Acetylation of insulin receptor substrate-1 is permissive for tyrosine phosphorylation

BACKGROUND: Insulin receptor substrate (IRS) proteins are key moderators of insulin action. Their specific regulation determines downstream protein-protein interactions and confers specificity on growth factor signalling. Regulatory mechanisms that have been identified include phosphorylation of IRS proteins on tyrosine and serine residues and ubiquitination of lysine residues. This study investigated other potential molecular mechanisms of IRS-1 regulation. RESULTS: Using the sos recruitment yeast two-hybrid system we found that IRS-1 and histone deacetylase 2 (HDAC2) interact in the cytoplasmic compartment of yeast cells. The interaction mapped to the C-terminus of IRS-1 and was confirmed through co-immunoprecipitation in vitro of recombinant IRS-1 and HDAC2. HDAC2 bound to IRS-1 in mammalian cells treated with phorbol ester or after prolonged treatment with insulin/IGF-1 and also in the livers of ob/ob mice but not PTP1B knockout mice. Thus, the association occurs under conditions of compromised insulin signalling. We found that IRS-1 is an acetylated protein, of which the acetylation is increased by treatment of cells with Trichostatin A (TSA), an inhibitor of HDAC activity. TSA-induced increases in acetylation of IRS-1 were concomitant with increases in tyrosine phosphorylation in response to insulin. These effects were confirmed using RNA interference against HDAC2, indicating that HDAC2 specifically prevents phosphorylation of IRS-1 by the insulin receptor. CONCLUSIONS: Our results show that IRS-1 is an acetylated protein, a post-translational modification that has not been previously described. Acetylation of IRS-1 is permissive for tyrosine phosphorylation and facilitates insulin-stimulated signal transduction. Specific inhibition of HDAC2 may increase insulin sensitivity in otherwise insulin resistant conditions

The Relationship between Work Related Injury and Participation in Exercise and Recreational Activities

Background/Purpose: The cost of health care is on the rise for both employers and employees. Research has shown that exercise in any capacity will improve overall health and fitness levels. Limited research has shown that proper exercise can lead to a decrease in musculoskeletal injuries. With the number of musculoskeletal injuries occurring in the workplace at high levels, establishing a connection between injury reduction and exercise is imperative. The purpose of this study was to determine if there is a relationship between participation in exercise and recreational activities and injury in the workplace. Methods: A random stratified sample of 396 persons was provided by the University of North Dakota payroll department, representing 20% of the university population. Surveys were sent out and 177 surveys were returned, which represented a 45% return rate. The survey included demographic data, work injury information, and exercise history information. Information of the 177 surveys was analyzed using the Statistical Package for the Social Sciences (SPSS) 11.0 program. Results: No significant difference was found between work injury and exercise {)(-1{1, n = 177) = .135, p\u3e .05). A significant relationship was found when comparing injury to cardiovascular RPE {)(-1{8, n = 137) = 16.188, P = .04). Discussion/Conclusion: Given the documented benefits of exercise and its relation to overall wellness, the assumption could be made that exercise and recreational activities would reduce the incidence of work injury. However, the results of this study did not meet that assumption. Future research needs to be done to expand on this area. The information collected from this research may be beneficial to the UNO Well ness Center, UNO Department of Physical Therapy, and the UNO Safety and Environmental Health Office

Galaxy-Galaxy Lensing in the Hubble Deep Field: The Halo Tully-Fisher Relation at Intermediate Redshift

A tangential distortion of background source galaxies around foreground lens galaxies in the Hubble Deep Field is detected at the 99.3% confidence level. An important element of our analysis is the use of photometric redshifts to determine distances of lens and source galaxies and rest-frame B-band luminosities of the lens galaxies. The lens galaxy halos obey a Tully-Fisher relation between halo circular velocity and luminosity; the typical lens galaxy, at a redshift z = 0.6, has a circular velocity of 210 +/-40 km/s at M_B = -18.5, if q_0 = 0.5. Control tests, in which lens and source positions and source ellipticities are randomized, confirm the significance level of the detection quoted above. Furthermore, a marginal signal is also detected from an independent, fainter sample of source galaxies without photometric redshifts. Potential systematic effects, such as contamination by aligned satellite galaxies, the distortion of source shapes by the light of the foreground galaxies, PSF anisotropies, and contributions from mass distributed on the scale of galaxy groups are shown to be negligible. A comparison of our result with the local Tully-Fisher relation indicates that intermediate-redshift galaxies are fainter than local spirals by 1.0 +/- 0.6 B mag at a fixed circular velocity. This is consistent with some spectroscopic studies of the rotation curves of intermediate-redshift galaxies. This result suggests that the strong increase in the global luminosity density with redshift is dominated by evolution in the galaxy number density.Comment: Revised version with minor changes. 13 pages, 7 figures, LaTeX2e, uses emulateapj and multicol styles (included). Accepted by Ap

A Mobile Agent Approach to Lightweight Process Workflow

The Programming Systems Lab at Columbia University has investigated software process modeling and enactment since its inception in the mid-1980s, initially in the Marvel project. In the early to mid-90s, we extended to cross-organizational processes operating over the Internet, in Oz and OzWeb. The successive prototype frameworks we developed and demonstrated were used on a daily basis in-house to maintain, deploy and monitor their own components, APIs and user interfaces. The new process technology first presented here is broadly based on our decade of research on and experimentation with architecting and using such prototype services and software development processes targeted to Internet/Web middleware and applications, but reflects a major departure from our own (and others') previous directions. In particular, current process and workflow systems, including our own, are often too rigid for open-ended creative intellectual work, unable to rapidly adapt either the models or the enactment to situational context and/or user role. On the other hand, the process/workflow ideal implies a flexible mechanism for composition and coordination of information system components. We now present our in-progress development of rehostable lightweight mobile agents for on-the-fly process construction, adaptation and evolution, system reconfiguration, and knowledge propagation

A Case of Statin-Associated Autoimmune Myopathy.

A 70-year-old previously independent man developed progressive proximal leg weakness resulting in a fall at home suffering traumatic brain injury. He was prescribed a statin medication two years prior, but this was discontinued on admission to the hospital due to concern for statin myopathy. His weakness continued to progress while in acute rehabilitation, along with the development of dysphagia requiring placement of gastrostomy tube and respiratory failure requiring tracheostomy. Corticosteroids and intravenous immunoglobulin were administered without response. Nerve conduction study demonstrated no evidence of neuropathy; electromyography revealed spontaneous activity suggestive of myopathy. A muscle biopsy was performed and demonstrated myonecrosis. Serology was positive for autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), verifying our diagnosis of statin-associated autoimmune myopathy (SAM). The patient was subsequently treated with rituximab and methotrexate and demonstrated mild clinical improvement. He was eventually liberated from the ventilator. However, later in the course of treatment, he developed respiratory distress and required ventilator support. The patient was discharged to long-term acute care two months after his initial presentation and died due to ventilator-acquired pneumonia three months later. Since their introduction 30 years ago, statin medications have been widely prescribed to prevent cardiovascular diseases. Myalgias and/or myopathic symptoms are among the most recognized side effects of the medication. Statin-associated autoimmune myopathy is a very rare complication of statin use and estimated to affect two to three for every 100,000 patients treated. Clinically, the condition presents as progressive symmetric weakness, muscle enzyme elevations, necrotizing myopathy on muscle biopsy, and the presence of autoantibodies to HMGCR. These findings will often persist and even progress despite discontinuation of the statin. Very few cases of SAM have been described in the literature. Describing this rare condition and the ultimately fatal outcome of our patient, we aim to further understanding of SAM, its presentation and clinical course to promote earlier diagnosis and prompt management

CASPER: Compiler-Assisted Securing of Programs at Runtime

Ensuring the security and integrity of computer systems deployed on the Internet is growing harder. This is especially true in the case of server systems based on open source projects like Linux, Apache, Sendmail, etc. since it is easier for a hacker to get access to the binary format of deployed applications if the source code to the software is publicly accessible. Often, having a binary copy of an application program is enough to help locate security vulnerabilities in the program. In the case of legacy systems where the source code is not available, advanced reverse-engineering and decompilation techniques can be used to construct attacks. This paper focuses on measures that reduce the effectiveness of hackers at conducting large-scale, distributed attacks. The first line of defense involves additional runtime checks that are able to counteract the majority of hacking attacks. Introducing diversity in deployed systems to severely diminish the probability of propagation to other systems helps to prevent effective attacks like the DDOS attack against the DNS root servers in October 21, 2002

Strategic Operations Research and the Edelman Prize Finalist Applications 1989-1998

In an earlier study we examined the available evidence on the Edelman Prize finalist applications 1989-1998. This study concluded that 13 of the 42 private sector applications provide examples of strategic operations research (SOR) when SOR is defined as operations research that creates a sustainable competitive advantage. In a follow-up study we tested our classifications, gathering longitudinal information on the continued success of the Edelman applications. We contacted people who were familiar with all the private sector applications that were Edelman finalists 1989-1996 and had at least five years of history since the competition. We describe the post-Edelman history of these applications and use this data to reassess their strategic role. We found that the longitudinal data provides evidence to support our original classification, but also suggests that several additional applications were more strategic than was originally apparent. We conclude that almost 60% (20 of 34) of these applications created a sustainable competitive advantage for their firms and provide examples of SOR

The Information Technology Workforce: A Comparision Of Critical Skills Of Clients And Service Providers

In this article the authors explore similarities and differences in skill needs of IT service providers and the firms that providers service (clients). The results show that providers and clients are more similar than different with regard to desired skills. Client firms emphasize technical skills for new hires more than providers do despite saying that these are the skills they would outsource to providers. The results have implications for organizations’ recruiting and retention, for individuals’ career development, and for educational programs