Application of multidisciplinary optimization methods to the design of a supersonic transport

An optimization design method is discussed. This method is based on integrating existing disciplinary analysis and sensitivity analysis techniques by means of generalized sensitivity equations. A generic design system implementing this method is described. The system is being used to design the configuration and internal structure of a supersonic transport wing for optimum performance. This problem combines the disciplines of linear aerodynamics, structures, and performance. Initial results which include the disciplines of aerodynamics and structures in a conventional minimum weight design under static aeroelastic constraints are presented

HIV Integrase Inhibitors Block Replication of Alpha-, Beta-, and Gammaherpesviruses

ABSTRACT The catalytic site of the HIV integrase is contained within an RNase H-like fold, and numerous drugs have been developed that bind to this site and inhibit its activity. Herpes simplex virus (HSV) encodes two proteins with potential RNase H-like folds, the infected cell protein 8 (ICP8) DNA-binding protein, which is necessary for viral DNA replication and exhibits recombinase activity in vitro, and the viral terminase, which is essential for viral DNA cleavage and packaging. Therefore, we hypothesized that HIV integrase inhibitors might also inhibit HSV replication by targeting ICP8 and/or the terminase. To test this, we evaluated the effect of 118-D-24, a potent HIV integrase inhibitor, on HSV replication. We found that 118-D-24 inhibited HSV-1 replication in cell culture at submillimolar concentrations. To identify more potent inhibitors of HSV replication, we screened a panel of integrase inhibitors, and one compound with greater anti-HSV-1 activity, XZ45, was chosen for further analysis. XZ45 significantly inhibited HSV-1 and HSV-2 replication in different cell types, with 50% inhibitory concentrations that were approximately 1 µM, but exhibited low cytotoxicity, with a 50% cytotoxic concentration greater than 500 µM. XZ45 blocked HSV viral DNA replication and late gene expression. XZ45 also inhibited viral recombination in infected cells and ICP8 recombinase activity in vitro. Furthermore, XZ45 inhibited human cytomegalovirus replication and induction of Kaposi’s sarcoma herpesvirus from latent infection. Our results argue that inhibitors of enzymes with RNase H-like folds may represent a general antiviral strategy, which is useful not only against HIV but also against herpesviruses

Non-monotonic variation with salt concentration of the second virial coefficient in protein solutions

The osmotic virial coefficient $B_2$ of globular protein solutions is calculated as a function of added salt concentration at fixed pH by computer simulations of the ``primitive model''. The salt and counter-ions as well as a discrete charge pattern on the protein surface are explicitly incorporated. For parameters roughly corresponding to lysozyme, we find that $B_2$ first decreases with added salt concentration up to a threshold concentration, then increases to a maximum, and then decreases again upon further raising the ionic strength. Our studies demonstrate that the existence of a discrete charge pattern on the protein surface profoundly influences the effective interactions and that non-linear Poisson Boltzmann and Derjaguin-Landau-Verwey-Overbeek (DLVO) theory fail for large ionic strength. The observed non-monotonicity of $B_2$ is compared to experiments. Implications for protein crystallization are discussed.Comment: 43 pages, including 17 figure

Mediterranean spotted fever and hearing impairment : a rare complication

Mediterranean spotted fever (MSF) is caused by Rickettsia conorii and transmitted by the brown dog tick Rhipicephalus sanguineus. It is prevalent in southern Europe, Africa and central Asia. The disease usually has a benign course and is characterized by fever, myalgia and a characteristic papular rash with an inoculation eschar ('tache noir') at the site of the tick bite. Severe forms of disease can have cardiac, neurologic or renal involvement. Nervous system complications are unusual and may develop in the early phase of disease or as a delayed complication. Neurological symptoms include headache and alterations of the level of consciousness, and some cases of meningoenchefalitis and Guillain-Barre syndrome have been also reported. Peripheral nerve involvement is reported only in a limited number of case reports. We describe a case of Rickettsia conorii that was complicated with hearing loss and did not respond to specific treatment. Hearing loss is a rare event, but clinicians should be aware of this complication

Together forever? Explaining exclusivity in party-firm relations

Parties and firms are the key actors of representative democracy and capitalism respectively and the dynamic of attachment between them is a central feature of any political economy. This is the first article to systematically analyse the exclusivity of party-firm relations. We consider exclusivity at a point in time and exclusivity over time. Does a firm have a relationship with only one party at a given point in time, or is it close to more than one party? Does a firm maintain a relationship with only one party over time, or does it switch between parties? Most important, how do patterns of exclusivity impact on a firm’s ability to lobby successfully? We propose a general theory, which explains patterns of party-firm relations by reference to the division of institutions and the type of party competition in a political system. A preliminary test of our theory with Polish survey data confirms our predictions, establishing a promising hypothesis for future research

Gain-through-filtering enables tuneable frequency comb generation in passive optical resonators

Optical frequency combs (OFCs), consisting of a set of phase-locked, equally spaced laser frequency lines, have enabled a great leap in precision spectroscopy and metrology since seminal works of Hänsch et al. Nowadays, OFCs are cornerstones of a wealth of further applications ranging from chemistry and biology to astrophysics and including molecular fingerprinting and light detection and ranging (LIDAR) systems, among others. Driven passive optical resonators constitute the ideal platform for OFC generation in terms of compactness and low energy footprint. We propose here a technique for the generation of OFCs with a tuneable repetition rate in externally driven optical resonators based on the gain-through-filtering process, a simple and elegant method, due to asymmetric spectral filtering on one side of the pump wave. We demonstrate a proof-of-concept experimental result in a fibre resonator, pioneering a new technique that does not require specific engineering of the resonator dispersion to generate frequency-agile OFCs

Biophysics and systems biology

Biophysics at the systems level, as distinct from molecular biophysics, acquired its most famous paradigm in the work of Hodgkin and Huxley, who integrated their equations for the nerve impulse in 1952. Their approach has since been extended to other organs of the body, notably including the heart. The modern field of computational biology has expanded rapidly during the first decade of the twenty-first century and, through its contribution to what is now called systems biology, it is set to revise many of the fundamental principles of biology, including the relations between genotypes and phenotypes. Evolutionary theory, in particular, will require re-assessment. To succeed in this, computational and systems biology will need to develop the theoretical framework required to deal with multilevel interactions. While computational power is necessary, and is forthcoming, it is not sufficient. We will also require mathematical insight, perhaps of a nature we have not yet identified. This article is therefore also a challenge to mathematicians to develop such insights