Spatio-temporal correlations can drastically change the response of a MAPK pathway

Multisite covalent modification of proteins is omnipresent in eukaryotic cells. A well-known example is the mitogen-activated protein kinase (MAPK) cascade, where in each layer of the cascade a protein is phosphorylated at two sites. It has long been known that the response of a MAPK pathway strongly depends on whether the enzymes that modify the protein act processively or distributively: distributive mechanism, in which the enzyme molecules have to release the substrate molecules in between the modification of the two sites, can generate an ultrasensitive response and lead to hysteresis and bistability. We study by Green's Function Reaction Dynamics, a stochastic scheme that makes it possible to simulate biochemical networks at the particle level and in time and space, a dual phosphorylation cycle in which the enzymes act according to a distributive mechanism. We find that the response of this network can differ dramatically from that predicted by a mean-field analysis based on the chemical rate equations. In particular, rapid rebindings of the enzyme molecules to the substrate molecules after modification of the first site can markedly speed up the response, and lead to loss of ultrasensitivity and bistability. In essence, rapid enzyme-substrate rebindings can turn a distributive mechanism into a processive mechanism. We argue that slow ADP release by the enzymes can protect the system against these rapid rebindings, thus enabling ultrasensitivity and bistability

Conceptual design studies of candidate V/STOL lift fan commercial short haul transport for 1980 - 1985 V/STOL lift fan study

Conceptual designs of V/STOL lift fan commercial short haul transport aircraft for the 1980-85 time period were studied to determine their technical and economic feasibility. The engine concepts included both integral and remote fans. The scope of the study included definition of the hover control concept for each propulsion system, aircraft design, aircraft mass properties, cruise performance, noise and ride qualities evaluation. Economic evaluating was also studied on a basis of direct operating costs and route structure

Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP

Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK modul

Assessments of Stream Flow and Flooding Along the Pere Marquette River, West Michigan

Understanding how stream flow in rivers across Michigan is responding to climate change is important because rivers are used for hydroelectricity, recreation, fisheries, and many people own property along them. Michigan’s annual rainfall has increased by three inches since 1940 and is expected to increase by 0.036 inches/year through the 21st century due to climate change. In this study, I test the hypothesis that increased rainfall will lead to more frequent flooding along Michigan’s rivers. I do so by analyzing river discharge data and flow-duration curves from a stream gaging station on the Pere Marquette River, the largest undammed river in Michigan. Results from this study show that the discharge on the Pere Marquette River was ≥1,643 cfs for 27 days and increased 6-fold to 164 days in the 1990s and 2000s. It is likely that other natural rivers in Michigan might also show increases in the historical 1.5 year discharge associated with them and that discharge with the 1% exceedance probability might also increase

Claude A. Swanson of Virginia: A Political Biography

Spanning most of the years of the one-party South, the public career of Virginian Claude A. Swanson, congressman, governor, senator, and secretary of the navy, extended from the second administration of Grover Cleveland into that of Franklin Roosevelt. His record, writes Henry C. Ferrell, Jr., in this definitive biography, is that of “a skillful legislative diplomat and an exceedingly wise executive encompassed in the personality of a professional politician.” As a congressman, Swanson abandoned Cleveland\u27s laissez faire doctrines to become the leading Virginia spokesman for William Jennings Bryan and the Democratic platform of 1896. His achievements as a reform governor are equaled by few Virginia chief executives. In the Senate, Swanson worked to advance the programs of Woodrow Wilson. In the 1920s, he contributed to formulation of Democratic alternatives to Republican policies. In Roosevelt\u27s New Deal cabinet, he helped the Navy obtain favorable treatment during a decade of isolation. The warp and woof of local politics are well explicated by Ferrell to furnish insight into personalities and events that first produced, then sustained, Swanson\u27s electoral success. He examines Virginia educational, moral, and social reforms; disfranchisement movements; racial and class politics; and the impact of the woman\u27s vote. And he records the growth of the Hampton Roads military-industrial complex, which Swanson brought about. In Virginia, Swanson became a dominant political figure, and Ferrell\u27s study challenges previous interpretations of Virginia politics between 1892 and 1932 that pictured a powerful, reactionary Democratic Organization, directed by Thomas Staples Martin and his successor Harry Flood Byrd, Sr., defeating would-be progressive reformers. A forgotten Virginia emerges here, one that reveals the pervasive role of agrarians in shaping the Old Dominion\u27s politics and priorities. Henry C. Ferrell Jr. is professor of history at East Carolina University.https://uknowledge.uky.edu/upk_political_history/1013/thumbnail.jp

Sum rules and three point functions

Sum rules constraining the R-current spectral densities are derived holographically for the case of D3-branes, M2-branes and M5-branes all at finite chemical potentials. In each of the cases the sum rule relates a certain integral of the spectral density over the frequency to terms which depend both on long distance physics, hydrodynamics and short distance physics of the theory. The terms which which depend on the short distance physics result from the presence of certain chiral primaries in the OPE of two R-currents which are turned on at finite chemical potential. Since these sum rules contain information of the OPE they provide an alternate method to obtain the structure constants of the two R-currents and the chiral primary. As a consistency check we show that the 3 point function derived from the sum rule precisely matches with that obtained using Witten diagrams.Comment: 41 page

Risk-shifting Through Issuer Liability and Corporate Monitoring

This article explores how issuer liability re-allocates fraud risk and how risk allocation may reduce the incidence of fraud. In the US, the apparent absence of individual liability of officeholders and insufficient monitoring by insurers under-mine the potential deterrent effect of securities litigation. The underlying reasons why both mechanisms remain ineffective are collective action problems under the prevailing dispersed ownership structure, which eliminates the incentives to moni-tor set by issuer liability. This article suggests that issuer liability could potentially have a stronger deterrent effect when it shifts risk to individuals or entities holding a larger financial stake. Thus, it would enlist large shareholders in monitoring in much of Europe. The same risk-shifting effect also has implications for the debate about the relationship between securities litigation and creditor interests. Credi-tors’ claims should not be given precedence over claims of defrauded investors (e.g., because of the capital maintenance principle), since bearing some of the fraud risk will more strongly incentivise large creditors, such as banks, to monitor the firm in jurisdictions where corporate debt is relatively concentrated

Hidden Order in the Cuprates

We propose that the enigmatic pseudogap phase of cuprate superconductors is characterized by a hidden broken symmetry of d(x^2-y^2)-type. The transition to this state is rounded by disorder, but in the limit that the disorder is made sufficiently small, the pseudogap crossover should reveal itself to be such a transition. The ordered state breaks time-reversal, translational, and rotational symmetries, but it is invariant under the combination of any two. We discuss these ideas in the context of ten specific experimental properties of the cuprates, and make several predictions, including the existence of an as-yet undetected metal-metal transition under the superconducting dome.Comment: 12 pages of RevTeX, 9 eps figure