Phosphatidylinositol 3-kinase is necessary and sufficient for insulin-stimulated stress fiber breakdown

Rat-1 fibroblasts overexpressing the human insulin receptor undergo rapid actin rearrangement in response to insulin. Breakdown of stress fibers present in quiescent cells is followed by transient membrane ruffling and a return of stress fibers. We investigated the signaling pathways that mediate this insulin-stimulated reorganization of the actin cytoskeleton, which was visualized with rhodamine-phalloidin. Treatment of cells with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor wortmannin prevented insulin action at the preliminary step of stress fiber breakdown. Cellular microinjection of a polyclonal antibody directed against the p85 subunit of PI3-kinase as well as a purified recombinant p85-SH2 domain protein also inhibited actin reorganization. Transient expression of a constitutively active form of PI3-kinase (p110*) was sufficient to cause both stress fiber breakdown and membrane ruffling in the absence of insulin. Microinjection of a polyclonal anti-Shc antibody or dominant negative N17-Ras protein did not affect actin dynamics, and although constitutively active V12-Ras caused modest cytoskeletal reorganization, this effect was blocked by pretreatment with wortmannin. In summary, activation of PI3-kinase is necessary and sufficient to stimulate actin rearrangement, indicating that PI3-kinase may initiate the only signaling cascade required for insulin to induce cytoskeletal restructuring.     

Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells

Evidence suggests that cholinergic input to the hippocampus plays an important role in learning and memory and that degeneration of cholinergic terminals in the hippocampus may contribute to the memory loss associated with Alzheimer's disease. One of the more prominent effects of cholinergic agonists on hippocampal physiology is the potentiation of N-methyl-D-aspartate (NMDA)-receptor currents by muscarinic agonists. Here, we employ traditional pharmacological reagents as well as m1-toxin, an m1 antagonist with unprecedented selectivity, to demonstrate that this potentiation of NMDA-receptor currents in hippocampal CA1 pyramidal cells is mediated by the genetically defined m1 muscarinic receptor. Furthermore, we demonstrate the colocalization of the m1 muscarinic receptor and the NR1a NMDA receptor subunit at the electron microscopic level, indicating a spatial relationship that would allow for physiological interactions between these two receptors. This work demonstrates that the m1-muscarinic receptor gene product modulates excitatory synaptic transmission, and it has important implications in the study of learning and memory as well as the design of drugs to treat neurodegenerative diseases such as Alzheimer's.     

Stimulus classes in matching to sample and sequence production: the emergence of numeric relations

We investigated interrelationships among stimulus classes established in matching-to-sample and sequence-production tasks. The analysis focused on the matching and sequencing of quantities, numerals, and arbitrary forms in two individuals with mental retardation. The basic protocol involved: (a) establishing both matching and sequencing performances with some stimuli, (b) training sequencing with a new set of stimuli and assessing whether new matching performances emerged, and (c) training matching with a new set of stimuli and assessing whether new sequencing emerged. The results showed that sequence training did not readily lead to new matching performances, unlike prior research with college students. In contrast, training in matching to sample yielded emergent sequence production; these data support prior studies involving children and adults without developmental disabilities. The results extend prior stimulus class research and suggest an important role for stimulus control processes in the production of generative numeric performances.     

Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian families originally classified as having Type I diabetes

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are the cause of maturity-onset diabetes of the young type 3 (MODY3), which is characterised by a severe impairment of insulin secretion and an early onset of the disease. Also at onset of diabetes some MODY patients show similar clinical symptoms and signs as patients with Type I (insulin-dependent) diabetes mellitus. The objective of this study was to estimate the prevalence of MODY3 patients misclassified as Type I diabetic patients. From a large population-based sample of unrelated Danish Caucasian Type I diabetic patients with an affected first degree relative, 39 patients (6.7%) who did not carry any high-risk HLA-haplotypes, i.e. DR3 or DR4 or both were examined by single-strand conformational polymorphism scanning and direct sequencing of the coding region and the minimal promoter of the HNF-1alpha gene. Four of the 39 Type I diabetic patients (10%) were identified as carrying mutations in the HNF-1alpha gene. One patient carried a missense mutation (Glu48Lys) in exon 1, two patients carried a missense mutation (Cys241Gly) in exon 4 and one patient carried a frameshift mutation (Pro291fsdelA) in exon 4. The mutations were all identified in heterozygous form, segregated with diabetes, and were not identified in 84 unrelated, healthy subjects. Furthermore, family history in three of the four families showed diabetes in four consecutive generations, suggestive of an autosomal dominant inheritance. In conclusion, about 10% of Danish diabetic patients without a high-risk HLA-haplotype, originally classified as having Type I diabetes could have diabetes caused by mutations in the HNF-1alpha gene. Clinical awareness of family history of diabetes and mode of inheritance might help to identify and reclassify these diabetic subjects as MODY3 patients.     

Electrochemical polymerization of chiral pyrrole derivatives in electrolytes containing chiral camphor sulfonic acid

N‐Substituted pyrrole derivatives with chiral side groups have been synthesized and electrochemically polymerized in acetonitrile containing tetrabutylammonium perchlorate (TBAClO₄) and (S)‐(+)‐camphor‐10‐sulfonic acid ((S)‐(+)‐CSA) or (R)‐(?)‐camphor‐10‐sulfonic acid ((R)‐(?)‐CSA). The resulting N‐substituted polypyrrole films were characterized by cyclic voltammetry, infrared, Raman and X‐ray photoelectron (XPS) spectroscopies. XPS results demonstrated that the as‐grown polymer films are preferably doped by CSA anions when the monomer and the CSA anion have the same optical rotation dispersion (ORD). Furthermore, the conductivities of the polymers synthesized in the media containing CSA with the same ORD of the corresponding monomers were measured to be about 2–10 times higher than those of polymers obtained from electrolytes without CSA. Copyright © 2004 Society of Chemical Industry     

A scalable model for interbandwidth broker resource reservation and provisioning

As the Internet evolves into global communication and commercial infrastructure, the need for quality-of-services (QoSs) in the Internet becomes more and more important. With a bandwidth broker (BB) support in each administrative domain, differentiated services (Diffserv) is seen as a key technology for achieving QoS guarantees in a scalable, efficient, and deployable manner in the Internet. In this paper, we present a scalable model for inter-BB resource reservation and provisioning. Our BB uses centralized network state maintenance and pipe-based intradomain resource management schemes that significantly reduce admission control time and minimize scalability problems present in prior research. For inter-BB communication, we design and implement a BB resource reservation and provisioning protocol (BBRP). BBRP performs destination-based aggregated resource reservation based on bilateral service level agreements (SLAs) between peer-BBs. BBRP significantly reduces the BB and border routers state scalability problem by maintaining reservation state based only on destination region. It minimizes inter-BB signaling scalability by using aggregated type resource reservation and provisioning. Both analytical and experimental results verify the BBRP achievements.     

Thermo-Oxidative aging of a primary lightguide coating in films and dual-coated fibers

The thermo-oxidative aging of a polyether urethane lightguide primary coating has been studied in films and dual-coated fibers, In films, oxygen absorption is correlated with changes in modulus, yellowness, glass transition temperature, and sample weight. Thermal aging of fibers shows similar trends with regards to coating weight loss and discoloration as those observed with films. In addition, the force to mechanically strip the fiber follows the same patterns of change as the modulus of aged films. For both films and fibers, the time for onset of property changes varies inversely with temperature and can be delayed by the incorporation of an antioxidant.     

Reliable heterogeneous applications

This paper explores the notion of computational resiliency to provide reliability in heterogeneous distributed applications. This notion provides both software fault-tolerance and the ability to tolerate information-warfare attacks. This technology seeks to strengthen a military mission, rather than to protect its network infrastructure using static defense measures such as network security, intrusion sensors, and firewalls. Even if a failure or attack is successful and never detected, it should be possible to continue information operations and achieve mission objectives. Computational resiliency involves the dynamic use of replicated software structures, guided by mission policy, to achieve reliable operation. However, it goes further to regenerate, automatically, replication in response to a failure or attack, allowing the level of system reliability to be restored and maintained. This paper examines a prototype concurrent programming technology to support computational resiliency in a heterogeneous distributed computing environment. The performance of the technology is explored through two example applications.     

Trends in breast cancer screening in Missouri from 1987 to 1995, and predictions for the years 2000 and 2010

BACKGROUND: Breast cancer is a major cause of morbidity and mortality in the United States (U.S.) and Missouri. In 1992, 3,915 new breast cancer cases were diagnosed and in 1995, 1,006 deaths from breast cancer were reported in Missouri. Although breast cancer incidence has increased in Missouri in the past 20 years, there are indications that early detection has also increased during the same period. Knowledge about which segments of the population have experienced the greatest increase in mammography screening rates helps in planning and implementation of breast cancer control programs at the state level. OBJECTIVES: Examine the prevalence and trends of lifetime mammography and 2-year mammography compliance in Missouri by age, race, and education from 1987 to 1995 and make predictions for the years 2000 and 2010. METHODS: We used data from the Missouri Behavioral Risk Factor Surveillance System (BRFSS), 1987 to 1995, to estimate the prevalence of ever having had a mammogram and compliance with mammography screening guidelines within two years by race, age, and education status among Missouri women over age 18. Using linear models, we regressed breast cancer screening prevalence estimates on time to obtain trends and predictions. RESULTS: Overall, African-American women were more likely to have had a lifetime mammogram than white women. However, we found a steady increase in the prevalence of ever having had a mammogram for all groups of women defined by age and education status, except among African Americans. Increase in the prevalence of ever having had a mammogram was much higher in women age 50 and older and slightly higher among women with a high school education or less. The average prevalence of 2-year mammography screening compliance was about 60% for all groups, a rate which did not significantly change between 1987 and 1995. By the year 2000, white women will have mammography rates equal to or higher than African-American women, and the majority of all women age 50 and older (98.3% to 100%) will have had a lifetime mammogram. CONCLUSION: Missouri target populations are predicted to attain Year 2000 National Health Objectives concerning lifetime mammography. Current efforts should be continued in order to maintain levels of mammography, particularly among African-American women.     

Expression of de novo high-lysine alpha-helical coiled-coil proteins may significantly increase the accumulated levels of lysine in mature seeds of transgenic tobacco plants

Transgenic insect technology will provide opportunities to explore the basic biology of a broad range of insect species in ways that will prove insightful and important. It is also a technology that will provide opportunities to manipulate the genotypes of insects of practical significance to the health and welfare of humans. The Hermes transposable element from the housefly, Musca domestica, is a short inverted repeat-type element related to hobo from Drosophila melanogaster, Ac from Zea mays, and Tam3 from Antirrhinum majus. It has potential to become a versatile and efficient broad host-range insect transformation vector. The ability of Hermes to transpose when introduced into five species of diptera from four divergent families was tested using an in vivo, interplasmid transpositional recombination assay. Hermes was capable of transposing in all species tested, demonstrating that Hermes has a broad host-range. In addition, the rates of transposition were sufficiently high in all species tested to suggest that Hermes will be an efficient gene transfer vector in a wide range of insect species. The Hermes element also revealed a pattern of integration into the target substrate that permitted factors determining integration site selection to be identified. Primary nucleotide sequence of the integration site played a role as did proximity to preferred integration sites and the nucleosomal organization of the target.