gebhart/patrepeval huggingface dataset:
Site-directed mutagenesis of mouse dihydrofolate reductase. Mutants with increased resistance to methotrexate and trimethoprim. (1988)

Site-directed mutagenesis was used to generate mutants of recombinant mouse dihydrofolate reductase to test the role of some amino acids in the binding of two inhibitors, methotrexate and trimethoprim. Eleven mutations changing eight amino acids at positions all involved in hydrogen bonding or hydrophobic interactions with dihydrofolate or one of the two inhibitors were tested. Nine mutants were obtained by site-directed mutagenesis and two were spontaneous mutants previously obtained by in vivo selection (Grange, T., Kunst, F., Thillet, J., Ribadeau-Dumas, B., Mousseron, S., Hung, A., Jami, J., and Pictet, R. (1984) Nucleic Acids Res. 12, 3585-3601). The choice of the mutated positions was based on the knowledge of the active site of chicken dihydrofolate reductase established by x-ray crystallographic studies since the sequences of all known eucaryotic dihydrofolate reductases are greatly conserved. Enzymes were produced in great amounts and purified using a plasmid expressing the mouse cDNA into a dihydrofolate reductase-deficient Escherichia coli strain. The functional properties of recombinant mouse dihydrofolate reductase purified from bacterial extracts were identical to those of dihydrofolate reductase isolated from eucaryotic cells. The Km(NADPH) values for all the mutants except one (Leu-22----Arg) were only slightly modified, suggesting that the mutations had only minor effects on the ternary conformation of the enzyme. In contrast, all Km(H2folate) values were increased, since the mutations were located in the dihydrofolate binding site. The catalytic activity was also modified for five mutants with, respectively, a 6-, 10-, 36-, and 60-fold decrease of Vmax for Phe-31----Arg, Ile-7----Ser, Trp 24----Arg and Leu-22----Arg mutants and a 2-fold increase for Val-115----Pro. All the mutations affected the binding of methotrexate and six, the binding of trimethoprim: Ile-7----Ser, Leu-22----Arg, Trp-24----Arg, Phe-31----Arg, Gln-35----Pro and Phe-34----Leu. The relative variation of Ki for methotrexate and trimethoprim were not comparable from one mutant to the next, reflecting the different binding modes of the two inhibitors. The mutations which yielded the greatest increases in Ki are those which involved amino acids making hydrophobic contacts with the inhibitor.
PULSAR: A phase 2, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of sotatercept (ACE-011) when added to standard of care (SOC) for treatment of pulmonary arterial hypertension (PAH) (2019)

<b>Background:</b> Novel therapies are needed to attenuate the progression of PAH. Disruptions in transforming growth-factor (TGF)-β and bone morphogenetic protein (BMP) signaling are associated with the development of PAH. Sotatercept (ACE-011) is a first-in-class fusion protein consisting of the extracellular domain of activin receptor IIa (ActRIIa) attached to the Fc portion of human IgG1 that sequesters TGF-β superfamily ligands such as activin A and B and growth differentiation factor (GDF)-11 to suppress TGF-β signaling and rebalance deficient BMPR2 signaling. <b>Aims:</b> To determine the efficacy and safety of sotatercept versus placebo when administered with SOC in adults with PAH. <b>Methods:</b> Eligible participants (pts) have World Health Organization (WHO) Group 1 functional class II-III PAH; age ≥18 years; baseline pulmonary vascular resistance (PVR) of ≥5 Wood units; 6-minute walk distance (6MWD) of 150–550m; and stable PAH SOC therapy. One hundred pts will be randomized 3:3:4 to placebo, 0.3 mg/kg sotatercept, or 0.7 mg/kg sotatercept administered SC every 21 days plus SOC for 24 weeks. The primary endpoint is change from baseline in PVR at 24 weeks. An 18-month extension period follows. <b>Results and Conclusions:</b> Primary analysis results for PULSAR (NCT03496207) are expected in the first half of 2020. A related study (SPECTRA; NCT03738150) will evaluate the effects of sotatercept on cardiopulmonary hemodynamics and functional capacity in pts with PAH.
A wheat histone H3 promoter confers cell division‐dependent and ‐independent expression of the gus A gene in transgenic rice plants (1993)

To investigate developmental regulation of wheat histone H3 gene expression, the H3 promoter, which has its upstream sequence to -1711 (relative to the cap site as +1), was fused to the coding region of the gus A gene (-1711H3/GUS) and introduced into a monocot plant, rice. Detailed histochemical analysis revealed two distinct types of GUS expression in transgenic rice plants; one is cell division-dependent found in the apical meristem of shoots and roots and in young leaves, and another is cell division-independent detected in flower tissues including the anther wall and the pistil. In this study, replication-dependent expression occurring in non-dividing cells which undergo endoreduplication could not be discriminated from strict replication-independent expression. The observed expression pattern in different parts of roots suggested that the level of the H3/GUS gene expression is well correlated with activity of cell division in roots. To identify 5' sequences of the H3 promoter necessary for an accurate regulation of the GUS expression, two constructs containing truncated promoters, -908H3/GUS and -185H3/GUS, were analyzed in transiently expressed protoplasts, stably transformed calli and transgenic plants. The results indicated that the region from -909 to -1711 contains the positive cis-acting element(s) and that the proximal promoter region (up to -185) containing the conserved hexamer, octamer and nonamer motifs is sufficient to direct both cell division-dependent and -independent expression. The use of the meristem of roots regenerated from transformed calli for the analysis of cell division-dependent expression of plant genes is discussed.
Channeling of Urea Cycle Intermediates in Situ in Permeabilized Hepatocytes (1989)

Preferential use of endogenously generated intermediates by the enzymes of the urea cycle was observed using isolated rat hepatocytes made permeable to low molecular weight compounds with alpha-toxin. The permeabilized cells synthesized [14C]urea from added NH4Cl, [14C]HCO3-, ornithine, and aspartate, using succinate as a respiratory substrate; with all substrates saturating, about 4 nmol of urea were formed per min/mg dry weight of cells. Urea usually accounted for about 40-50% of the total (NH3 + ornithine)-dependent counts, arginine for less than 10%, and citrulline for about 30%. Very tight channeling of arginine between argininosuccinate lyase and arginase was shown by the fact that the addition of a 200-fold excess of unlabeled arginine to the incubations did not decrease the percentage of counts found in urea or increase that found in arginine, even though a substantial amount of the added arginine was hydrolyzed inside the cells. The channeling of argininosuccinate between its synthetase and lyase was demonstrated by similar observations; unlabeled argininosuccinate added in 200-fold excess decreased the percentage of counts in urea by only 25%. Channeling of citrulline from its site of synthesis by ornithine transcarbamylase in the mitochondrial matrix to argininosuccinate synthetase in the cytoplasmic space was also shown. These results strongly suggest that the three "soluble" cytoplasmic enzymes of the urea cycle are grouped around the mitochondria and are spatially organized within the cell in such a way that intermediates can be efficiently transferred between them.
Central Serotonin and Impulsive Aggression (1989)

The role of central serotonergic (5-HT) system dysfunction in the regulation of aggression in both animals and man has been investigated for more than the past two decades. Evidence for reduced central 5-HT in the mediation of aggression comes from both behavioural and correlative studies. Functional reduction and augmentation of 5-HT activity is respectively associated with increased and decreased aggression in various animal models of aggression. While similar studies in man have not been performed, strong and consistent associations between indices reflecting reduced pre-synaptic 5-HT activity and aggression have been reported. Evidence of post-synaptic receptor upregulation in the brains of suicide victims has also been reported leaving the functional status 5-HT activity in such patients an open question. However, reduced neuroendocrine (i.e. prolactin) responses to fenfluramine, a 5-HT uptake inhibitor/releaser, which activates both pre- and post-synaptic sides of the 5-HT synapse, strongly suggest that overall central 5-HT activity is reduced in mood and/or personality disorder patients with history of suicidal and/or impulsive aggressive behaviour. Preliminary data with the 5-HT receptor agonist m-chlorophenylpiperazine further suggest that reduced activity of post-synaptic 5-HT receptors may be an important correlate of impulsive aggressive behaviour. Pharmacological agents with potent 5-HT pre- and/or post-synaptic augmenting effects should be tested clinically to determine their efficacy in the treatment of impulsive aggressive behaviour in psychiatric patients.
Hybrid Nanostructured Textile Bioelectrode for Unobtrusive Health Monitoring (2013)

Coronary heart disease, cardiovascular diseases and strokes are the leading causes of mortality in United States of America. Timely point-of-care health diagnostics and therapeutics for person suffering from these diseases can save thousands of lives. However, lack of accessible minimally intrusive health monitoring systems makes timely diagnosis difficult and sometimes impossible. To remedy this problem, a textile based nano-bio-sensor was developed and evaluated in this research. The sensor was made of novel array of vertically standing nanostructures that are conductive nano-fibers projecting from a conductive fabric. These sensor electrodes were tested for the quality of electrical contact that they made with the skin based on the fundamental skin impedance model and electromagnetic theory. The hybrid nanostructured dry electrodes provided large surface area and better contact with skin that improved electrode sensitivity and reduced the effect of changing skin properties, which are the problems usually faced by conventional dry textile electrodes. The dry electrodes can only register strong physiological signals because of high background noise levels, thus limiting the use of existing dry electrodes to heart rate measurement and respiration. Therefore, dry electrode systems cannot be used for recording complete ECG waveform, EEG or measurement of bioimpedance. Because of their improved sensitivity these hybrid nanostructured dry electrodes can be applied to measurement of ECG and bioimpedance with very low baseline noise. These textile based electrodes can be seamlessly integrated into garments of daily use such as vests and bra. In combination with embedded wireless network device that can communicate with smart phone, laptop or GPRS, they can function as wearable wireless health diagnostic systems.
A hidden-surface algorithm with anti-aliasing (1978)

In recent years we have gained understanding about aliasing in computer generated pictures and about methods for reducing the symptoms of aliasing. The chief symptoms are staircasing along edges and objects that pop on and off in time. The method for reducing these symptoms is to filter the image before sampling at the display resolution. One filter that is easy to understand and that works quite effectively is equivalent to integrating the visible intensities over the area that the pixel covers. There have been several implementations of this method - mostly unpublished - however most algorithms break down when the data for the pixel is complicated. Unfortunately, as the quality of displays and the complexity of pictures increase, the small errors that can occur in a single pixel become quite noticeable. A correct solution for this filter requires a hidden-surface algorithm at each pixel! If the data at the pixel is presented as a depth-ordered list of polygons then the average visible intensity can be found using a polygon clipper in a way similar to that employed by two known hidden-surface algorithms. All of the polygons in a pixel are clipped against some front unclipped edge into two lists of polygons. The algorithm is recursively entered with each new list and halts when the front polygon is clipped on all sides, thereby obscuring the polygons behind. The area weighted colors are then returned as the value to be added to the other pieces in the pixel.
Sufficient conditions for river meandering: A simulation approach (1984)

A digital simulation model produces realistic meandering patterns starting from an initially straight channel with small random perturbations. The model assumes that nominal migration rates increase as channel curvature increases but reach a maximum when bend radius divided by channel width is about 3, with decreasing rates for sharper bends, in accord with observations of Nanson and Hickin (1983) and others. However, it is also necessary to assume that local migration rates are a weighted average of local and upstream nominal rates, with the weighting decreasing upstream. The model includes provisions for neck cutoffs and may be used to forecast future patterns of channel migration in meandering streams.
Towards Industrial-Strength Measurement Programs for Reuse and Experience Repository Systems (2022)

Learning from daily work to constantly improve products and processes is seen as a key feature to master today s needs of competitive system development. To support these tasks the Experience Factory approach with its central reuse and experience repository is widely accepted in research and practice. While measurement programs are implemented to intensively monitor applied processes and control product quality, seldom there are any endeavors taken to measure and evaluate the supporting repository system itself. In this paper we suggest an approach to iteratively build up a measurement program for gaining feedback and, thereby, controlling and improving such a reuse and experience repository system.
Sb surface segregation during heavy doping of Si(100) grown at low temperature by molecular beam epitaxy (1993)

Sb surface segregation and doping during Si(100) molecular beam epitaxy at low temperature have been studied by depth profiling with secondary ion mass spectrometry, x-ray photoelectron spectroscopy, and conductivity measurements. We find that at a growth temperature near 320 °C complete donor activation and doping densities near 5×1020 cm−3 are obtainable. For temperatures between 320–500 °C, measurements point to the existence of distinct surface segregation regimes. For dilute surface and bulk Sb concentrations the measurements reveal a region where the surface segregation is constant and bulk and surface concentrations are linearly related. For bulk concentrations near the solid solubility limit, the surface segregation increases rapidly with increasing bulk concentration for temperatures between 350–450 °C. Finally, for Sb-saturated surfaces the surface segregation actually decreases, and doping levels exceeding the solid solubility limit are possible.
A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation (1988)

Picornavirus RNAs are uncapped messengers and have unusually long 5' nontranslated regions (5'NTRs) which contain many noninitiating AUG triplets. The translational efficiency of different picornavirus RNAs varies between different cell-free extracts and even in the same extract, such as micrococcal nuclease-treated rabbit reticulocyte lysates. The effect of the poliovirus 5'NTR on in vitro translation was compared with that of the 5'NTR of encephalomyocarditis virus by the use of synthetic mRNAs, micrococcal nuclease-treated HeLa cell extracts, and rabbit reticulocyte lysates. Artificial mono- and dicistronic mRNAs synthesized with T7 RNA polymerase were used to investigate whether the 5'NTR of encephalomyocarditis virus RNA contains a potential internal ribosomal entry site. The sequence between nucleotides 260 and 484 in the 5'NTR of encephalomyocarditis RNA was found to play a critical role in the efficient translation in both mono- and dicistronic mRNAs. Our data suggest that an internal ribosomal entry site resides in this region.
Significance of Enamel Remineralization (1974)

Longitudinal Study of Cariostatic Effects of Sodium Trimetaphosphate and Sodium Fluoride When Fed Separately and Together in Diets of Rats
Cyst(e)ine Requirements in Enterally Fed Very Low Birth Weight Preterm Infants (2008)

These data do not support the hypothesis that endogenous cyst(e)ine synthesis is limited in very low birth weight preterm infants with gestational ages of <29 weeks, both at 32 and 35 weeks postmenstrual age. It is safe to conclude that cyst(e)ine requirement is <18 mg/kg per day in enterally fed very low birth weight preterm infants who are older than 32 weeks' postmenstrual age and whose methionine intake is adequate. Therefore, cyst(e)ine is probably not a conditionally essential amino acid in these infants.
Quasi-Nature Catalysis:  Developing C−C Bond Formations Catalyzed by Late Transition Metals in Air and Water (2002)

This Account outlines the recent efforts of developing catalysis under the ambient conditions of air and water for synthetic purposes from the author's laboratory. The discussions are focused on catalytic reactions (mostly C-C bond formations) other than oxidations via late transition metals. It includes the following aspects: (1) copper-catalyzed C-C bond formations; (2) palladium-catalyzed C-C bond formations; (3) rhodium-catalyzed C-C bond formations; (4) ruthenium-catalyzed olefin isomerizations and C-H activations. The mechanism, limitations, and synthetic applications of these reactions are also discussed.
Identification of chromophore binding domains of yeast DNA photolyase. (1992)

Photolyases contain two chromophores, flavin plus either methenyltetrahydrofolate (MTHF) or 8-OH-5-deazaflavin (HDF). Amino acid sequence comparison reveals that all photolyases sequenced to date have extensive sequence homology in the carboxyl-terminal half; in the amino-terminal region the folate and deazaflavin class enzymes are more homologous to other members of the same class. This modular arrangement of sequence homologies suggests that the amino-terminal half of photolyase is involved in MTHF or HDF binding whereas the carboxyl-terminal half carries the flavin binding site. In this study we attempted to identify such structural domains of yeast photolyase by partial proteolysis and gene fusion techniques. Partial digestion with chymotrypsin yielded an amino-terminal 34-kDa fragment containing tightly bound MTHF and a carboxyl-terminal 20-kDa polypeptide which lacked chromophore or DNA binding activity. However, a fusion protein carrying the carboxyl-terminal 275 amino acids of yeast photolyase bound specifically to FAD but not to MTHF or DNA. We conclude that the amino-terminal half of yeast photolyase constitutes the folate binding domain and that the carboxyl-terminal half carries the flavin binding site.
Acidic Cesium Salts of Keggin-type Heteropolytungstic Acids as Insoluble Solid Acid Catalysts for Estenfication and Hydrolysis Reactions (1993)

Abstract Acidic cesium salts of the Keggin-type heteropolyacids, Cs2.5H0.5PW12O40 and Cs2.5H1.5SiW12O40, retained their strong acidity in water-containing organic media, and worked as insoluble, efficient acid catalysts in the hydrolysis of ethyl acetate and the estenfication of acetic acid with ethanol. Silica-bound Cs2.5H0.5PW12O40, a newly prepared composite, was an active and easily recoverable solid acid catalyst for the hydrolysis of ethyl acetate with excess water.
On Clustering Graph Streams (2010)

In this paper, we will examine the problem of clustering massive graph streams. Graph clustering poses significant challenges because of the complex structures which may be present in the underlying data. The massive size of the underlying graph makes explicit structural enumeration very difficult. Consequently, most techniques for clustering multi-dimensional data are difficult to generalize to the case of massive graphs. Recently, methods have been proposed for clustering graph data, though these methods are designed for static data, and are not applicable to the case of graph streams. Furthermore, these techniques are especially not effective for the case of massive graphs, since a huge number of distinct edges may need to be tracked simultaneously. This results in storage and computational challenges during the clustering process. In order to deal with the natural problems arising from the use of massive disk-resident graphs, we will propose a technique for creating hash-compressed micro-clusters from graph streams. The compressed micro-clusters are designed by using a hash-based compression of the edges onto a smaller domain space. We will provide theoretical results which show that the hash-based compression continues to maintain bounded accuracy in terms of distance computations. We will provide experimental results which illustrate the accuracy and efficiency of the underlying method.
Productive infection of isolated human alveolar macrophages by respiratory syncytial virus. (1990)

Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract disease in children and individuals with cell-mediated immunodeficiencies. Airway epithelial cells may be infected with RSV, but it is unknown whether other cells within the lung permit viral replication. We studied whether human alveolar macrophages supported RSV replication in vitro. Alveolar macrophages exposed to RSV demonstrated expression of RSV fusion gene, which increased in a time-dependent manner and correlated with RSV protein expression. RSV-exposed alveolar macrophages produced and released infectious virus into supernatants for at least 25 d after infection. Viral production per alveolar macrophage declined from 0.053 plaque-forming units (pfu)/cell at 24 h after infection to 0.003 pfu/cell by 10 d after infection and then gradually increased. The capability of alveolar macrophages to support prolonged RSV replication may have a role in the pulmonary response to RSV infection.
Drug Delivery Systems Employing 1,6-Elimination:  Releasable Poly(ethylene glycol) Conjugates of Proteins (2001)

Using lysozyme as a representative protein substrate that loses its activity when PEGylation takes place on the epsilon-amino group of lysine residues, various amounts of a novel releasable PEG linker (rPEG) were conjugated to the protein. rPEG-lysozyme conjugates were relatively stable in pH 7.4 buffer for over 24 h. However, regeneration of native protein from the rPEG conjugates occurred in a predictable manner during incubation in high pH buffer or rat plasma, as demonstrated by enzymatic activity and structural characterization. The rates of regeneration were also correlated with PEG number: native lysozyme was released more rapidly from the monosubstituted conjugate than from the disubstituted conjugate, suggesting possible steric hindrance to the approach of cleaving enzymes. Recovery of normal activity and structure for the regenerated native lysozyme was shown by a variety of assays.