Energy barrier in the two-Higgs model

The electroweak model is extended by a second Higgs doublet and a numerical investigation of static, finite energy classical solutions is performed. The results indicate that for a large domain of the parameters of the Higgs potential, the energy barrier between topologically distinct vacua of the Lagrangian is constituted by a bisphaleron.Comment: 19 pages, including 4 eps figures, LaTex format, new results include

Salvaging the septic heart through targeting the IL-6/p38 MAPK signaling network

Depression of myocardial function during severe sepsis, which currently accounts for approx. 200,000 deaths/year in the United States (1), is characterized by a decrease in contractility and a poor response to fluid therapy (2). Since the md-1980s it has been recognized that the decreased cardiac function, which undoubtedly contributes to the overall pathophysiology of the septic state, does not arise from factors that are intrinsic to the myocardium, but instead results from the presence of circulating myocardial depressant factors (3, 4). Since much of the massive inflammation and multi-organ dysfunction in sepsis result from the secretion of various cytokines, it was long suspected that these proteins were also responsible, at least in part, for the observed myocardial dysfunction, although their identification, and the molecular basis for their effects on myocyte function were poorly understood

14-3-3 Proteins, FHA Domains and BRCT Domains in the DNA Damage Response

The DNA damage response depends on the concerted activity of protein serine/threonine kinases and modular phosphoserine/threonine-binding domains to relay the damage signal and recruit repair proteins. The PIKK family of protein kinases, which includes ATM/ATR/DNA-PK, preferentially phosphorylate Ser-Gln sites, while their basophilic downstream effecter kinases, Chk1/Chk2/MK2 preferentially phosphorylate hydrophobic-X-Arg-X-X-Ser/Thr-hydrophobic sites. A subset of tandem BRCT domains act as phosphopeptide binding modules that bind to ATM/ATR/DNA-PK substrates after DNA damage. Conversely, 14-3-3 proteins interact with substrates of Chk1/Chk2/MK2. FHA domains have been shown to interact with substrates of ATM/ATR/DNA-PK and CK2. In this review we consider how substrate phsophorylation together with BRCT domains, FHA domains and 14-3-3 proteins function to regulate ionizing radiation-induced nuclear foci and help to establish the G2/M checkpoint. We discuss the role of MDC1 a molecular scaffold that recruits early proteins to foci, such as NBS1 and RNF8, through distinct phosphodependent interactions. In addition, we consider the role of 14-3-3 proteins and the Chk2 FHA domain in initiating and maintaining cell cycle arrest

Exploiting synthetic lethal interactions for targeted cancer therapy

March 15, 2011Emerging data suggests that synthetic lethal interactions between mutated oncogenes/tumor suppressor genes and molecules involved in DNA damage signaling and repair can be therapeutically exploited to preferentially kill tumor cells. In this review, we discuss the concept of synthetic lethality, and describe several recent examples in which this concept was successfully implemented to target tumor cells in culture, in mouse models, and in human cancer patients.National Institutes of Health (U.S.) (Grant GM68762)National Institutes of Health (U.S.) (Grant CA112967)National Institutes of Health (U.S.) (Grant ES015339)National Cancer Institute (U.S.). Integrative Cancer Biology Program (Grant U54-CA112967-03)German Research Foundation (RE2246/1-1)David H. Koch Cancer Research FundGerman Kidney Foundatio

Systematic Multi-Domain Alzheimer's Risk Reduction Trial (SMARRT): Study Protocol.

This article describes the protocol for the Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer's disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70-89 years with subjective cognitive complaints, low normal performance on cognitive screen, and ≥ two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer's risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70-79, 80-89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months

From Instantons to Sphalerons: Time-Dependent Periodic Solutions of SU(2)-Higgs Theory

We solve numerically for periodic, spherically symmetric, classical solutions of SU(2)-Higgs theory in four-dimensional Euclidean space. In the limit of short periods the solutions approach tiny instanton-anti-instanton superpositions while, for longer periods, the solutions merge with the static sphaleron. A previously predicted bifurcation point, where two branches of periodic solutions meet, appears for Higgs boson masses larger than $3.091 M_W$.Comment: 14 pages, RevTeX with eps figure

Comments on large-N volume independence

We study aspects of the large-N volume independence on R**3 x L**G, where L**G is a G-site lattice for Yang-Mills theory with adjoint Wilson-fermions. We find the critical number of lattice sites above which the center-symmetry analysis on L**G agrees with the one on the continuum S**1. For Wilson parameter set to one and G>=2, the two analyses agree. One-loop radiative corrections to Wilson-line masses are finite, reminiscent of the UV-insensitivity of the Higgs mass in deconstruction/Little-Higgs theories. Even for theories with G=1, volume independence in QCD(adj) may be guaranteed to work by tuning one low-energy effective field theory parameter. Within the parameter space of the theory, at most three operators of the 3d effective field theory exhibit one-loop UV-sensitivity. This opens the analytical prospect to study 4d non-perturbative physics by using lower dimensional field theories (d=3, in our example).Comment: 12 pages; added small clarifications, published versio

Effective Kinetic Theory for High Temperature Gauge Theories

Quasiparticle dynamics in relativistic plasmas associated with hot, weakly-coupled gauge theories (such as QCD at asymptotically high temperature $T$) can be described by an effective kinetic theory, valid on sufficiently large time and distance scales. The appropriate Boltzmann equations depend on effective scattering rates for various types of collisions that can occur in the plasma. The resulting effective kinetic theory may be used to evaluate observables which are dominantly sensitive to the dynamics of typical ultrarelativistic excitations. This includes transport coefficients (viscosities and diffusion constants) and energy loss rates. We show how to formulate effective Boltzmann equations which will be adequate to compute such observables to leading order in the running coupling $g(T)$ of high-temperature gauge theories [and all orders in $1/\log g(T)^{-1}$]. As previously proposed in the literature, a leading-order treatment requires including both $22$ particle scattering processes as well as effective ``$12$'' collinear splitting processes in the Boltzmann equations. The latter account for nearly collinear bremsstrahlung and pair production/annihilation processes which take place in the presence of fluctuations in the background gauge field. Our effective kinetic theory is applicable not only to near-equilibrium systems (relevant for the calculation of transport coefficients), but also to highly non-equilibrium situations, provided some simple conditions on distribution functions are satisfied.Comment: 40 pages, new subsection on soft gauge field instabilities adde

A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo

A fundamental limitation in devising new therapeutic strategies for killing cancer cells with DNA damaging agents is the need to identify synthetic lethal interactions between tumor-specific mutations and components of the DNA damage response (DDR) in vivo. The stress-activated p38 mitogen-activated protein kinase (MAPK)/MAPKAP kinase-2 (MK2) pathway is a critical component of the DDR network in p53-deficient tumor cells in vitro. To explore the relevance of this pathway for cancer therapy in vivo, we developed a specific gene targeting strategy in which Cre-mediated recombination simultaneously creates isogenic MK2-proficient and MK2-deficient tumors within a single animal. This allows direct identification of MK2 synthetic lethality with mutations that promote tumor development or control response to genotoxic treatment. In an autochthonous model of non-small-cell lung cancer (NSCLC), we demonstrate that MK2 is responsible for resistance of p53-deficient tumors to cisplatin, indicating synthetic lethality between p53 and MK2 can successfully be exploited for enhanced sensitization of tumors to DNA-damaging chemotherapeutics in vivo.National Institutes of Health (U.S.) (Grant ES015339)National Institutes of Health (U.S.) (Grant GM60594)National Institutes of Health (U.S.) (Grant GM59281)National Institutes of Health (U.S.) (Grant CA112967)Janssen Pharmaceutical Ltd.Massachusetts Institute of Technology. Center for Environmental Health Sciences (Core Grant P30-CA14051)Massachusetts Institute of Technology. Center for Environmental Health Sciences (Core Grant ES-002109

Quantum limit of deterministic theories

We show that the quantum linear harmonic oscillator can be obtained in the large $N$ limit of a classical deterministic system with SU(1,1) dynamical symmetry. This is done in analogy with recent work by G.'t Hooft who investigated a deterministic system based on SU(2). Among the advantages of our model based on a non--compact group is the fact that the ground state energy is uniquely fixed by the choice of the representation.Comment: 4 pages, 2 figures, minor corrections added. To appear in the Proceedings of Waseda International Symposium on Fundamental Physics: "New Perspectives in Quantum Physics", 12-15 November 2002, Waseda University, Tokyo, Japa