gebhart/patrepeval huggingface dataset:
Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance (2019)

Drug resistance continues to be a growing global problem. The efficacy of small molecule inhibitors is threatened by pools of genetic diversity in all systems, including antibacterials, antifungals, cancer therapeutics, and antivirals. Resistant variants often include combinations of active site mutations and distal "secondary" mutations, which are thought to compensate for losses in enzymatic activity. HIV-1 protease is the ideal model system to investigate these combinations and underlying molecular mechanisms of resistance. Darunavir (DRV) binds wild-type (WT) HIV-1 protease with a potency of <5 pM, but we have identified a protease variant that loses potency to DRV 150 000-fold, with 11 mutations in and outside the active site. To elucidate the roles of these mutations in DRV resistance, we used a multidisciplinary approach, combining enzymatic assays, crystallography, and molecular dynamics simulations. Analysis of protease variants with 1, 2, 4, 8, 9, 10, and 11 mutations showed that the primary active site mutations caused ∼50-fold loss in potency (2 mutations), while distal mutations outside the active site further decreased DRV potency from 13 nM (8 mutations) to 0.76 μM (11 mutations). Crystal structures and simulations revealed that distal mutations induce subtle changes that are dynamically propagated through the protease. Our results reveal that changes remote from the active site directly and dramatically impact the potency of the inhibitor. Moreover, we find interdependent effects of mutations in conferring high levels of resistance. These mechanisms of resistance are likely applicable to many other quickly evolving drug targets, and the insights may have implications for the design of more robust inhibitors.
A 3 GHz Wideband $\Sigma \Delta$ Fractional-N Synthesizer With Switched-RC Sample-and-Hold PFD (2011)

Designing high linearity phase-frequency-detectors (PFDs) in low-voltage, deep submicrometer processes is a challenging problem. Nonlinear PFDs can fold out of band phase noise, and increase in-band phase noise of fractional-N PLLs in deep submicron processes. A 3-GHz Type-I ΣΔ fractional-N PLL with an exponentially settling voltage-mode switched-RC phase frequency detector (PFD) is presented. A voltage-mode, fully settled switched-RC (SRC)-based sample-and-hold PFD, providing benefits of both an RC loop-filter and a zero-order hold sinc( ) suppressing reference clock leakage is presented. The exponentially settled SRC PFD is shown to reduce the in-band leakage of quantization noise by 13 dB in comparison to a similar current-mode charge pump PFD, enabling a measured loop-bandwidth of 890-kHz. The fractional-N PLL is fabricated in a 180-nm CMOS technology with 6 metal layers and consumes 18-mA from a 1.8-V power supply. The worst-case near-integer in-band spur is measured at -62 dBc. The measured in-band phase noise at 100-kHz offset from the 3-GHz carrier is -107 dBc/Hz and out-of-band phase noise at 3-MHz offset is -130 dBc/Hz. The phase-locked loop settling time for a frequency step of 45-MHz and 0.1-ppm accuracy is less than 10-μs.
Improved Intrinsic Motion Detection Using Time-of-Flight PET (2015)

Intrinsic or data-driven respiratory and cardiac motion detection often track the center-of-mass (COM) change in PET data to derive a motion gating signal. The effectiveness of this method depends on the contrast of the moving target to the relatively stationary background. The stationary background leads to a reduced COM displacement in PET data. Further, the COM calculated using axially truncated PET data is biased. To improve intrinsic motion detection for motion compensated image reconstruction, we use the time-of-flight (TOF) PET data of the original object f(x) to calculate the non-TOF PET data of a volume-of-interest (VOI) weighted object f(x)w(x) . The VOI-weighting w(x) can be chosen to reduce contribution from the stationary background. The reduced background in f(x)w(x) leads to an observed increase in the COM displacement. We also derive rebinning equations to obtain the exact axial COM using axially truncated PET data. To assess the quality of the motion gating signal, we analyze the variance property of the COM using different methods, including with(out) VOI weighting and with(out) compensation for axial data truncation. Analytical simulations, phantom and patient data demonstrate the effectiveness of the proposed approach in identifying the motion phase and in deriving a gating signal to be used for motion-compensated image reconstruction.
Electromagnetic and thermal analysis of distributed cooled high power millimeter wave windows (1996)

The sectional high‐frequency internally‐cooled window, as proposed by General Atomics(1), has unique potential for allowing microwave sources to reach multi‐megawatt CW levels with application to ECRH. Designs are being investigated using computational electromagnetic (EM), thermal, and mechanical codes at 110 GHz and 170 GHz to examine the design tradeoffs between RF performance and thermal mechanical safety margins. The EM analyses are for the window, under vacuum at one MW and includes variations in the shapes of the cooling fins, the surface treatment of the window elements themselves, the cooling fin tip treatment, the window pitch angle, and the waveguide effects. One advantage of the distributed cooled window is it’s extensibility to higher power levels. Results in the modeling efforts are presented showing the EM field concentrations (which then will feed into the thermal analysis), the energy scattering/reflection, the transmitted launch angle variation as a function of physical geometry, and the spatial energy distribution and loss as a function of time and position.
Surface reactivity of zeolites type H-Y and Na-Y with methanol (1977)

The surface reactions of methanol with zeolites type H-Y and Na-Y, between 20 and 350°C, were studied by infrared spectroscopy, gas liquid chromatography, adsorption isotherms and thermo-gravimetric techniques.At room temperature methanol is physically adsorbed on both zeolites. In the case of zeolite H-Y the adsorption occurs via hydrogen bonds between the OH-groups of the methanol molecules and the surface hydroxyl groups and the structural oxygen atoms of the zeolite. At 20°C, a part of the surface hydroxyl groups reacts with the methanol molecules, initiating the methoxylation of the surface, according to the scheme Si—OH + CH3OH →SiOCH3+ H2O. This esterification of the silanol groups is enhanced as the temperature increases, and reaches a maximum at ∼130°C. Above 120°C a new reaction of the surface methoxyl groups with methanol occurs, with formation of dimethylether. The production of dimethylether reaches its maximum at 210°C. Around 250°C, secondary reactions forming gaseous cracking products, predominantly butane and propene, were detected. In the temperature range studied no chemical reaction of methanol with the surface of the dehydrated Na-Y was observed. Therefore, it is concluded that the surface activity of the zeolite H-Y in dehydration of methanol is mainly due to the high Brönsted acidic character of its surface. The analysis of the methoxylation reaction in terms of surface diffusion of the methanol molecules, and of the proton exchange frequency between adsorbed methanol molecules and the zeolite surface, shows that the lifetime of the protonated CH3OH+2 molecule is the rate controlling factor of the methoxylation process.
Cocaine Intoxication in a Breast-Fed Infant (1987)

A case report of a 2-week-old infant girl who ingested cocaine via her mother's breast milk is presented. Because of the increasing prevalence of cocaine use, physicians should educate breast-feeding women concerning the hazards of cocaine use and its potential effects on the developing infant.
HMG-CoA Reductase Inhibitors (Statins) Reduce Hypertrophic Scar Formation in a Rabbit Ear Wounding Model (2012)

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors reduce hypertrophic scar formation by means of CTGF inhibition when administered at low doses, and the novel application of these commonly prescribed medications may lead to innovative and effective antiscarring therapies.
Lasso peptides: structure, function, biosynthesis, and engineering (2012)

Lasso peptides are a class of ribosomally-synthesized and posttranslationally-modified natural products with diverse bioactivities. This review describes the structure and function of all known lasso peptides (as of mid-2012) and covers our current knowledge about the biosynthesis of those molecules. The isolation and characterization of lasso peptides are also covered as are bioinformatics strategies for the discovery of new lasso peptides from genomic sequence data. Several studies on the engineering of new or improved function into lasso peptides are highlighted, and unanswered questions in the field are also described.
A new genus and species of the tribe Labenini from Australia (Pimplinae, Ichneumonidae) (1955)

(Uploaded by Plazi from the Biodiversity Heritage Library) No abstract provided.
Multiscale Finite Volume Methods: Extension to Unstructured Grids with Applications in Reservoir Simulation (2012)

In reservoir simulations, one of the biggest challenges is solving large modelswith complex geological properties. Because reservoirs can be several kilome-ters long, and still be geologically inhomogeneous over centimeters, the com-putational power required to solve a full set of mass balance equations can beimmense. Several methods for overcoming this challenge has been proposed,including various upscaling and multiscale methods.One of these approaches is the Multiscale Finite Volume (MsFV) method, whichaims to create a set of basis functions for the pressure which can be computedin parallel and reused for different boundary conditions. This thesis aims togive a thorough study of the MsFV-method itself, before extending it to threedimensional, unstructured grids. An implementation was done as a modulefor the MATLAB Reservoir Simulation Toolbox developed by SINTEF AppliedMathematics. A new variant of the method designed to overcome some of thecomputational challenges arising from an extension to 3D was also formulated.The implementation was then applied to both synthetic and realistic gridsand permeabilities, and compared against a full two point flux approximation(TPFA) solver.
Magnetic nanographite: an approach to molecular magnetism (2005)

Nanographene, defined as a nano-sized two-dimensional hexagonal network of π-electron systems, has an edge-inherited non-bonding π-state, which results in unconventional nanomagnetic properties, such as spin glass states, magnetic switching, and edge-state spin gas probing. Nanographene is expected to provide important ‘ingredients’ for molecular spintronics, as a large variety of magnetic functions can be produced by chemically modifying its edges.
Edge-oriented spatial filtering of images with application to post-processing of vector quantized images (2005)

An important application of spatial filtering techniques is in the post-processing-of images degraded by coding. Linear post-processing methods are inadequate to reduce the degradations in block-coded images. In this paper, a new nonlinear, space-variant filtering algorithm is proposed, which sharpens jagged edges without blurring them, and smoothes out small abrupt changes in the grey-level in monotone areas. It is not much more complex to implement than simple linear filtering. We show that this kind of post-processing significantly reduces the subjective effects of quantization noise in decoded images with almost no degradation of the signal.
DNA Fingerprinting of<i>Mycobacterium tuberculosis</i>: Lessons Learned and Implications for the Future (2002)

DNA fingerprinting of Mycobacterium tuberculosis--a relatively new laboratory technique--offers promise as a powerful aid in the prevention and control of tuberculosis (TB). Established in 1996 by the Centers for Disease Control and Prevention (CDC), the National Tuberculosis Genotyping and Surveillance Network was a 5-year prospective, population-based study of DNA fingerprinting conducted from 1996 to 2000. The data from this study suggest multiple molecular epidemiologic and program management uses for DNA fingerprinting in TB public health practice. From these data, we also gain a clearer understanding of the overall diversity of M. tuberculosis strains as well as the presence of endemic strains in the United States. We summarize the key findings and the impact that DNA fingerprinting may have on future approaches to TB control. Although challenges and limitations to the use of DNA fingerprinting exist, the widespread implementation of the technique into routine TB prevention and control practices appears scientifically justified.
Distributed beat length measurement in single-mode optical fibers using stimulated Brillouin-scattering and frequency-domain analysis (2000)

We present a method for distributed measurement of beat length, differential group delay, strain, and temperature in long length single-mode optical fibers. Toward this aim, we employ the polarization state sensitive effect of stimulated Brillouin scattering (SBS). The distributed measurement is realized by applying frequency-domain analysis. We present the analytical relationships between the Brillouin interaction of two counterpropagating waves in the fiber and the polarization states. Experimental results confirm the ability of the method to measure distributed beat length.
Disruption of<i>N</i>-Linked Glycosylation of Bovine Luteinizing Hormone β-Subunit by Site-Directed Mutagenesis Dramatically Increases Its Intracellular Stability But Does Not Affect Biological Activity of the Secreted Heterodimer (1989)

The single site for N-linked glycosylation of the beta-subunit of bovine LH (LH beta) was disrupted by oligonucleotide-directed mutagenesis to assess its potential roles in the biosynthesis, transport, and hormonal activity of the LH alpha/beta heterodimer. Pulsechase studies performed with stably transfected Chinese hamster ovary cells that expressed both alpha-subunit (fully glycosylated) and nonglycosylated LH beta revealed that turnover, transport, and secretion of newly synthesized, nonglycosylated LH beta were effectively blocked over a 22-h span. Free nonglycosylated LH beta, like free wild-type LH beta, was sequestered inside the cell; therefore, the intracellular retention of uncombined LH beta-subunit is not due to a signal located within the N-glycan moiety. Nevertheless, an older pool of unlabeled, nonglycosylated LH beta-subunit was available for combination with newly synthesized alpha-subunit, as verified by immunoprecipitation of radiolabeled alpha-subunit from cell lysates and culture medium with anti-LH beta-antiserum. This heterodimer displayed normal kinetics of secretion (t 1/2 = 2.4 h) as compared to fully glycosylated LH (t 1/2 = 2.1 h). The wild-type and mutant forms of LH were also purified from culture supernatants of the two cell lines, and were compared for their relative abilities to stimulate progesterone secretion in cultured rat Leydig cells. Both proteins displayed similar potency (ED50 = 32 vs. 41 ng/ml, respectively) and maximal stimulation of progesterone release Pmax = 2.7 vs 2.5 micrograms/ml), indicating that N-linked glycosylation of the LH beta-subunit does not play a significant role in LH signal transduction. Collectively, these results indicate that N-linked glycosylation is important for intracellular degradation of free LH beta, but is not essential for either its assembly with alpha-subunit or the transport and secretion of biologically active heterodimer.
Microtubules: A dynamic target in cancer therapy (2008)

The tubulin/microtubule system is an important target for anticancer therapy. Two of the most clinically valuable groups of these agents are the vinca alkaloids and taxanes. In recent years, new tubulin-binding agents have been under preclinical or clinical development. One of these classes of agents, epothilones, has shown great promise in phase III clinical trials. What all these agents share in common, is that they bind to beta-tubulin and disrupt microtubule function during mitosis which in turn leads to mitotic arrest and cell death. In addition, these agents can inhibit angiogenesis. Not withstanding their effectiveness, drug resistance can pose a major clinical problem. This review provides an overview of the mechanisms mediating resistance to tubulin-binding agents related to the cellular target and discusses strategies to overcome this important clinical problem.
El español en el actual debate del régimen lingüístico en las instituciones europeas (2003)

La próxima ampliación de la Unión Europea a los países de Europa Central y Oriental hace necesario que se encuentre una solución al problema logístico y presupuestario que supone el paso de 11 a 20 lenguas oficiales en la UE, especialmente para la interpretación en las reuniones en las que participan representantes de los Estados miembros.\n\nÉste es un asunto fundamental para España. La discusión de esta cuestión presenta una oportunidad para consagrar al español como lengua de trabajo y lengua “pivote” en la UE (las que se utilizan como intermediarias en la interpretación de otras dos lenguas); pero también la amenaza de que la solución que se adopte ahora pueda relegar a nuestra lengua a un segundo plano en la Unión ampliada. El peligro fundamental al que nos enfrentamos es que se consagre en las instituciones de la Unión Europea un régimen limitado de “lenguas de trabajo” que no incluya al español. Por ello, se hace necesaria una acción decidida, sistemática y concertada de todos los órganos de administración española implicados en las relaciones con las instituciones europeas y en la promoción de la lengua española.
Minimum Porosity Formation in Pressure Die Casting by Taguchi Method (2013)

Die casting process is significantly used in the industry for its high productivity and less postmachining requirement. Due to light weight and good formability, aluminum die casting plays an important role in the production of transportation and vehicle components. In the current study of die casting for Automobile starter motor casing, the following issues are focused: shot piston simulation, defect analysis, and, finally, the use of the Taguchi multiquality analytical method to find the optimal parameters and factors to increase the aluminium ADC10 die casting quality and efficiency. Experiments were conducted by varying molten alloy temperature, die temperature, plunger velocities in the first and second stage, and multiplied pressure in the third stage using L<sub>27</sub> orthogonal array of Taguchi method. After conducting a series of initial experiments in a controlled environment, significant factors for pressure die casting processes are selected to construct an appropriate multivariable linear regression analysis model for developing a robust performance for pressure die casting processes. The appropriate multivariable linear model is a useful and efficient method to find the optimal process conditions in pressure die casting associated with the minimum shrinkage porosity percent.
Le rôle de la frontière dans un problème elliptique avec non-linéarité critique et conditions au bord de Neumann (1994)

Séminaire EDP de l'École polytechnique, 1993-1994
Novel Agents and Approaches for Advanced Renal Cell Carcinoma (2012)

Although many agents are approved or in development for renal cell carcinoma, comparative effectiveness data are lacking. Ongoing and future head-to-head trials using appropriate comparators are essential to update renal cell carcinoma treatment guidelines. Future research should be aimed at identifying agents that improve patient outcomes and have decreased toxicity compared with currently approved agents with the goal of complete remission.
MuCor: mutation aggregation and correlation (2016)

james.blachly@osumc.eduSupplementary data: Supplementary data are available at Bioinformatics online.
Hypotensive activity and toxicology of constituents from root bark ofPolyalthia longifolia var.pendula (2005)

A defatted extract of Polyalthia longifolia var. pendula root bark (PRB) in 50% methanol showed a significant ability to reduce blood pressure. It caused a 22% and 47% fall in mean arterial blood pressure (MABP) in rats at doses of 3 mg/kg and 30 mg/kg, respectively. Compounds purified from this extract include kolavenic acid (3), clerodane (1) and its isomer (2), liriodenine (4), lysicamine (5) and bisclerodane imide (6) and its isomer (7). Of these, only kolavenic acid produced a 22% fall in MABP, at a dose of 30 mg/kg. PRB showed a decrease in blood pressure of normotensive and egg yolk induced hypertensive rats. The LD50 of PRB was determined as 100 mg/kg in mice.
The genetic diversity of cacao and its utilization (2005)

The Terminology Specific to Cacao The Indicators of Variability The Manifestation of the Diversity and its Conservation The Foundations of the Diversity The Cultivated Populations as Secondary Depositories of the Diversity The Genetics of the Diversity The Relationships among Populations The Utilization of the Genetic Resources
CONTINUING INCREASES IN SEXUAL RISK BEHAVIOR AND SEXUALLY TRANSMITTED DISEASES AMONG MEN WHO HAVE SEX WITH MEN: SAN FRANCISCO, CALIF, 1999–2001 (2002)

We recently reported on worrisome increases in sexual risk behavior, sexually transmitted diseases (STDs), and HIV incidence among men who have sex with men (MSM) during a period of increasing use of highly active antiretroviral therapy (HAART), from 1994 to 1999.1 We have since obtained data on sexual risk behavior for 2000 and 2001. In addition, we have added to our surveys questions on whether unsafe sex was occurring with partners of unknown HIV serostatus, updated trends in male rectal gonorrhea, and provided data on primary and secondary syphilis cases among MSM.

As previously reported, the Stop AIDS Project conducts serial cross-sectional surveys of MSM in a variety of community settings in the course of outreach health education. The street-based intercept survey asks questions about sexual behavior in the preceding 6 months, including anal sex, condom use, number of sexual partners, and knowledge of partners’ HIV serostatus.

Overall, 10 568 MSM completed the survey between 1999 and 2001. The proportion of MSM reporting any anal sex in the last 6 months increased from 67% in 1999 to 74% in 2001 (Figure 1a ▶). The proportion of respondents reporting any unprotected anal sex increased from 32% to 38%, with a parallel increase from 18% to 23% in the proportion reporting unprotected anal sex with 2 or more partners (Figure 1b ▶). Between 1999 and 2001, the proportion reporting unprotected anal sex with 2 or more partners of unknown HIV serostatus increased from 10% to 15% for respondents who reported being HIV-negative and from 19% to 25% for those who said they were HIV-positive (Figure 1c ▶). Although a decline in the number of respondents was noted from 1999 to 2001, there were no substantial shifts in respondents’ age or race over time and no differences in trends in sexual risk behavior within demographic groups.



FIGURE 1

—Trends in sexual risk behavior and sexually transmitted diseases among men who have sex with men: San Francisco, Calif, 1999–2001.



STD surveillance data corroborate continued increases in sexual risk behavior. Reported cases of male rectal gonorrhea increased from 162 in 1999 (updated from 160 in our prior report1 owing to delays in reporting) to 237 in 2001 (Figure 1d ▶). The number of primary and secondary syphilis cases among MSM increased from only 6 cases in 1998 to 115 cases in 2001.

We conclude that the increases in unsafe sex seen from 1994 to 1999, in association with the availability of HAART, were not isolated but rather reflect an ongoing trend. Moreover, data on HIV serostatus of partners suggest that much of this unsafe sex is occurring among partners who are serodiscordant.