Preferential exclusion of sucrose from recombinant interleukin-1 receptor antagonist: role in restricted conformational mobility and compaction of native state

Understanding the mechanism for sucrose-induced protein stabilization is important in many diverse fields, ranging from biochemistry and environmental physiology to pharmaceutical science. Timasheff and Lee [Lee, J. C. & Timasheff, S. N. (1981) J. Biol. Chem. 256, 7193-7201] have established that thermodynamic stabilization of proteins by sucrose is due to preferential exclusion of the sugar from the protein's surface, which increases protein chemical potential. The current study measures the preferential exclusion of 1 M sucrose from a protein drug, recombinant interleukin 1 receptor antagonist (rhIL-1ra). It is proposed that the degree of preferential exclusion and increase in chemical potential are directly proportional to the protein surface area and that, hence, the system will favor the protein state with the smallest surface area. This mechanism explains the observed sucrose-induced restriction of rhIL-1ra conformational fluctuations, which were studied by hydrogen-deuterium exchange and cysteine reactivity measurements. Furthermore, infrared spectroscopy of rhlL-1ra suggested that a more ordered native conformation is induced by sucrose. Electron paramagnetic resonance spectroscopy demonstrated that in the presence of sucrose, spin-labeled cysteine 116 becomes more buried in the protein's interior and that the hydrodynamic diameter of the protein is reduced. The preferential exclusion of sucrose from the protein and the resulting shift in the equilibrium between protein states toward the most compact conformation account for sucrose-induced effects on rhIL-1ra.     

Antibody-IL-2 fusion proteins: a novel strategy for immune protection

Advances in genetic engineering and expression systems have led to a rapid progress in the development of immunoglobulins fused to other proteins. These 'antibody fusion proteins' have novel properties and include antibodies fused to the cytokine interleukin-2. In the present review we describe strategies for construction of these antibody-interleukin-2 fusion proteins and discuss their in vitro and in vivo properties. Antibody-interleukin-2 fusion proteins retain both antibody associated functions such as antigen binding, complement activation and Fc gamma receptor binding as well as interleukin-2 associated functions such as the stimulation of proliferation of CTLL2 cells. In vivo, they produce strong potentiation of the host immune response against any associated antigen. In addition, these novel molecules are able to target tumor cells and produce a specific and effective T cell response capable of eliminating the tumor. These properties suggest that antibody-interleukin-2 fusion proteins will be useful in the diagnosis and/or treatment of human cancer as well as in the potentiation of human response against any associated antigen.     

Morphological and functional polymorphism within clonal thyroid nodules

Thirty-nine thyroid nodules, removed because of recent growth, were analyzed morphologically by serial histological sections for the classical histomorphological hallmarks of follicular cell replication and for immunohistochemically demonstrable overexpression of the growth-associated ras-gene product p21ras. Clonal analysis was performed using the highly informative probe M27 beta that detects polymorphisms on the locus DXS255 of the X-chromosome. Twenty-four nodules were of clonal and 15 nodules were of poly-clonal origin. Only 3 out of the 24 clonal nodules were histomorphologically uniform. In all others, the structural hallmarks of active growth and the P21ras growth-marker expression were remarkably heterogeneous throughout the tumors. There were no histomorphological characteristics distinguishing these clonal tumors from polyclonal nodules. Even if a clonal thyroid tumor may be originally homogeneous in respect to the parameters studied here, mechanisms must exist that create wide heterogeneity of growth and of morphogenetic potential among the individual follicular cells during further expansion of the nodule. Thus, clonal nodules are much more common in nodular goiters than hitherto assumed on grounds of the classical morphological criteria. The diagnosis of a true monoclonal nodule can no longer rely on morphological and functional criteria alone but requires molecular or cytogenetic analysis of clonality.     

Right atrial contractile performance in patients with myocardial infarction

To evaluate right atrial (RA) contractile performance in patients with myocardial infarction, we validated a cineangiographic method of RA volume measurement, and investigated RA volume change in 'normal' individuals and patients with a previous myocardial infarction. Sixteen silicone rubber RA casts made from human cadavers were filmed in the postero-anterior and left lateral projections. The cast volumes calculated following Simpson's rule were in good agreement with those measured by water replacement (r = 0.992, P < 0.01). At cardiac catheterization, biplane RA cineangiography was performed in 19 'normal' individuals (N group), in 14 patients with a previous antero-septal infarction (AMI group) and in seven patients with a previous inferior infarction (IMI group). The RA volume-time curve was constructed at 20-40 ms intervals for one cardiac cycle. RA volume at the beginning of the atrial contraction (RAVd), which was defined as the 'preload' of the RA, tended to be larger in both the AMI and IMI groups compared with 'normal' individuals. The RA ejection volume was significantly larger in both the AMI (18.4 +/- 2.1 ml.m-2, P < 0.01) and IMI groups (19.4 +/- 2.8, P < 0.01) than in the N group (14.5 +/- 1.9), even for a comparable level of RAVd (range from 26 to 36 ml.m-2) (18.6 +/- 2.1, P < 0.01, 18.2 +/- 2.0, P < 0.01, 14.7 +/- 1.9, respectively). These results suggest that RA contraction increases in patients with myocardial infarction by increasing both the 'preload' and 'contractility' of the RA.     

Cyclosporine in glomerular disease

Cyclosporine was introduced in 1981 as an immunosuppressive agent in renal transplantation. Its use was soon extended to the treatment of various glomerular disorders. In light of its known immunomodulating effects, the use of cyclosporine has been most prominent in those glomerular diseases thought to have an immune basis. The most careful studies of cyclosporine in glomerular diseases have been performed in the pediatric population with idiopathic nephrotic syndrome (i.e., minimal change disease and focal segmental glomerulosclerosis), although data are accumulating regarding efficacy and safety in adults with idiopathic nephrotic syndrome. In patients who are steroid-dependent, cyclosporine therapy can induce complete or partial remission in a significant proportion of cases; success rates in patients with steroid-resistant nephrotic syndrome are less encouraging. Treatment with cyclosporine allows for dose reduction or elimination of corticosteroids, and the consequent salutary effect on growth in the child and glucose and bone metabolism in all patients. Studies that suggest a potential benefit of cyclosporine in recurrent nephrotic syndrome in renal allografts and in other glomerular diseases are also discussed.     

Fuzzy rule-based signal processing and its application to imagerestoration

A novel signal processing technique based on fuzzy rules is proposed for estimating nonstationary signals, such as image signals, contaminated with additive random noises. In this filter, fuzzy rules concerning the relationship between signal characteristics and filter design are utilized to set the filter parameters, taking the local characteristics of the signal into consideration. The fuzzy rules are found to be quite effective, since the rules to set the filter parameters are usually expressed in an ambiguous style. The high performance of this filter is demonstrated in noise reduction of a 1-D test signal and a natural image with various training signals     

Virtual Fiber Configuration for Dynamic Lightpath Establishment in Large-scaled Optical Networks

Recently, progress has been made in the Generalized Multi-Protocol Label Switching (GMPLS) and Automatic Switched Optical Networks (ASON) standardizations. These technologies realize construction of large-scaled optical networks, interconnections among single-domain Wavelength Division Multiplexing (WDM) networks, and direct communication over multi-domain WDM networks. Meanwhile, it is known that the topology of the Internet exhibits the power-law attribute. Since the topology of the Internet, which is constructed by interconnecting ASs, exhibits the power-law, there is a possibility that large-scale WDM networks, which are constructed by interconnecting WDM networks, will also exhibit the power-law attribute. One of the structural properties of a topology that adheres to the power-law is that most nodes have just a few links, although some have a tremendous number of them. Another property is that the average distance between nodes is smaller than in a mesh-like network. A natural question is how such a structural property performs in WDM networks. In this paper, we first investigate the property of the power-law attribute of physical topologies for WDM networks. We compare the performance of WDM networks with mesh-like and power-law topologies, and show that links connected to high-degree nodes are bottlenecks in power-law topologies. To relax this, we introduce a concept of virtual fiber, which consists of two or more fibers, and propose its configuration method to utilize wavelength resources more effectively. We compare performances of power-law networks with and without our method by computer simulations. The results show that our method reduces the blocking probabilities by more than one order of magnitude.     

Benefits of collecting local data on breast cancer and mammography practices in northwestern Pennsylvania

OBJECTIVES: A randomized trial was conducted to evaluate the effectiveness of a work-site health promotion program in reducing obesity and the prevalence of cigarette smoking. METHODS: Thirty-two work sites were randomized to treatment or no treatment for 2 years. Treatment consisted of health education classes combined with a payroll-based incentive system. Evaluation was based on cohort and cross-sectional surveys. RESULTS: Of 10,000 total employees in treatment work sites, 2041 and 270 participated in weight control and smoking cessation programs, respectively. Weight losses averaged 4.8 lbs, and 43% of smoking participants quit. Net 2-year reductions in smoking prevalence in treatment vs control work sites were 4.0% and 2.1% in cross-sectional and cohort surveys, respectively. No treatment effect was found for weight. Treatment effects for smoking prevalence and weight were both positively correlated with participation rates in the intervention programs (r = .45 for smoking and r = .55 for weight). CONCLUSIONS: This work-site health promotion program was effective in reducing smoking prevalence at a cost that is believed to make the investment worthwhile.