Catch Me If You Can: Big Food Using Big Tobacco’s Playbook? Applying the Lessons Learned from Big Tobacco to Attack the Obesity Epidemic

This paper applies the lessons learned from the regulation of the tobacco industry to counter the obesity epidemic. The similarities between the tobacco industry and food industry are more than meets the eye. Both industries are dominated by a few major companies. Big Food and Big Tobacco both rely on marketing to lure children into buying their products, creating life-long customers. And, both industries focus on creating habits and addictions to keep children and adults to keep coming back for more. For decades, beginning in the mid-twentieth century, Big Tobacco has been the bulls-eye target for federal and state regulators as well as plaintiffs’ lawyers. And for decades, the tobacco industry managed to dodge the onslaught. Big Tobacco poured massive lobbying dollars into Congressional coffers, denied the science underlying the deadly and addictive effects of nicotine, and acted “socially responsible.” It then put a mask on, acquiring the major food companies and sometimes changing its brand name to burnish its public image in the American eye. By acquiring the food companies, Big Tobacco found the right partner in luring kids early through advertising. Now, the very food companies that Big Tobacco saw as relatively socially responsible are coming under attack for promoting the obesity crisis. And some of these food companies are using tactics from Big Tobacco’s playbook to evade the regulators and deny claims in court. Our nation waited for too long before it made inroads into regulating the nicotine that contributed to an epidemic of lung cancer, emphysema, and atherosclerosis. We cannot afford to wait again. We have to take active measures in adopting both a collaborative and regulatory approach to the food industry before the obesity epidemic becomes a crisis crippling our health care system, our workforce, and our children. This paper offers some proposals for regulating the food industry by exploring lessons from tobacco regulation

Reviewing the Government's Numbers on Regulation

This paper has two objectives: first, to provide more information on the data used to construct a controversial economic analysis published by the Joint Center that makes use of over 100 government regulatory impact analyses; and second, to provide further sensitivity analysis of key variables in that study. A key finding of this paper is that the results of the earlier analysis of government regulatory impact analyses appear to be fairly robust within the data set that was constructed. We offer the following conclusions. First, aggregate net benefits for final regulations are positive under a wide variety of assumptions. Second, a substantial number of final regulations do not pass a benefit-cost test under a wide variety of assumptions. By rejecting at least some of these regulations, government could have increased aggregate net social benefits. Third, aggregate net benefits exhibit a wide range across regulations. And fourth, agencies should improve the quality of their regulatory impact analyses. Also of interest from the Joint Center: The Economic Analysis of Regulation: A Response to the Critics Robert W. Hahn

Is Regulation Good For You?

Will all federal regulations soon pass a benefit-cost test? If the OMB's 2003 report is any indicator, the answer may be yes, at least for some categories of regulations. Applying the midpoint of OMB's estimates for quantified costs and benefits of agency rules, we find that 100 percent of regulations studied would pass a benefit-cost test for several agencies, and about 80 percent would pass for all agencies considered. Moreover, these regulations would confer at least $100 billion annually in net benefits, again using OMB's numbers. Sound too good to be true? That's probably because it is. We argue that OMB's numbers are plausible, given the methodology that OMB uses. Whether they are reasonable is less clear. Some work by economists on related sets of regulations suggests that the percentage could be lower. A survey of experts in the field also casts doubt on the estimates of the number of regulations that would pass a benefit-cost test derived from OMB's report. The experts also suggest, in line with academic research, that there is considerable room for improvement in regulations that pass a benefit-cost test. We conclude withseveral suggestions for improving the regulatory process.

Molecular Mechanisms Regulating Chemokine Receptor CXCR4 Signaling and Trafficking

CXCR4 is a G protein-coupled receptor (GPCR) that binds to the chemokine, stromal cell-derived factor-1 (SDF-1alpha; a.k.a. CXCL12). The SDF-1alpha/CXCR4 signaling axis plays an essential role during embryogenesis in the development of the heart, brain and vasculature and in the adult mediating immune cell trafficking and stem cell homing to the bone marrow. Dysregulation of SDF-1alpha/CXCR4 signaling is linked to several pathological conditions, including cardiovascular disease, immunological disorders as well as cancer growth and metastasis. However, the mechanisms that govern CXCR4 signaling remain poorly understood. In this dissertation project, we attempt to further our understanding of the molecular mechanisms that regulate CXCR4 signaling. CXCR4 signaling is tightly controlled by a complex series of events that rapidly terminates its signaling. Activated CXCR4 is rapidly phosphorylated and ubiquitinated by the E3 ubiquitin ligase AIP4 at the plasma membrane. Ubiquitinated CXCR4 is rapidly internalized onto early endosomes and targeted for lysosomal degradation, giving rise to long-term attenuation of signaling. The ubiquitin moiety on CXCR4 serves as a sorting signal for entry into the endosomal sorting complex required for transport (ESCRT) pathway. This pathway consists of four different protein complexes (ESCRT-0, I, II and III), plus several accessory factors, that act in a sequential and coordinated manner to target proteins for lysosomal degradation. Although CXCR4 is targeted into the ESCRT pathway, mechanistic insight by which this occurs remains poorly defined. In previous work from our laboratory, it was shown that adaptor protein arrestin-2 interacts with AIP4 to regulate endosomal sorting of CXCR4 into the degradative pathway. However, the precise mechanism by which arrestin-2 performs this function remains unknown. We set out to determine how arrestin-2 integrates with the sorting machinery on endosomes to control the amount of CXCR4 that is degraded. We show that arrestin-2 interacts with ESCRT-0 protein STAM-1. ESCRT-0 consists of two proteins: signal-transducing adaptor molecule (STAM) and hepatocyte growth factor-regulated tyrosine kinase substrate (HRS). It is the first complex that recognizes ubiquitinated CXCR4 and targets it for lysosomal degradation. We show that depletion of STAM-1 by siRNA and selective disruption of the STAM-1/arrestin-2 interaction accelerates agonist promoted degradation of CXCR4, suggesting that STAM-1 via its interaction with arrestin-2 negatively regulates CXCR4 endosomal sorting. Interestingly, disruption of this interaction also blocks agonist promoted ubiquitination of HRS, the other ESCRT-0 protein, but not ubiquitination of CXCR4 and STAM-1, suggesting that arrestin-2 via its interaction with STAM-1 mediates ubiquitination of HRS. We propose a model, whereby arrestin-2 initially recruits CXCR4 to the ESCRT machinery and subsequently interacts with ESCRT-0 to regulate its sorting function, thereby ultimately controlling the amount of CXCR4 that is degraded. Here, we also report novel roles for AIP4 and STAM-1 in CXCR4 signaling, which are different from their roles in CXCR4 trafficking. Treatment of cells with siRNA against AIP4 and STAM-1 attenuates CXCR4-induced activation of extracellular regulated kinase 1 and 2 (ERK-1/2). We show that STAM-1 via its SH3 domain interacts with the proline-rich region (PRR) in AIP4. AIP4 mediates STAM-1 ubiquitination and expression of AIP4-C830A, a catalytically inactive mutant that fails to ubiquitinate STAM-1, and an AIP4 mutant (AIP4-delta PRR) that shows poor binding to STAM-1 fail to enhance CXCR4-induced ERK-1/2 activation, suggesting that interaction with STAM-1 as well as ubiquitination activity of AIP4 are important for CXCR4-induced ERK-1/2 activation. Remarkably, a discrete subpopulation of AIP4 and STAM-1 co-localize with CXCR4 at the plasma membrane and with caveolin-1, a protein that is enriched in caveolae (a specialized lipid raft). Disrupting caveolae using caveolin-1 siRNA or nystatin, a cholesterol-depleting agent, significantly attenuated CXCR4-induced ERK-1/2 activation. Based upon our data, we propose that AIP4-mediated ubiquitination of STAM-1 in caveolae coordinates CXCR4 activation of ERK-1/2 signaling. Taken together, our study has provided novel insight into the regulation of CXCR4 both at the levels of signaling as well as trafficking. We provide novel mechanistic insight into the role of arrestin-2 in targeting CXCR4 into the degradative pathway and we have also identified a novel function for AIP4 and STAM-1 in CXCR4 signaling

Experimental investigation of high-power continuous-wave fiber optical parametric amplifiers and oscillators.

Fiber optical parametric amplifiers (OPAs) are based on a highly-efficient four-wave mixing process. Their capability to give very high gain and large bandwidths have made them an attractive candidate for providing higher bandwidths for future telecommunication systems, such as wavelength-division multiplexed (WDM) photonics networks. In dynamic photonic networks a where number of channels are dropped and/or added all the time, the OPA gain for the other channels is affected. In this thesis we employed a well-known gain control technique, all-optical gain clamping (AOGC), and reduced the gain variation of fiber OPAs below 0.5 dB, under varying input conditions. We also showed an improvement in power penalties o at the bit-error rate of 10-8, from 2.5 dB to 0.5 dB for on/off keying modulation. We also investigated fiber optical parametric oscillators (OPOs). Using fiber OPAs as gain medium we realized two different continuous-wave (CW) OPOs, centred at 1561 nm and 1593 nm. One gave us watt-level output power from 1600 nm to 1670 nm, with overall tuning range of 211 nm. The output linewidth of signal and idler was measured to be 0.08 nm and 0.15 nm respectively. The OPO centred at 1593 nm gave us a record tuning range of 254 nm, and with 3 dB output coupling fraction, it gave us large output powers (20-27 dBm) from 1610 nm to 1720 nm. Using a large seed generated by a watt-level fiber OPO in the U-band, and using 3 W of CW pump source in the C-band for Raman amplification, we generated 3 W of CW output power. This gave us nearly 100% conversion efficiency. Launching a high-power CW pump with narrow linewidth into a fiber makes stimulated Brillouin scattering (SBS) a major problem. We investigated an SBS suppressor, based on a common technique of phase dithering of the pump to suppress the SBS. We compared a multitone modulation technique to modulation with a pseudo-random bit sequence (PRBS), and we showed that it can increase the SBS threshold by 4.18 dB, and is less expensive to implement

Optical signal to noise ratio improvement through unbalanced noise beating in phase-sensitive parametric amplifiers

We investigate the beating of signal and idler waves, which have imbalanced signal to noise ratios, in a phase-sensitive parametric amplifier. Imbalanced signal to noise ratios are achieved in two ways; first by imbalanced noise loading; second by varying idler to signal input power ratio. In the case of imbalanced noise loading the phase-sensitive amplifier improved the signal to noise ratio from 3 to 6 dB, and in the case of varying idler to signal input power ratio, the signal to noise ratio improved from 3 to in excess of 20 dB

An Analysis of the Eighth Government Report On the Costs and Benefits of Federal Regulations

This paper critically reviews the draft of the Office of Management and Budget's eighth report on the benefits and costs of federal regulation. The draft report offers two modest improvements over previous reports. First, it discusses the importance of information quality in regulatory analyses and the agencies' implementation of the Information Quality Act. Second, it compares ex ante benefit-cost estimates with ex post benefit-cost estimates in some detail. While there has been progress, there is room for significant improvement. We offer seven recommendations, six for OMB and one for Congress, that would help hold lawmakers and regulators more accountable for the regulations they produce. Our recommendations focus on getting the regulatory agencies to produce better analysis, making that analysis more transparent and readily available, and making the regulatory process itself more transparent. We recommend that OMB: examine the extent to which regulations maximize net benefits; include a scorecard showing the number and percentage of final regulations that pass a benefit-cost test based on factors that can be quantified and monetized; request that all agencies report on the extent to which they comply with OMB's guidelines for conducting regulatory analysis; provide guidelines for assessing the effectiveness of antiterrorism regulations; include a discussion of the costs and benefits of antitrust activities in its annual report; and facilitate the use of information markets to increase overall economic efficiency and to inform regulatory decision making. We also recommend that Congress require all agencies to comply with OMB's guidelines for conducting regulatory analysis.

Development and Validation of UPLC-MS/MS Method for Rapid Simultaneous Determination of Levothyroxine and Liothyronine in Human Serum

A simple ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method was developed and fully validated to simultaneously determine levothyroxine (LT4) and liothyronine (LT3) in human serum. Sample preparation was done through protein precipitation with acetonitrile. HyPURITY C18 column was selected to achieve rapid separation for LT4 and LT3 within 4 min. Electrospray ionization (ESI) under multiple reaction monitoring (MRM) was used to monitor the ion transitions for LT4 (m/z 777.54→731.52), LT3 (m/z 651.64→ 605.65) and internal standard LT4-D3 (m/z 780.53 →734.19), operating in the positive ion mode. The method was proved to be accurate (82.35% to 113.56%) and precise (0.73% to 8.28%) over concentration range of 50.37 ng/ml – 300.13 ng/ml for LT4 and 0.5 ng/ml – 50.37 ng/ml for LT3. The validated method could be applied for pharmacokinetic study or bioequivalence testing of combination products of LT4 and LT3. Keywords: Levothyroxine; Liothyronine; Ultra Performance Liquid Chromatographic; Mass Spectrometry; Human Seru

Frequency-resolved noise figure measurements of phase (in)sensitive fiber optical parametric amplifiers

We measure the frequency-resolved noise figure of fiber optical parametric amplifiers both in phase-insensitive and phase-sensitive modes in the frequency range from 0.03 to 3 GHz. We also measure the variation in noise figure due to the degradation in pump optical signal to noise ratio and also as a function of the input signal powers. Noise figure degradation due to stimulated Brillouin scattering is observed