Thermodynamics of Neutral Protein Evolution

Naturally evolving proteins gradually accumulate mutations while continuing to fold to thermodynamically stable native structures. This process of neutral protein evolution is an important mode of genetic change, and forms the basis for the molecular clock. Here we present a mathematical theory that predicts the number of accumulated mutations, the index of dispersion, and the distribution of stabilities in an evolving protein population from knowledge of the stability effects (ddG values) for single mutations. Our theory quantitatively describes how neutral evolution leads to marginally stable proteins, and provides formulae for calculating how fluctuations in stability cause an overdispersion of the molecular clock. It also shows that the structural influences on the rate of sequence evolution that have been observed in earlier simulations can be calculated using only the single-mutation ddG values. We consider both the case when the product of the population size and mutation rate is small and the case when this product is large, and show that in the latter case proteins evolve excess mutational robustness that is manifested by extra stability and increases the rate of sequence evolution. Our basic method is to treat protein evolution as a Markov process constrained by a minimal requirement for stable folding, enabling an evolutionary description of the proteins solely in terms of the experimentally measureable ddG values. All of our theoretical predictions are confirmed by simulations with model lattice proteins. Our work provides a mathematical foundation for understanding how protein biophysics helps shape the process of evolution

A Multiwavelength Investigation of Unidentified EGRET Sources

Statistical studies indicate that the 271 point sources of high-energy gamma rays belong to two groups: a Galactic population and an isotropic extragalactic population. Many unidentified extragalactic sources are certainly blazars, and it is the intention of this work to uncover gamma-ray blazars missed by previous attempts. Until recently, searches for blazar counterparts to unidentified EGRET sources have focused on finding AGN that have 5-GHz radio flux densities S_5 near or above 1 Jy. However, the recent blazar identification of 3EG J2006-2321 (S_5 = 260 mJy) and other work suggest that careful studies of weaker flat-spectrum sources may be fruitful. In this spirit, error circles of 4 high-latitude unidentified EGRET sources have been searched for 5-GHz sources. The gamma-ray sources are 3EG J1133+0033, 3EG J1212+2304, 3EG J1222+2315, and 3EG J1227+4302. Within the error contours of each of the four sources are found 6 radio candidates; by observing the positions of the radio sources with the 0.81-m Tenagra II telescope it is determined that 14 of these 24 radio sources have optical counterparts with R < 22. Eight of these from two different EGRET sources have been observed in the B, V, and R bands in more than one epoch and the analysis of these data is ongoing. Any sources that are found to be variable will be the objects of multi-epoch polarimetry studies.Comment: 6 pages, 2 tables. To appear in Astrophysics & Space Scienc

Estimates for solutions of reduced hyperbolic equations of the second order with a large parameter

AbstractWe consider solutions of inhomogeneous, reduced hyperbolic equations of the second order, with a large parameter multiplying the unknown function. These solutions are defined on the m-dimensional region outside a star-shaped body. They satisfy an “outgoing” radiation condition at infinity and a Dirichlet boundary condition.We obtain a priori estimates for these solutions, at every point outside or on the surface of a two- or three-dimensional star-shaped body, that hold for sufficiently large values of the parameter. We prove that each solution is bounded by a linear combination of (i) the maximum norm of its prescribed boundary values, (ii) the L2 norm of the prescribed values of its tangential derivative, (iii) an L2 norm of the source term. This result is based on similar inequalities that we first obtain for a certain L2 norm of the gradient, and of the normal derivative on the boundary, of each solution defined outside an m-dimensional star-shaped body.For the special case of the reduced wave equation, Morawetz and Ludwig [1] have obtained similar estimates. Just as their results have been used in [3] to confirm the geometrical theory of diffraction, the estimates obtained in this paper can be used to establish the validity of certain formal asymptotic solutions of reduced hyperbolic equations

What is the best treatment for Osgood-Schlatter disease?

Osgood-Schlatter disease is a common cause of pain and tenderness at the tibial tuberosity in active adolescents. It is typically a self-limited condition that waxes and wanes, but which often takes months to years to resolve entirely. It is best managed with conservative measures (activity modification, ice, anti- inflammatory agents) and time (strength of recommendation [SOR]: B, several case series and retrospective studies). In chronic cases that are refractory to conservative treatment, surgical intervention yields good results, particularly for patients with bony or cartilaginous ossicles. Excision of these ossicles produces resolution of symptoms and return to activity in several weeks (SOR: C, several case series). Corticosteroid injections are not recommended (SOR: C, case reports and expert opinion)

Altered leukocyte gene expression after traumatic spinal cord injury: clinical implications

In addition to changes in motor and sensory function, individuals with spinal cord injury (SCI) experience immunological changes. These changes are clinically significant, as infections are the leading cause of death for this population. Along with increased infections, inflammation is commonly observed in persons with SCI, where it may promote many common medical consequences. These include elevated risk of cardiovascular disease, impaired wound healing, diabetes and neuropathic pain. It has also been proposed that chronic inflammation dampens neurological recovery. In order to identify therapeutic strategies to improve immune function, we need a greater understanding of the molecular changes that occur in immune cells after SCI. The purpose of this mini-review is to discuss two recent studies that used functional genomics to investigate gene expression in circulating leukocytes isolated from persons with SCI. In the future, the molecular pathways that are altered after SCI may be targeted to improve immunological function, as well as overall health and functional recovery, after SCI

Bloom-Gilman duality of the nucleon structure function and the elastic peak contribution

The occurrence of the Bloom-Gilman duality in the nucleon structure function is investigated by analyzing the Q**2-behavior of low-order moments, both including and excluding the contribution arising from the nucleon elastic peak. The Natchmann definition of the moments has been adopted in order to cancel out target-mass effects. It is shown that the onset of the Bloom-Gilman duality occurs around Q**2 ~ 2 (GeV/c)**2 if only the inelastic part of the nucleon structure function is considered, whereas the inclusion of the nucleon elastic peak contribution leads to remarkable violations of the Bloom-Gilman duality.Comment: in Proc. of the XVI European Conference on Few-body Problems in Physics, Autrans (France), July 199

Do antioxidants (vitamins C, E) improve outcomes in patients with coronary artery disease?

Antioxidant supplements of vitamins E and C do not reduce cardiovascular death in people with coronary artery disease. Vitamin E supplementation, in a variety of doses, does not decrease the incidence of cardiovascular or all-cause mortality (grade of recommendation: A, 4 high quality randomized controlled trials [RCTs]). There is no evidence that vitamin C decreases mortality in patients at risk for coronary disease (grade of recommendation: A, meta-analysis of 3 small RCTs). Combination antioxidant regimens (Vitamins E, C, and betacarotene) seem safe, but do not decrease mortality or incidence of major coronary and vascular events (grade recommendation: A, 1 high-quality RCT)

Ocean Thermal Energy Conversion: The Codification of a Potential Technology

Rapid technological advancement has been the hallmark of post-industrial societies for more than a quarter of a century. This progress is forever disrupting our established legal systems. Nowhere is this tension more evident than in the discoveries of the developing energy industry. An exception to this process is the infant industry of ocean thermal energy conversion (OTEC). The United States Congress recently enacted legislation establishing the legal framework for the OTEC process, which has not yet been proven on a commercial scale. OTEC is a form of solar energy that takes advantage of the vertical temperature differentials in those regions of the ocean generally between twenty degrees North latitude and twenty degrees South latitude. An OTEC system consists of a power plant, a floating platforms to house the plant, a surface-level seawater system, a deep water seawater system, and a method of transmitting or utilizing the energy produced. Warm surface water is pumped into a heat exchanger to vaporize a working fluid. A turbo-generator converts the resulting vapor\u27s thermal energy into mechanical and then electrical energy. The vapor leaving the turbine flows into a condenser where it is cooled by cold water pumped up from the deep ocean through a long pipe descending as much as 700 meters or deeper. Although commercial facilities are not expected to be available prior to the late 1980\u27s, two types of OTEC systems are presently under consideration. The closed cycle system6 is closer to commercial realization. In this system, heat derived from surface waters evaporates a working fluid such as ammonia and forces the resulting vapor through a turbine. The turbine powers a generator to create electricity. The vapor returns to liquid form after being chilled with cold water from the ocean depths. The second system is the open cycle system. In this process, warm surface seawater is evaporated in a vacuum. The resulting steam powers a turbine and is then condensed with cold seawater drawn from the ocean depths. OTEC has the potential to fulfill the energy needs of oil-dependent communities. Because OTEC\u27s energy source is solar, it is renewable. Unlike other solar technologies, however, OTEC can operate twenty-four hours a day, year-round due to the ocean\u27s immense solar-collection properties. Yet OTEC will be used for much more than electrical power generation. It has the potential for ammonia production, which presently requires nearly three percent of the total United States output of natural gas. OTEC can be used to process and refine minerals and produce other energy-intensive products such as aluminum. OTEC power can be used to produce fuel for fuel cells that can be transported and used for electricity elsewhere. Considering all these potential uses, OTEC will be a promising area of renewable energy technology if it evolves in a cost-effective and environmentally acceptable manner

Breaking proteins with mutations: threads and thresholds in evolution

A common high school science experiment involves anchoring one end of a rubber band to a desk and then attaching a small weight to the other end. The weight stretches the rubber band, and adding another weight causes the rubber band to dangle even lower. More weights can be added, and each one pulls the rubber band a little further towards the floor. Now, instead imagine attaching the weights to a thread. The thread stretches only slightly; so the first couple of weights have just a small effect. But if you add enough weights, the thread suddenly breaks and the weights fall to the floor. In the first case, each additional weight stretches the rubber band by the same amount, whereas in the second, it is the combination of several weights that breaks the thread. Mutating proteins is like adding weights, as mutations eventually ‘break’ the individual proteins, dragging down the fraction of proteins that still function (this fraction is the average fitness)