gebhart/patrepeval huggingface dataset:
Discovery of the First C-Nucleoside HCV Polymerase Inhibitor (GS-6620) with Demonstrated Antiviral Response in HCV Infected Patients (2013)

Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.
Clinical Methods for Monitoring Intracranial Pressure and Measuring Cerebral Blood Flow (1975)

Neurosurgery: January 1975 - Volume 22 - Issue - p 302-320 doi: 10.1093/neurosurgery/22.CN_suppl_1.302
A Comparison of Some Measures for the Determination of Inter‐Molecular Structural Similarity Measures of Inter‐Molecular Structural Similarity (1986)

Abstract Six weighting schemes and six similarity coefficients have been used in a systematic comparison of measures for the determination of inter‐molecular structural similarity. The effectiveness of the measures for molecular property prediction was tested using sixteen small sets of compounds for which property data was available. The comparison suggests that the weighting of fragments by their frequency of occurrence in molecules is often useful, but that there are only small differences in performance between the similarity coefficients tested.
Kalman Filter Engineering (2000)

Practical aspects of Kalman filtering applications are considered in this chapter, as follows: 1. how performance of the Kalman filter can degrade due to computer roundoff errors and alternative implementation methods with better robustness against roundoff; 2. how to determine computer memory, word length, and throughput requirements for implementing Kalman filters in computers; 3. ways to implement real-time monitoring and analysis of filter performance; 4. the Schmidt–Kalman suboptimal filter, designed for reducing computer requirements; 5. covariance analysis, which uses the Riccati equations for performance-based predictive design of sensor systems; and 6. Kalman filter architectures for GPS/INS integration.
A New Approach to Near-Infrared Spectral Data Analysis Using Independent Component Analysis (2001)

This paper presents a new approach to near-infrared spectral (NIR) data analysis that is based on independent component analysis (ICA). The main advantage of the new method is that it is able to separate the spectra of the constituent components from the spectra of their mixtures. The separation is a blind operation, since the constituent components of mixtures can be unknown. The ICA based method is therefore particularly useful in identifying the unknown components in a mixture as well as in estimating their concentrations. The approach is introduced by reference to case studies and compared to other techniques for NIR analysis including principal component regression (PCR), multiple linear regression (MLR), and partial least squares (PLS) as well as Fourier and wavelet transforms.
Making Negative Poisson’s Ratio Microstructures by Soft Lithography (1999)

Negative Poisson's ratio (NPR) materials—which shrink along one axis when compressed along an orthogonal one—are currently composed of reentrant cells with dimensions greater than 1 mm. The fabrication of NPR materials from various materials and in various cell geometries with dimensions in the micrometer range, for example the epoxy NPR material shown in the Figure, is described.
Indian Convict Workers in Southeast Asia in the Late Eighteenth and Early Nineteenth Centuries (2003)

South Asian convicts transported to Southeast Asia in the late eighteenth and early nineteenth centuries were part of a global system of forced migration. Together with slaves and bonded and indentured laborers, they helped settle and colonize the overseas European empires. No wonder, then, that recent writings have designated them as "convict workers," an emphasis that shifts attention away from their earlier characterization as "professional and habitual criminals" to highlight their actual lived experiences in the penal settlements. Indeed, Indian "convict workers" filled a critical need for labor in Southeast Asia, playing an especially significant role in carrying out the public works projects that were so essential to the establishment and consolidation of the British Empire in the region. This convict system came to an end in the late nineteenth century.
ZrOCl2·8H2O catalysts for the esterification of long chain aliphatic carboxylic acids and alcohols. The enhancement of catalytic performance by supporting on ordered mesoporous silica (2005)

ZrOCl2·8H2O is an efficient catalyst for the esterification of long chain carboxylic acids with long chain primary and secondary alcohols. Supporting ZrOCl2·8H2O on ordered mesoporous silica enhances the catalytic activity of the esterification. The esters of C10–C18 normal acid and alcohol are obtained in high yield by supported ZrOCl2·8H2O on MCM-41 although the yield of the esters decreases with the chain length of acids and alcohols. The esterification of less reactive branched acids and secondary alcohols gives excellent to good yield of the corresponding esters over supported catalysts. Zirconium cation cluster [Zr4(OH)8(H2O)16]8+ is suggested as the catalytic active species. The enhancement of catalytic performance by supporting on MCM-41 is due to increased contact between substrate and catalyst because the cation cluster is highly dispersed over MCM-41 with high surface area. The hydrophobic properties of mesoporous silica accelerate the removal of water during the esterification by controlling hydrated water in the cluster. The catalyst is recyclable without significant loss of activity.
Complement-Coagulation Cross-Talk: A Potential Mediator of the Physiological Activation of Complement by Low pH (2015)

The complement system is a major constituent of the innate immune system. It not only bridges innate and adaptive arms of the immune system but also links the immune system with the coagulation system. Current understanding of the role of complement has extended far beyond fighting of infections, and now encompasses maintenance of homeostasis, tissue regeneration, and pathophysiology of multiple diseases. It has been known for many years that complement activation is strongly pH sensitive, but only relatively recently has the physiological significance of this been appreciated. Most complement assays are carried out at the physiological pH 7.4. However, pH in some extracellular compartments, for example, renal tubular fluid in parts of the tubule, and extracellular fluid at inflammation loci, is sufficiently acidic to activate complement. The exact molecular mechanism of this activation is still unclear, but possible cross-talk between the contact system (intrinsic pathway) and complement may exist at low pH with subsequent complement activation. The current article reviews the published data on the effect of pH on the contact system and complement activity, the nature of the pH sensor molecules, and the clinical implications of these effects. Of particular interest is chronic kidney disease (CKD) accompanied by metabolic acidosis, in which therapeutic alkalinization of urine has been shown significantly to reduce tubular complement activation products, an effect, which may have important implications for slowing progression of CKD.
Multichannel digital TV distribution and local video networking (1988)

A new sampling technique for demultiplexing and channel selection is described with application to both CATV distribution systems and interactive video ring systems. Up to 32 channel capability has been demonstrated at 2.2 Gbit/s.
Citalopram-Induced Long QT Syndrome and the Mammalian Dive Reflex (2015)

While SCUBA diving, a 44-year-old Caucasian patient had an abnormal cardiac rhythm, presumably Torsade de Pointes (TdP), during the initial descent to depth. Upon surfacing, she developed ventricular fibrillation and died. The patient had been treated for mild depression for nearly a year with citalopram 60 mg per day, a drug known to cause prolonged QT interval. She had also been treated with two potentially hepatotoxic drugs. Liver impairment causes selective loss of cytochrome P450 (CYP) 2C19 activity, the major pathway for metabolism of citalopram. The post mortem blood level of citalopram was 1300 ng/mL. The patient was found to be an intermediate metabolizer via CYP2D6, the major pathway for metabolism of desmethylcitalopram; the level of which was also abnormally high. It is suggested that drug-induced long QT syndrome (DILQTS), caused by citalopram, combined with the mammalian dive reflex triggered malignant ventricular rhythms resulting in the patient's death. It is further suggested that, in general, the dive reflex increases the risk of fatal cardiac rhythms when the QT interval is prolonged by drugs.
A methodology for performing virtual measurements in a nuclear reactor system (1992)

A novel methodology is presented for monitoring nonphysically measurable variables in an experimental nuclear reactor. It is based on the employment of artificial neural networks to generate fuzzy values. Neural networks map spatiotemporal information (in the form of time series) to algebraically defined membership functions. The entire process can be thought of as a virtual measurement. Through such virtual measurements the values of nondirectly monitored parameters with operational significance, e.g., transient-type, valve-position, or performance, can be determined. Generating membership functions is a crucial step in the development and practical utilization of fuzzy reasoning, a computational approach that offers the advantage of describing the state of the system in a condensed, linguistic form, convenient for monitoring, diagnostics, and control algorithms.
Future Strategies in Immunotherapy (2003)

Abstract The following chapter discusses cutting edge, current, and future immunotherapeutic strategies. The first section reviews basic molecular and cellular components of the immune system. The second section emphasizes FDA‐approved humanized and chimeric antibodies for the treatment of cancer and rheumatoid arthritis including herceptin, rituxan, mylotarg, campath, remicade, and Enbrel, because these types of genetically engineered molecules represent the future of molecular medicine treatments. The function and significance of antibody targets are defined where possible. A brief description of clinical trial results and adverse drug reactions is provided for each humanized or chimeric antibody. Formulations of each antibody are also discussed where appropriate. Next, cutting edge strategies using dendritic cells pulsed with tumor associated peptides, tumor cell lysates, apoptotic tumor cells, tumor RNA, and tumor‐derived exosomes are also addressed. Transduction of DC with adenovirus and pox virus vectors is discussed along with ongoing clinical trials and exciting pre‐clinical developments of promising strategies. The chapter concludes with a summary of what must occur in the immunotherapy field for success in the near future.
AN INVESTIGATION ON THE FILMS USED AS THE WINDOWS OF ULTRA-SOFT X-RAY COUNTERS (1978)

This paper deals with the properties of films used as entrance window of a gas-flow type ultrasoft X-ray counter. The effects of the base material and conductive coatings of the films on performance characteristics of the counter are investigated. Experimental results show that, among the material under study, Formvar exhibits more satisfactory gas-sealing property and has higher transmissivity for X-rays. In addition, it is found that the conductive coating on the film has a significant effect on the stability of the measured intensity. An interpretation on these effects by taking into acounts of the feature of electron multiplication process in the counter caused by ultra-soft X-rays is proposed.
Bottlebrush Block Polymers: Quantitative Theory and Experiments (2015)

The self-assembly of bottlebrush block polymers into a lamellar phase was investigated using a combination of experiment and self-consistent field theory (SCFT). Nine diblock bottlebrush polymers were synthesized with atactic polypropylene side chains (block A) and polystyrene side chains (block B) attached to poly(norbornene) backbones of various contour lengths, L, and the resulting lamellar structures were analyzed using small-angle X-ray scattering. The scaling of the lamellar period, d0 ∼ L(γ), exhibited an increasing exponent from γ ≈ 0.3 at small L to γ ≈ 0.9 at large L. The small exponents occurred for starlike molecules where the size of the side chains is comparable to L, while the larger exponents occurred for the more brushlike molecules where the side chains extend radially outward from the backbone. The bottlebrushes were then modeled using flexible side chains of types A and B attached to a semiflexible backbone with an adjustable persistence length, ξb. The resulting SCFT predictions for d0 showed remarkable quantitative agreement with the experimental data, where ξb was similar to the radius of the bottlebrushes. The theory was then used to examine the joint-distribution functions for the position and orientation of different segments along the backbone. This revealed a bilayer arrangement of the bottlebrushes in the lamellar phase, with a high degree of backbone orientation at the A/B interfaces that almost completely vanished near the center of the domains. This finding clearly refutes the prevailing interpretation that the large scaling exponent γ is a result of highly extended backbone conformations.
Massively multiplex chemical transcriptomics at single-cell resolution (2019)

High-throughput chemical screens typically use coarse assays such as cell survival, limiting what can be learned about mechanisms of action, off-target effects, and heterogeneous responses. Here, we introduce "sci-Plex," which uses "nuclear hashing" to quantify global transcriptional responses to thousands of independent perturbations at single-cell resolution. As a proof of concept, we applied sci-Plex to screen three cancer cell lines exposed to 188 compounds. In total, we profiled ~650,000 single-cell transcriptomes across ~5000 independent samples in one experiment. Our results reveal substantial intercellular heterogeneity in response to specific compounds, commonalities in response to families of compounds, and insight into differential properties within families. In particular, our results with histone deacetylase inhibitors support the view that chromatin acts as an important reservoir of acetate in cancer cells.
IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy (2016)

IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN.
Gene locus FPD1 of the dystonic Mount-Reback type of autosomal-dominant paroxysmal choreoathetosis (1997)

Genes for paroxysmal choreoathetosis have been localized to chromosomes 1p and 2q. We have reinvestigated one of the classic large autosomal-dominant pedigrees of the dystonic Mount-Reback type of paroxysmal choreoathetosis 20 years after its first assessment. These patients prefer diazepam for both prevention and treatment of attacks and did not develop addiction on an intermittent regime. Migraine occurred in a third of the patients. Genetic data localized the underlying mutation to the FPD1 locus (familial paroxysmal dyskinesia type 1) on chromosome 2q and support locus homogeneity for the Mount-Reback syndrome. The data also refine the FPD1 candidate region to 3.6 cM between the markers D2S164 and D2S2359, which may facilitate the investigation of the role of the candidate ion channel gene SLC2C.
The dynamics of genomic-length DNA molecules in 100-nm channels (2004)

We show that genomic-length DNA molecules imaged in nanochannels have an extension along the channel that scales linearly with the contour length of the polymer, in agreement with the scaling arguments developed by de Gennes for self-avoiding confined polymers. This fundamental relationship allows us to measure directly the contour length of single DNA molecules confined in the channels, and the statistical analysis of the dynamics of the polymer in the nanochannel allows us to compute the SD of the mean of the extension. This statistical analysis allows us to measure the extension of lambda DNA multimers with a 130-nm SD in 1 min.
Synthesis and hybridization of a series of biotinylated oligonucleotides (1988)

A series of oligonucleotides containing biotin-11-dUMP at various positions were synthesized and compared in quantitative, colorimetric hybridization-detection studies. A deoxyuridine phosphoramidite containing a protected allylamino sidearm was synthesized and used in standard, automated synthesis cycles to prepare oligonucleotides with allylamino residues at various positions within a standard 17-base sequence. Biotin substituents were subsequently attached to the allylamino sidearms by reaction with N-biotinyl-6-aminocaproic acid N-hydroxysuccinimide ester. These oligomers were hybridized to target DNA immobilized on microtiter wells (ELISA plates), and were detected with a streptavidin-biotinylated horseradish peroxidase complex using hydrogen peroxide as substrate and o-phenylenediamine as chromogen. We found that the sensitivity of detection of target DNA by biotin-labeled oligonucleotide probes was strongly dependent upon the position of the biotin label. Oligonucleotides containing biotin labels near or off the ends of the hybridizing sequence were more effective probes than oligonucleotides containing internal biotin labels. An additive effect of increasing numbers of biotin-dUMP residues was found for some labeling configurations.
Bivalent recognition of nucleosomes by the tandem PHD fingers of the CHD4 ATPase is required for CHD4-mediated repression (2012)

CHD4 is a catalytic subunit of the NuRD (nucleosome remodeling and deacetylase) complex essential in transcriptional regulation, chromatin assembly and DNA damage repair. CHD4 contains tandem plant homeodomain (PHD) fingers connected by a short linker, the biological function of which remains unclear. Here we explore the combinatorial action of the CHD4 PHD1/2 fingers and detail the molecular basis for their association with chromatin. We found that PHD1/2 targets nucleosomes in a multivalent manner, concomitantly engaging two histone H3 tails. This robust synergistic interaction displaces HP1γ from pericentric sites, inducing changes in chromatin structure and leading to the dispersion of the heterochromatic mark H3K9me3. We demonstrate that recognition of the histone H3 tails by the PHD fingers is required for repressive activity of the CHD4/NuRD complex. Together, our data elucidate the molecular mechanism of multivalent association of the PHD fingers with chromatin and reveal their critical role in the regulation of CHD4 functions.
Two‐dimensional fluorescence difference gel electrophoresis analysis of the urine proteome in human diabetic nephropathy (2005)

Urinary proteins may provide clues regarding pathogenesis of kidney disease as well as providing markers of disease activity. We employed two-dimensional differential in-gel electrophoretic analysis (2-D DIGE) to assess multiple urine samples in patients with diabetic nephropathy. Patient samples were collected as timed overnight collections. All the patients had longstanding diabetes, impaired renal function, and overt proteinuria. Control and patient urinary protein were analyzed by 2-D DIGE and DeCyder analysis. Ninety-nine spots were significantly regulated in the urine proteome of the diabetic samples, with 63 up- and 36 down-regulated. One spot corresponding to a pI 5-6 and a molecular weight between 45 and 66 kDa was consistently up-regulated by 19-fold across individuals in the diabetic group. Surface-enhanced laser desorption/ionization-time of flight analysis of in-gel tryptic digest of this spot identified this protein as alpha 1 antitrypsin (AAT). ELISA of urine samples from a separate group of patients and controls confirmed a marked increase of AAT in diabetic patients. Immunostaining of human diabetic kidneys revealed up-regulation of AAT in areas of renal fibrosis. In conclusion, we developed a method to analyze numerous urine samples from patients and allowed for detection and identification of regulated urine protein spots.
Clinical Comparison of an Enhanced-Sensitivity Branched-DNA Assay and Reverse Transcription-PCR for Quantitation of Human Immunodeficiency Virus Type 1 RNA in Plasma (1998)

The performance characteristics of an enhanced-sensitivity branched-DNA assay (bDNA) (Quantiplex HIV-1 version 2.0; Chiron Corp., Emeryville, Calif.) and a reverse transcription (RT)-PCR assay (AMPLICOR HIV-1 Monitor; Roche Diagnostic Systems, Inc., Branchburg, N.J.) were compared in a molecular diagnostic laboratory. Samples used in this evaluation included linearity and reproducibility panels made by dilution of a human immunodeficiency virus type 1 (HIV-1) stock culture of known virus particle count in HIV-1-negative plasma, a subtype panel consisting of HIV-1 subtypes A through F at a standardized level, and 64 baseline plasma specimens from HIV-1-infected individuals. Plots of log10 HIV RNA copies per milliliter versus log10 nominal virus particles per milliliter demonstrated that both assays were linear over the stated dynamic ranges (bDNA, r = 0.98; RT-PCR, r = 0.99), but comparison of the slopes of the regression lines (bDNA, m = 0.96; RT-PCR, m = 0.83) suggested that RT-PCR had greater proportional systematic error. The between-run coefficients of variation for bDNA and RT-PCR were 24.3 and 34.3%, respectively, for a sample containing 1,650 nominal virus particles/ml and 44.0 and 42.7%, respectively, for a sample containing 165 nominal virus particles/ml. Subtypes B, C, and D were quantitated with similar efficiencies by bDNA and RT-PCR; however, RT-PCR was less efficient in quantitating subtypes A, E, and F. One non-B subtype was recognized in our clinical specimens based on the ratio of values obtained with the two methods. HIV-1 RNA was quantitated in 53 (83%) baseline plasma specimens by bDNA and in 55 (86%) specimens by RT-PCR. RT-PCR values were consistently greater than bDNA values, with population means of 142,419 and 67,580 copies/ml, respectively (P < 0.01). The results were highly correlated (r = 0.91), but the agreement was poor (mean difference in log10 copies per milliliter +/- 2 standard deviations, 0.45 +/- 0.61) for the 50 clinical specimens that gave discrete values with both methods.