The Gumbel pre-factor k for gapped local alignment can be estimated from simulations of global alignment

The optimal gapped local alignment score of two random sequences follows a Gumbel distribution. The Gumbel distribution has two parameters, the scale parameter λ and the pre-factor k. Presently, the basic local alignment search tool (BLAST) programs (BLASTP (BLAST for proteins), PSI-BLAST, etc.) use all time-consuming computer simulations to determine the Gumbel parameters. Because the simulations must be done offline, BLAST users are restricted in their choice of alignment scoring schemes. The ultimate aim of this paper is to speed the simulations, to determine the Gumbel parameters online, and to remove the corresponding restrictions on BLAST users. Simulations for the scale parameter λ can be as much as five times faster, if they use global instead of local alignment [R. Bundschuh (2002) J. Comput. Biol., 9, 243–260]. Unfortunately, the acceleration does not extend in determining the Gumbel pre-factor k, because k has no known mathematical relationship to global alignment. This paper relates k to global alignment and exploits the relationship to show that for the BLASTP defaults, 10 000 realizations with sequences of average length 140 suffice to estimate both Gumbel parameters λ and k within the errors required (λ, 0.8%; k, 10%). For the BLASTP defaults, simulations for both Gumbel parameters now take less than 30 s on a 2.8 GHz Pentium 4 processor

Targeting early stages in non-mammalian isoprenoid biosynthesis: 1-deoxy-D-xylulose 5-phosphate (DXP) synthase and reductoisomerase (IspC).

This dissertation research is focused on mechanistic studies of early stage, non-mammalian isoprenoid biosynthesis enzymes, toward the development of selective inhibitors that will target serious human pathogens including Mycobacterium tuberculosis and Plasmodium falciparum. A major focus of this research has been toward elucidating the random sequential, preferred order mechanism of the first enzyme in the pathway, 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, an unprecedented enzyme in the thiamine diphosphate-dependent family of enzymes. Understanding this mechanism has been integral for selective inhibitor design and we have demonstrated, for the first time, selective inhibition of E. coli DXP synthase by butylacetylphosphonate (BAP). Further, selective inhibition is conserved in Y. pestis, S. enterica, and M. tuberculosis. This discovery is significant because DXP synthase is underdeveloped as a drug target and few inhibitors of this enzyme exist. Subsequently, BAP was evaluated as an antimicrobial agent against E. coli. Results of these studies demonstrated DXP synthase as an intracellular target of BAP showed that antimicrobial activity is dramatically enhanced in combination with several established antibiotic classes. These results indicate that BAP has the potential to be further developed as a broad spectrum antibiotic. With antibiotic resistance on the rise, this could have great impact in the treatment of resistant bacterial infections. In addition to mechanistic studies of E. coli DXP synthase, initial studies were carried out to understand the mechanism of the M. tuberculosis enzyme (Dxs1), as homology modeling (Jürgen Bosch, Ph.D.) suggested differences in the active site of Dxs1 compared to enzymes from E. coli and D. radiodurans. Mutagenesis and inhibition studies performed during the course of this research demonstrate interesting differences in the active site of Dxs1 near the cofactor binding site. This is an important consideration for inhibitor development and will contribute to the efforts of those in the field targeting DXP synthase. DXP reductoisomerase (IspC), the second enzyme in the pathway, was also targeted. In order to overcome poor pharmacokinetics of fosmidomycin, N-acetyl fosfoxacin analogs and a FR900098 phosphonamidate prodrug were biochemically evaluated as inhibitors of E. coli IspC. Acetohydroxamic acid (AHA) exhibited enhanced activity against IspC in the presence of phosphate. The activated FR900098 phosphonamidate prodrug also exhibited inhibitory activity against IspC, and displayed anti-parasitic activity against P. falciuparum comparable to fosmidomycin

Components and principles of a pediatric palliative care consultation: results of a Delphi study

Background: Pediatric palliative care is a distinct specialty that requires input from pediatric and palliative medicine specialists to provide comprehensive high-quality care. Consultations undertaken early in a child's illness trajectory, when end-of-life care is not anticipated to be required, enables relationships to be established and may enhance the quality of care provided

Piecewise continuous partition function method in the theory of wave perturbations of inhomogeneous gas

The problem of wave disturbance propagation in rarefied gas in gravity field is explored. The system of hydrodynamic-type equations for a stratified gas in gravity field is derived from BGK equation by method of piecewise continuous partition function. The obtained system of the equations generalizes the Navier-Stokes at arbitrary density (Knudsen numbers). The verification of the model is made for a limiting case of a homogeneous medium. Results are in the good agreement with experiment and former theories at arbitrary Knudsen numbers.Comment: 12 pages, 5 figure

Piecewise continuous distribution function method: Fluid equations and wave disturbances at stratified gas

Wave disturbances of a stratified gas are studied. The description is built on a basis of the Bhatnagar -- Gross -- Krook (BGK) kinetic equation which is reduced down the level of fluid mechanics. The double momenta set is introduced inside a scheme of iterations of the equations operators, dividing the velocity space along and opposite gravity field direction. At both half-spaces the local equilibrium is supposed. As the result, the momenta system is derived. It reproduce Navier-Stokes and Barnett equations at the first and second order in high collision frequencies. The homogeneous background limit gives the known results obtained by direct kinetics applications by Loyalka and Cheng as the recent higher momentum fluid mechanics results of Chen, Rao and Spiegel. The ground state declines from exponential at the Knudsen regime. The WKB solutions for ultrasound in exponentially stratified medium are constructed in explicit form, evaluated and plotted.Comment: 20 pages, 7 figures, 14 ISNA conference, 199

MicroRNA Function in Human Diseases

MicroRNAs are emerging as a hot topic in research, and rightfully so. They show great promise as targets of treatment and as markers for common human diseases, such as cancer and metabolic diseases. In this review, we address some of the basic questions regarding micro- RNA function in human disease and the clinical significance of microRNAs. Specifically, micro- RNAs in epigenetics, cancer, and metabolic diseases are discussed, with examples taken from cholangiocarcinoma and nonalcoholic fatty liver disease

MicroRNA Function in Human Diseases

MicroRNAs are emerging as a hot topic in research, and rightfully so. They show great promise as targets of treatment and as markers for common human diseases, such as cancer and metabolic diseases. In this review, we address some of the basic questions regarding micro- RNA function in human disease and the clinical significance of microRNAs. Specifically, micro- RNAs in epigenetics, cancer, and metabolic diseases are discussed, with examples taken from cholangiocarcinoma and nonalcoholic fatty liver disease

A Further Study of the Inertia of the Electric Carrier in Copper

Nature of the experiments.—An apparatus similar to that of Tolman, Karrer and Guernsey, in which a copper cylinder is oscillated around its axis and the current due to the lag of the electrons in the cylinder detected by means of a secondary of many turns of fine wire connected through an amplifier with a tuned vibration galvanometer, has been used for a further study of the inertia of the electric carrier in metals. The method has been improved, among other ways by arranging to measure the direction, phase, and magnitude of the alternating current produced by the acceleration instead of merely determining the amplitude of the effect, as was done in the earlier experiments. The null method of balancing out the electromotive force of interest, introduced for this purpose, also had the advantage of eliminating the previous uncertain correction for the "zero effect." A thorough study of the effect of the earth's field on the moving cylinder was also made, which has not been previously done. Results.—The effect of the earth's field in inducing currents in the moving apparatus was found to be in accord with that theoretically predicted, and it was satisfactorily demonstrated that this effect is eliminated when the cylinder is set parallel to the field and the coil set parallel to the cylinder. The final best value for the electromotive force produced by the acceleration was found to have an amplitude 19% less and a phase lagging 10° behind that predicted on the basis of an elementary theory which assumes a perfectly rigid conductor with "free" conducting electrons having the same mass as electrons in free space. It is not certain whether this discrepancy is due to errors still present in the experimental work, or due to the over simplification introduced in the deduction of the elementary theory. The results are presumably more reliable than those of Tolman, Karrer and Guernsey which gave an amplitude 8% lower than the predicted, using the same apparatus in a less satisfactory form. The results should also be compared with those of Tolman and Stewart who measured the pulse of current produced by suddenly stopping a coil of wire rotating around its axis, and found values about 15% greater than the predicted. A possible source of error in their experiments, due to interaction between metal and insulation, was discovered in the present work, but it may be that there is a real difference in the effective mass of the carrier in the two kinds of experiment. It is believed that the present work demonstrates more satisfactorily than ever before the actual existence of an electromotive force due to the inertia of the electrons in an accelerated metallic conductor