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Bifunctional thrombin inhibitors based on the sequence of hirudin45-65.

The interaction of alpha-thrombin with the hirudin (HV1) fragment N alpha-acetyl desulfo hirudin45-65 (P51) was investigated. Kinetic analysis revealed that P51 inhibits the proteolysis of a tripeptidyl substrate with Ki = 0.72 +/- 0.13 and 0.11 +/- 0.03 microM for bovine and human alpha-thrombins, respectively. The inhibition was partially competitive, affecting substrate binding to the enzyme-inhibitor complex by a factor alpha = 2 (bovine) and alpha = 4 (human) characteristic of hyperbolic inhibitors. P51 also inhibited thrombin-induced fibrin clot formation with IC50 values of 0.94 +/- 0.20 and 0.058 +/- 0.006 microM for bovine and human alpha-thrombins, respectively. The enhanced antithrombin activity for human thrombin could be attributed to species variations in the putative auxiliary "anion" exosite since N alpha-acetyl desulfo hirudin55-65 displayed the same rank order of potency shift in a clotting assay without inhibiting the amidolytic activity of either enzyme. From these observations, a potent thrombin inhibitor was designed having modified residues corresponding to the P1 and P3 recognition sites. N alpha-Acetyl[D-Phe45, Arg47] hirudin45-65 (P53) emerged as a pure competitive inhibitor with a Ki = 2.8 +/- 0.9 nM and IC50 = 4.0 +/- 0.8 nM (human alpha-thrombin) and is designated as a "bifunctional" inhibitor. Its enhanced potency could be explained by a cooperative intramolecular interaction between the COOH-terminal domain of the inhibitor and the auxiliary exosite of thrombin on the one hand, and the modified NH2-terminal residues with the catalytic site on the other

Rate-dependent propagation of cardiac action potentials in a one-dimensional fiber

Action potential duration (APD) restitution, which relates APD to the preceding diastolic interval (DI), is a useful tool for predicting the onset of abnormal cardiac rhythms. However, it is known that different pacing protocols lead to different APD restitution curves (RCs). This phenomenon, known as APD rate-dependence, is a consequence of memory in the tissue. In addition to APD restitution, conduction velocity restitution also plays an important role in the spatiotemporal dynamics of cardiac tissue. We present new results concerning rate-dependent restitution in the velocity of propagating action potentials in a one-dimensional fiber. Our numerical simulations show that, independent of the amount of memory in the tissue, waveback velocity exhibits pronounced rate-dependence and the wavefront velocity does not. Moreover, the discrepancy between waveback velocity RCs is most significant for small DI. We provide an analytical explanation of these results, using a system of coupled maps to relate the wavefront and waveback velocities. Our calculations show that waveback velocity rate-dependence is due to APD restitution, not memory.Comment: 17 pages, 7 figure

Turnip mosaic potyvirus probably first spread to Eurasian brassica crops from wild orchids about 1000 years ago

Turnip mosaic potyvirus (TuMV) is probably the most widespread and damaging virus that infects cultivated brassicas worldwide. Previous work has indicated that the virus originated in western Eurasia, with all of its closest relatives being viruses of monocotyledonous plants. Here we report that we have identified a sister lineage of TuMV-like potyviruses (TuMV-OM) from European orchids. The isolates of TuMV-OM form a monophyletic sister lineage to the brassica-infecting TuMVs (TuMV-BIs), and are nested within a clade of monocotyledon-infecting viruses. Extensive host-range tests showed that all of the TuMV-OMs are biologically similar to, but distinct from, TuMV-BIs and do not readily infect brassicas. We conclude that it is more likely that TuMV evolved from a TuMV-OM-like ancestor than the reverse. We did Bayesian coalescent analyses using a combination of novel and published sequence data from four TuMV genes [helper component-proteinase protein (HC-Pro), protein 3(P3), nuclear inclusion b protein (NIb), and coat protein (CP)]. Three genes (HC-Pro, P3, and NIb), but not the CP gene, gave results indicating that the TuMV-BI viruses diverged from TuMV-OMs around 1000 years ago. Only 150 years later, the four lineages of the present global population of TuMV-BIs diverged from one another. These dates are congruent with historical records of the spread of agriculture in Western Europe. From about 1200 years ago, there was a warming of the climate, and agriculture and the human population of the region greatly increased. Farming replaced woodlands, fostering viruses and aphid vectors that could invade the crops, which included several brassica cultivars and weeds. Later, starting 500 years ago, inter-continental maritime trade probably spread the TuMV-BIs to the remainder of the world

A Pilot Study of Urokinase-Type Plasminogen Activator (uPA) Overexpression in the Brush Cytology of Patients with Malignant Pancreatic or Biliary Strictures

We have previously demonstrated that uPA is overexpressed in pancreatic tumors. In an attempt to diagnose these tumors earlier, we sought to determine whether uPA could be identified in endoscopic retrograde cholangiopancreatography obtained brushings in patients with malignant pancreatic and biliary strictures. Secondarily, uPA was measured in the serum of this patient population. uPA overexpression was identified in the cytologic tissue in 8 of 11 patients (72.7%). Serum analysis demonstrated a 2-fold higher concentration of uPA in the pancreaticobiliary cancer patients (1.27 versus 0.56 ng/mL; P = .0182). Also, uPA overexpression correlated with serum levels (P < .0001). This study confirms that uPA can be detected in the ERCP cytologically obtained tissue and is frequently present in a higher concentration in the serum of pancreaticobiliary cancer patients. A larger sample size will be required to address its value as a sensitive marker for the diagnosis of pancreatic or biliary cancers

Energy Expenditure and Enjoyment of Active Television Viewing

International Journal of Exercise Science 9(1): 64-76, 2016. This study examined energy expenditure and enjoyment during sedentary television viewing (SED-TV), stepping in place during television commercials (COMM-TV), and physical activity prompted by common character phrases/mannerisms within a television program (PA-TV). Adults (N=38, age: 27.0±8.0 years, BMI: 25.4±4.2 kg/m2) completed three 30-minute sessions in random order: SED-TV, COMM-TV, and PA-TV. Energy expenditure and heart rate were assessed during each session. Enjoyment was assessed after the initial experimental session and at completion of the study. Energy expenditure was greater in the active versus sedentary sessions (COMM-TV vs SED-TV: difference = 32.7±1.9 kcal, p3.0 METS was lower in SED-TV (median = 0 minutes) compared to COMM-TV [median = 4.0 minutes (Inter-Quartile Range: 0.8, 7.3)] (p50% of age-predicted maximal heart rate. Both COMM-TV and PA-TV were reported to be significantly more enjoyable than SED-TV. COMM-TV and PA-TV resulted in higher energy expenditure, more minutes of moderate intensity physical activity, and higher reported enjoyment compared to SED-TV. These findings have implications for reducing sedentary time during television viewing, which may impact health-related outcomes. Intervention trials are warranted to determine the effectiveness of these strategies

Pilot Feasibility Study of a Campaign Intervention for Weight Loss among Overweight and Obese Adults

Background: Behavioral interventions produce significant short-term weight loss. However, these interventions typically require regular in-person sessions, which may not be feasible for all individuals. Purpose: The purpose of this pilot study was to evaluate the feasibility of a 12-week campaign intervention (CI) compared to a standard on-site, group-based behavioral weight loss intervention (SBWL) among overweight/obese adults. Methods: SBWL participants (n=13; age: 42.5 ± 9.1 years; BMI: 33.4 ± 3.8 kg/m²) attended weekly group meetings, were prescribed a daily reduced caloric goal and 200 minutes of moderate-intensity physical activity per week. CI participants (n=13; age: 43.8 ± 9.0 years; BMI: 33.2 ± 3.8 kg/m²) received the same recommendations as the SBWL, attended in-person group meetings at weeks 0 and 12, and received e-mail messages weeks 2-11. Additional CI features included a thematic framework and an incentive-based point system targeting behavioral goals. Results: Significant weight loss was demonstrated for intention-to-treat (SBWL: -5.6 ± 2.9 kg; CI: -3.1 ± 3.4 kg) (

Pathologies of Quenched Lattice QCD at non--zero Density and its Effective Potential

We simulate lattice QCD at non--zero baryon density and zero temperature in the quenched approximation, both in the scaling region and in the infinite coupling limit. We investigate the nature of the forbidden region -- the range of chemical potential where the simulations grow prohibitively expensive, and the results, when available, are puzzling if not unphysical. At weak coupling we have explored the sensitivity of these pathologies to the lattice size, and found that using a large lattice ($64 \times 16^3$) does not remove them. The effective potential sheds considerable light on the problems in the simulations, and gives a clear interpretation of the forbidden region. The strong coupling simulations were particularly illuminating on this point.Comment: 49 pages, uu-encoded expanding to postscript;also available at ftp://hlrz36.hlrz.kfa-juelich.de/pub/mpl/hlrz72_95.p

The Chandra Source Catalog

The Chandra Source Catalog (CSC) is a general purpose virtual X-ray astrophysics facility that provides access to a carefully selected set of generally useful quantities for individual X-ray sources, and is designed to satisfy the needs of a broad-based group of scientists, including those who may be less familiar with astronomical data analysis in the X-ray regime. The first release of the CSC includes information about 94,676 distinct X-ray sources detected in a subset of public ACIS imaging observations from roughly the first eight years of the Chandra mission. This release of the catalog includes point and compact sources with observed spatial extents <~ 30''. The catalog (1) provides access to the best estimates of the X-ray source properties for detected sources, with good scientific fidelity, and directly supports scientific analysis using the individual source data; (2) facilitates analysis of a wide range of statistical properties for classes of X-ray sources; and (3) provides efficient access to calibrated observational data and ancillary data products for individual X-ray sources, so that users can perform detailed further analysis using existing tools. The catalog includes real X-ray sources detected with flux estimates that are at least 3 times their estimated 1 sigma uncertainties in at least one energy band, while maintaining the number of spurious sources at a level of <~ 1 false source per field for a 100 ks observation. For each detected source, the CSC provides commonly tabulated quantities, including source position, extent, multi-band fluxes, hardness ratios, and variability statistics, derived from the observations in which the source is detected. In addition to these traditional catalog elements, for each X-ray source the CSC includes an extensive set of file-based data products that can be manipulated interactively.Comment: To appear in The Astrophysical Journal Supplement Series, 53 pages, 27 figure

Search for Ultra High Energy (UHE) γ-ray counterparts of BATSE 3B catalog events

We search for a Ultra High Energy (E>1014 eV)(E>1014eV) counterpart source to cosmic γ-ray bursts detected with the BATSE detectors. Using the 3B catalog positions, we examine 115 candidate bursts with the CASA-MIA detector for UHE γ-ray emission at or near the time of the observed γ-ray burst. No statistically significant excess of γ-rays is found from any of the candidate event regions. Based upon these results, we calculate the flux limits for UHE emission from these candidate event regions. Typical 95% confidence level flux limits are about 6×10−12 γ  cm−2 sec−16×10−12γcm−2sec−1 at a γ-ray detection threshold of 160 TeV. © 1996 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87368/2/598_1.pd