumer IoT devices which are then passed through Nessus to determine whether potential vulnerabilities exist. Results of this study indicate that a significant number of consumer IoT devices are vulnerable to exploits that can compromise user information and privacy.

Assessing medical device vulnerabilities on the Internet of Things

Internet enabled medical devices offer patients with a level of convenience. In recent years, the healthcare industry has seen a surge in the number of cyber-attacks. Given the potentially fatal impact of a compromised medical device, this study aims to identify vulnerabilities of medical devices. Our approach uses Shodan to obtain a large collection of IP addresses that will be passed through Nessus to verify if any vulnerabilities exist. We determined some devices manufactured by primary vendors such as Omron Corporation, FORA, Roche, and Bionet contain serious vulnerabilities such as Dropbear SSH Server and MS17-010. These allow remote execution of code and authentication bypassing potentially giving attackers control of their systems.

Collusion and Efficiency in Horizontal Mergers: Evidence from Geographic Overlap

We explore the sources of gains in horizontal mergers by exploiting heterogeneity between the merging firms’ geographic footprints. We calculate the geographic overlap between the bidder, target, and their rivals and customers to identify variation in the competitive impact of horizontal mergers. We document significantly positive rival reactions and negative customer reactions when the bidder and target operate in similar geographic regions, consistent with anticompetitive effects in these deals. We also exploit staggered changes in the political affiliation of state Attorneys General (AGs) to identify variation in local antitrust enforcement. We show that bidders avoid concentrating mergers when they operate in a high proportion of states with Democratic AGs, and Democratic AGs moderate the effects of concentrating mergers on local rivals and customers. Our evidence supports the argument that geographically-concentrating horizontal mergers are more likely to be anticompetitive. We also document a significant role of state-level AGs in the M&A regulatory process.

Do Compensation Consultants Have Distinct Styles

Using hand-collected compensation consultant data, we investigate whether compensation consultants exhibit distinct styles in the determination of CEO pay level and compensation structure. Our tests, which include the use of placebo samples that involve the scrambling of consultants as benchmarks, yield little evidence of idiosyncratic compensation consultant style. However, we do observe style-like effects and some resultant perverse outcomes either when (i) there is greater potential for client firms’ managers to take actions in their self-interest or (ii) consultants face conflicts of interest. Overall, we find evidence consistent with both the “efficient” and “agency” views of CEO compensation contracts.