gebhart/patrepeval huggingface dataset:
Cyclobutane-Derived Diamines: Synthesis and Molecular Structure (2010)

Cyclobutane diamines (i.e., cis- and trans-1,3-diaminocyclobutane, 6-amino-3-azaspiro[3.3]heptane, and 3,6-diaminospiro[3.3]heptane) are considered as promising sterically constrained diamine building blocks for drug discovery. An approach to the syntheses of their Boc-monoprotected derivatives has been developed aimed at the preparation of multigram amounts of the compounds. These novel synthetic schemes exploit classical malonate alkylation chemistry for the construction of cyclobutane rings. The conformational preferences of the cyclobutane diamine derivatives have been evaluated by X-ray diffraction and compared with the literature data on sterically constrained diamines, which are among the constituents of commercially available drugs.
Three-dimensional QSAR of human immunodeficiency virus (I) protease inhibitors. 1. A CoMFA study employing experimentally-determined alignment rules (1993)

Comparative molecular field analysis (CoMFA), a three-dimensional, quantitative structure-activity relationship (QSAR) paradigm, was used to examine the correlations between the calculated physicochemical properties and the in vitro activities of a series of human immunodeficiency virus (HIV-1) protease inhibitors. The training set consisted of 59 molecules from five structurally-diverse transition-state isostere classes: hydroxyethylamine, statine, norstatine, keto amide, and dihydroxyethylene. The availability of X-ray crystallographic data for at least one representative from each class bound to the protease provided information regarding not only the active conformation of each ligand but also, via superimposition of protease backbones, the relative positions of each ligand with respect to one another in the active site of the enzyme. Once aligned, these molecules served as templates on which additional congeners were field-fit minimized. Additional alignment rules were derived from minimizations of the ligands in the active site of the semirigid protease. The predictive ability of each resultant model was evaluated using a test set comprised of molecules containing a novel transition-state isostere: hydroxyethylurea. Crystallographic studies (Getman, D.P.; et al. J. Med. Chem. 1993, 36, 288-291) indicated an unexpected binding mode for this series of compounds which precluded the use of the field-fit minimization alignment technique. The test set molecules were, therefore, subjected to a limited systematic search in conjunction with active-site minimization. The conformer of each molecule expressing the lowest interaction energy with the active site was included in the test set. Field-fit minimization of neutral molecules to crystal ligands and active-site minimizations of protonated ligands yielded predictive correlations for HIV-1 protease inhibitors. The use of crystallographic data in the determination of alignment rules and field-fit minimization as a molecular alignment tool in the absence of direct experimental data regarding binding modes is strongly supported by these results.
Wav2Letter: an End-to-End ConvNet-based Speech Recognition System (2016)

This paper presents a simple end-to-end model for speech recognition, combining a convolutional network based acoustic model and a graph decoding. It is trained to output letters, with transcribed speech, without the need for force alignment of phonemes. We introduce an automatic segmentation criterion for training from sequence annotation without alignment that is on par with CTC while being simpler. We show competitive results in word error rate on the Librispeech corpus with MFCC features, and promising results from raw waveform.
Human pegivirus RNA is found in multiple blood mononuclear cells in vivo and serum-derived viral RNA-containing particles are infectious in vitro (2014)

Human pegivirus (HPgV; previously called GB virus C/hepatitis G virus) has limited pathogenicity, despite causing persistent infection, and is associated with prolonged survival in human immunodeficiency virus-infected individuals. Although HPgV RNA is found in and produced by T- and B-lymphocytes, the primary permissive cell type(s) are unknown. We quantified HPgV RNA in highly purified CD4(+) and CD8(+) T-cells, including naïve, central memory and effector memory populations, and in B-cells (CD19(+)), NK cells (CD56(+)) and monocytes (CD14(+)) using real-time reverse transcription-PCR. Single-genome sequencing was performed on viruses within individual cell types to estimate genetic diversity among cell populations. HPgV RNA was present in CD4(+) and CD8(+) T-lymphocytes (nine of nine subjects), B-lymphocytes (seven of ten subjects), NK cells and monocytes (both four of five). HPgV RNA levels were higher in naïve (CD45RA(+)) CD4(+) cells than in central memory and effector memory cells (P<0.01). HPgV sequences were highly conserved among subjects (0.117±0.02 substitutions per site; range 0.58-0.14) and within subjects (0.006±0.003 substitutions per site; range 0.006-0.010). The non-synonymous/synonymous substitution ratio was 0.07, suggesting a low selective pressure. Carboxyfluorescein succinimidyl ester (CFSE)-labelled HPgV RNA-containing particles precipitated by a commercial exosome isolation reagent delivered CSFE to uninfected monocytes, NK cells and T- and B-lymphocytes, and HPgV RNA was transferred to PBMCs with evidence of subsequent virus replication. Thus, HPgV RNA-containing serum particles including microvesicles may contribute to delivery of HPgV to PBMCs in vivo, explaining the apparent broad tropism of this persistent human RNA virus.
"Thinking Within the Box": How Proof Models are Used to Limit the Scope of Sexual Harassment Law (2001)

Audrey DeClue brought a sexual harassment claim against her employer arising out of her employer’s failure to provide her with private, or any, restroom facilities. She was the only woman working for the power company as a linesperson, and often found herself on worksites with no restroom within walking distance. Her male counterparts seemingly had little problem with this situation; if nature called, they would simply relieve themselves wherever and whenever they needed. They took no pains to seek privacy, and, in fact, seemed to enjoy the discomfort Audrey experienced when they would urinate in her presence. These male counterparts also enjoyed looking at pornographic materials, which they kept on company trucks and brought onto company property on days the crews could not do site work due to inclement weather. They teased and harassed Audrey when she complained about the lack of restroom facilities, the unfettered urination, and the pornographic materials. Audrey alleged that the actions of her co-workers plus the company’s failure to provide her with the means to relieve herself in
Polymeric nanoparticles for targeted delivery of therapeutic vaccines to dendritic cells (2004)

Dendritic cells (DCs) are the sentries of the immune system. They detect pathogens entering the body and activate immune responses against them through multiple nanoscopic molecular interactions. Pathogen-mimicking nanoparticles capable of such interactions were fabricated by incorporating monophosphoryl lipid A in a biodegradable polymer, poly(D,L-lactic-co-glycolic acid) (PLGA). The uptake of PLGA nanoparticles by human and mouse DCs was conclusively demonstrated by confocal laser scanning microscopy. Delivery of antigens in PLGA nanoparticles was shown to be more efficient than their delivery in soluble form for activation of T cell responses against a variety of antigens including a MUCI peptide (BLP25) cancer vaccine. A PLGA nanoparticulate formulation of BLP25 induced potent T cell responses and anticancer effects in a mouse lung cancer model. These results indicate that PLGA nanoparticles mimicking certain features of pathogens are efficient delivery systems for targeting therapeutic vaccines to DCs and activation of potent T cell responses.
Molecular evidence for induction of intracellular adhesion molecule-1 in the viable border zone associated with ischemia-reperfusion injury of the dog heart. (1994)

Evidence is presented that induction of ICAM-1 mRNA has highly specific localization to ischemic but viable myocardium. Induction of ICAM-1 mRNA transcription in early reperfusion may render the viable "border zone" susceptible to neutrophil-induced injury.
Effect of Ca intake on saturable and nonsaturable components of duodenal Ca transport (1981)

Calcium absorption was studied by an in situ ligated-loop procedure in 9-wk-old male Wistar rats that had been placed from weaning on one of three semisynthetic regimens, 0.17% Ca, 0.44% Ca, or 0.44% Ca plus lactose. Lactose was added because it is known to increase intestinal calcium retention. When the amount of calcium absorbed was expressed as a function of calcium instilled in the loop, it became possible to describe absorption as the sum of a hyperbolic and a linear function, equivalent to a saturable and a nonsaturable process, respectively. The slope of the nonsaturable component was independent of prior calcium intake, while the maximum saturable flux (Jmax) decreased as calcium intake increased. Analysis of the duodenal content of the vitamin D-dependent calcium-binding protein (CaBP, Mr congruent to 10(4)) revealed a positive relation between Jmax and CaBP. Thus, vitamin D appears to be implicated in the saturable, but not in the nonsaturable, component of calcium absorption.
Dynamic Load Distribution in the Borealis Stream Processor (2005)

Distributed and parallel computing environments are becoming cheap and commonplace. The availability of large numbers of CPU's makes it possible to process more data at higher speeds. Stream-processing systems are also becoming more important, as broad classes of applications require results in real-time. Since load can vary in unpredictable ways, exploiting the abundant processor cycles requires effective dynamic load distribution techniques. Although load distribution has been extensively studied for the traditional pull-based systems, it has not yet been fully studied in the context of push-based continuous query processing. In this paper, we present a correlation based load distribution algorithm that aims at avoiding overload and minimizing end-to-end latency by minimizing load variance and maximizing load correlation. While finding the optimal solution for such a problem is NP-hard, our greedy algorithm can find reasonable solutions in polynomial time. We present both a global algorithm for initial load distribution and a pair-wise algorithm for dynamic load migration.
Quasi Resonant DC Link Converters - Analysis and Design for a Battery Charger Application (1999)

Environmental aspects have during the last years made electric vehicles an interesting competitor to the present internal combustion engine driven vehicles. For a broad introduction of pure electric vehicles, a battery charging infrastructure is deemed necessary. However, to build and maintain such an infrastructure is costly. Active power line conditioning capabilities could be included in the battery charger, making the infrastructure advantageous from the distribution network point of view. Another option is that the battery charger could be able to support the grid with peak power during periods of stability problems or emergency situations. This means that energy is borrowed from the batteries of vehicles connected to a charger. The price for energy supplied by the batteries is likely to be several times higher than the normal electric energy price, due to the wear costs of the batteries. Therefore, the battery charger losses also represents a high cost. It is often stated that resonant converters have a high efficiency compared to hard switched. Since carrier based pulse width modulation is employed, quasi resonant DC link converters are of interest. Four of the most promising quasi resonant DC link topologies reported in the literature are compared. A fair comparison is obtained by designing them to meet certain common design criteria, in this case the duration of the zero voltage interval and the maximum output voltage time derivative. The derivation of the design expressions are given, and also the simulation results, by means of efficiency. A 10 kW battery charger, equipped with one of the quasi resonant DC links investigated is implemented. A hard switched battery charger with the same rating is also tested to compare the measured efficiency with the simulated. Both the simulations and measurements shows that the efficiency decrease for quasi resonant battery chargers compared to the hard switched case. Furthermore, low frequency harmonics appear in the battery charger input and output currents. However, full control of the output voltage derivatives is obtained.
Collagen-Polymer Guidance of Vessel Network Formation and Stabilization by Endothelial Colony Forming Cells In Vitro (2013)

Vessel morphogenesis is vital to regenerative medicine strategies. Here, collagen polymers, specified by intermolecular cross-link composition, are used to independently vary microstructure (fibril density, interfibril branching) and physical properties (stiffness) to guide 3D vessel network formation by endothelial colony forming cells (ECFC) in vitro. Increasing stiffness, by modulation of fibril density or interfibril branching, increases vessel diameter, length and branching. Oligomer matrices also induce vessel stabilization via type IV collagen deposition. This work shows that ECFC vessel formation depends on the interplay of collagen microstructure and physical properties and names oligomers and intermolecular cross-links as key design parameters for vascular-inductive matrices.
12-O-Acetylphorbol-13-decanoate Potently Inhibits Cytopathic Effects of Human Immunodeficiency Virus Type 1(HIV-1), without Activation of Protein Kinase C. (1999)

Through bioactivity-guided fractionation, eight phorbol diesters, including five new ones (1-5), were isolated from the seeds of Croton tiglium collected in Egypt. 12-O-Acetylphorbol-13-decanoate (6) and 12-O-decanoylphorbol-13-(2-methylbutyrate) (4) potently inhibited the HIV-1-induced cytopathic effect on MT-4 cells (IC100 values of 7.6 ng/ml and 7.81 micrograms/ml, and CC0 values of 62.5 micrograms/ml and 31.3 micrograms/ml, respectively) without activating protein kinase C.
Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein (2003)

Hepcidin is a liver-made peptide proposed to be a central regulator of intestinal iron absorption and iron recycling by macrophages. In animal models, hepcidin is induced by inflammation and iron loading, but its regulation in humans has not been studied. We report that urinary excretion of hepcidin was greatly increased in patients with iron overload, infections, or inflammatory diseases. Hepcidin excretion correlated well with serum ferritin levels, which are regulated by similar pathologic stimuli. In vitro iron loading of primary human hepatocytes, however, unexpectedly down-regulated hepcidin mRNA, suggesting that in vivo regulation of hepcidin expression by iron stores involves complex indirect effects. Hepcidin mRNA was dramatically induced by interleukin-6 (IL-6) in vitro, but not by IL-1 or tumor necrosis factor alpha (TNF-alpha), demonstrating that human hepcidin is a type II acute-phase reactant. The linkage of hepcidin induction to inflammation in humans supports its proposed role as a key mediator of anemia of inflammation.
Intracellular Na+:K+ ratios in human cancer cells as revealed by energy dispersive x-ray microanalysis. (1981)

Intranuclear sodium, potassium, and chloride contents were measured by energy-dispersive x-ray microanalysis in freeze-fractured, freeze-dried, bulk-tumor samples taken from 10 patients suffering from invasive urogenital cancers. Human biopsies were carried out during the first diagnostic interventions before any cytostatic treatment had been applied. Pathohistological diagnosis established the malignancy in each case. The cancers were classified in three types: keratinizing, transitional cell, and hypernephroid carcinoma. More than 250 cell nuclei were measured from each type of cancer. The results were compared with those obtained in intact human urothelium taken from patients having no malignant processes. Proximal and distal tubular epithelial cell nuclei representing the origin of human hypernephroid cancer were also measured in rat kidney because corresponding healthy human material cannot be obtained. The analyses revealed, in all three types of cancer cells, that the average intranuclear sodium content increased more than three-fold, the potassium content decreased 32, 16, and 13%, respectively; meanwhile the chloride content increased, but to a lesser extent than did the sodium. The intranuclear Na+:K+ ratios were more than five-fold higher in the cancer cells on the average, and their distribution histograms were much broader than in the normal human urothelium and in the tubular cell nuclei of the rat kidney. The results obtained fit well with the theory of Cone, C. D., Jr. 1971. J. Theor. Biol. 30: 151-181 according to which the sustained depolarization of the cell membrane may be of mitogenic effect.
Characterization of Binding of Human Lactoferrin to Pneumococcal Surface Protein A (2001)

Human lactoferrin is an iron-binding glycoprotein that is particularly prominent in exocrine secretions and leukocytes and is also found in serum, especially during inflammation. It is able to sequester iron from microbes and has immunomodulatory functions, including inhibition of both complement activation and cytokine production. This study used mutants lacking pneumococcal surface protein A (PspA) and PspC to demonstrate that the binding of human lactoferrin to the surface of Streptococcus pneumoniae was entirely dependent on PspA. Lactoferrin bound both family 1 and family 2 PspAs. Binding of lactoferrin to PspA was shown by surface colocalization with PspA and was verified by the lack of binding to PspA-negative mutants. Lactoferrin was expressed on the body of the cells but was largely absent from the poles. PspC showed exactly the same distribution on the pneumococcal surface as PspA but did not bind lactoferrin. PspA's binding site for lactoferrin was mapped using recombinant fragments of PspA of families 1 and 2. Binding of human lactoferrin was detected primarily in the C-terminal half of the alpha-helical domain of PspA (amino acids 167 to 288 of PspA/Rx1), with no binding to the N-terminal 115 amino acids in either strain. The interaction was highly specific. As observed previously, bovine lactoferrin bound poorly to PspA. Human transferrin did not bind PspA at all. The binding of lactoferrin to S. pneumoniae might provide a way for the bacteria to interfere with host immune functions or to aid in the acquisition of iron at the site of infection.
PI-55Population pharmacokinetics and pharmacodynamics of febuxostat in a phase-III study of patients with gout (2006)

AIMS The objective of this study was to evaluate the population (pop) PK and PD of febuxostat (FBX), a non-purine selective inhibitor of xanthine oxidase, in gout patients and to identify fixed effect sources of variability. METHODS In a Phase III, double-blind, 28-week study (N=1072), a subgroup (115Male/10Female) of gout patients receiving 80, 120, or 240 mg of FBX once daily were evaluated for pop PK-PD. Steady-state trough and sparse post dose blood samples were collected from Week 16–24. FBX pop PK and PD[serum uric acid (sUA)] was assessed using NONMEM/XPOSE/SPLUS, including GAM analyses followed by a stepwise selection/elimination process for covariate screening. External validation was done using PK and PD data from a prior Phase II study in gout patients. RESULTS Parameter pop means in the final simultaneous pop PK-PD model (FO method) were: (See Table) Type PK-PD Model (2-compartment with indirect response) PK Cl/F = 4.93a + 0.0142*CrClb + 0.0155*WTc − 1.23*FIBd L/h; Vc/F = 32.2 L; Vp/F = 22.2 L; tlag = 0.23 h; Ka = 13.7e h−1; Residual CV = 71% PD Kin = 0.0462 + 0.0211*BUAf mg/dL/h; EC50 = 0.239g μg/mL; Kout = 0.0255 h−1; Residual SD = 0.863 mg/dL a CV=18; b baseline creatinine clearance in mL/min; c total body weight in kg; d fibrates (no=0, yes=1); e CV=176; f BUA: baseline sUA in mg/dL; g CV=67. The covariate analyses identified CrCl, wt, and fib for Cl/F and bua for kIn as statistically significant (p<0.001) covariates. external validation results indicated that the inclusion of the covariates for Cl/F in the final model did not improve the bias/precision of the predicted PK parameters/concentrations. CONCLUSION A simplified version of the final simultaneous PK-PD model with no covariates for Cl/F is suggested to be as effective in predicting the PK and PD parameters/concentrations in gout patients. Clinical Pharmacology & Therapeutics (2005) 79, P21–P21; doi: 10.1016/j.clpt.2005.12.076
Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis (2001)

The efficacy of ASU at a dosage of 300mg/day and 600mg/day was consistently superior to that of placebo at all endpoints, with no differences observed between the two doses.
Synthesis of a carbocyclic analogue of N-acetylneuraminic acid (pseudo-N-acetylneuraminic acid) (1992)

S. Ogawa, M. Yoshikawa and T. Taki, J. Chem. Soc., Chem. Commun., 1992, 406 DOI: 10.1039/C39920000406
Structural Basis of Serine/Threonine Phosphatase Inhibition by the Archetypal Small Molecules Cantharidin and Norcantharidin (2009)

The inhibition of a subgroup of human serine/threonine protein phosphatases is responsible for the cytotoxicity of cantharidin and norcantharidin against tumor cells. It is shown that the anhydride rings of cantharidin and norcantharidin are hydrolyzed when bound to the catalytic domain of the human serine/threonine protein phosphatases 5 (PP5c), and the high-resolution crystal structures of PP5c complexed with the corresponding dicarboxylic acid derivatives of the two molecules are reported. Norcantharidin shows a unique binding conformation with the catalytically active Mn2PP5c, while cantharidin is characterized by a double conformation in its binding mode to the protein. Different binding modes of norcantharidin are observed depending of whether the starting ligand is in the anhydride or in the dicarboxylic acid form. All these structures will provide the basis for the rational design of new cantharidin-based drugs.
Ratio of Serum Urea to Serum Creatinine in Wild Black Bears (1984)

In winter, the ratio of serum urea to serum creatinine is 10 or less in denning female and male bears. In midsummer it is 22 or more, similar to that of other mammals. However, in late summer and early fall, while food is available, the urea-to-creatinine ratio approaches or becomes 10 or less. The low value of this ratio appears to indicate the biochemical state of hibernation, and many bears are in this state weeks before they den.