gebhart/patrepeval huggingface dataset:
Phenylalanine 393 Exerts Thermodynamic Control over the Heme of Flavocytochrome P450 BM3 (2001)

Site-directed mutants of the phylogenetically conserved phenylalanine residue F393 were constructed in flavocytochrome P450 BM3 from Bacillus megaterium. The high degree of conservation of this residue in the P450 superfamily and its proximity to the heme (and its ligand Cys400) infers an essential role in P450 activity. Extensive kinetic and thermodynamic characterization of mutant enzymes F393A, F393H, and F393Y highlighted significant differences from wild-type P450 BM3. All enzymes expressed to high levels and contained their full complement of heme. While the reduction and subsequent treatment of the mutant P450s with carbon monoxide led to the formation of the characteristic P450 spectra in all cases, the absolute position of the Soret absorption varied across the series WT/F393Y (449 nm), F393H (445 nm), and F393A (444 nm). Steady-state turnover rates with both laurate and arachidonate showed the trend WT > F393Y >> F393H > F393A. Conversely, the trend in the pre-steady-state flavin-to-heme electron transfer was the reverse of the steady-state scenario, with rates varying F393A > F393H >> F393Y approximately wild-type. These data are consistent with the more positive substrate-free [-312 mV (F393A), -332 mV (F393H)] and substrate-bound [-151 mV (F393A), -176 mV (F393H)] reduction potentials of F393A and F393H heme domains, favoring the stabilization of the ferrous-form in the mutant P450s relative to wild-type. Elevation of the heme iron reduction potential in the F393A and F393H mutants facilitates faster electron transfer to the heme. This results in a decrease in the driving force for oxygen reduction by the ferrous heme iron, so explaining lower overall turnover of the mutant P450s. We postulate that the nature of the residue at position 393 is important in controlling the delicate equilibrium observed in P450s, whereby a tradeoff is established between the rate of heme reduction and the rate at which the ferrous heme can bind and, subsequently, reduce molecular oxygen.
Cosmid-derived map ofE.colistrain BHB2600 in comparison to the map of strain W3110 (1989)

A physical map for the genome of E. coli K12 strain BHB2600 was constructed by use of 570 cloned DNA elements (CDEs) withdrawn from a cosmid library. Dot blot hybridisation was applied to establish contig interrelations with subsequent fine mapping achieved by analysis of EcoR1 restriction patterns on Southern blots. The derived map covers nearly 95% of the E. coli genome resulting in 12 minor gaps. It may be compared to the almost complete map for strain W3110 of Kohara et al. (1). Except for one tiny gap (lpp,36.5') remaining gaps in BHB2600 do not coincide with those in W3110 so that both maps complement each other establishing an essentially complete clone represented map. Besides numerous minute differences (site and fragment gains and losses) both strains harbour at differing positions extended rearrangements flanked by mutually inverted repetitive elements, in our case insertion elements (IS1 and IS5).
Differential expression of cell surface heparan sulfate proteoglycans in human mammary epithelial cells and lung fibroblasts. (1992)

Treating the liposome-intercalatable heparan sulfate proteoglycans from human lung fibroblasts and mammary epithelial cells with heparitinase and chondroitinase ABC revealed different core protein patterns in the two cell types. Lung fibroblasts expressed heparan sulfate proteoglycans with core proteins of approximately 35, 48/90 (fibroglycan), 64 (glypican), and 125 kDa and traces of a hybrid proteoglycan which carried both heparan sulfate and chondroitin sulfate chains. The mammary epithelial cells, in contrast, expressed large amounts of a hybrid proteoglycan and heparan sulfate proteoglycans with core proteins of approximately 35 and 64 kDa, but the fibroglycan and 125-kDa cores were not detectable in these cells. Phosphatidylinositol-specific phospholipase C and monoclonal antibody (mAb) S1 identified the 64-kDa core proteins as glypican, whereas mAb 2E9, which also reacted with proteoglycan from mouse mammary epithelial cells, tentatively identified the hybrid proteoglycans as syndecan. The expression of syndecan in lung fibroblasts was confirmed by amplifying syndecan cDNA sequences from fibroblastic mRNA extracts and demonstrating the cross-reactivity of the encoded recombinant core protein with mAb 2E9. Northern blots failed to detect a message for fibroglycan in the mammary epithelial cells and in several other epithelial cell lines tested, while confirming the expression of both glypican and syndecan in these cells. Confluent fibroblasts expressed higher levels of syndecan mRNA than exponentially growing fibroblasts, but these levels remained lower than observed in epithelial cells. These data formally identify one of the cell surface proteoglycans of human lung fibroblasts as syndecan and indicate that the expression of the cell surface proteoglycans varies in different cell types and under different culture conditions.
The CHK1 inhibitor SRA737 synergizes with PARP1 inhibitors to kill carcinoma cells (2018)

Inhibitors of PARP1 are approved therapeutic agents in ovarian carcinomas. We determined whether the novel clinically relevant CHK1 inhibitor SRA737 interacted with PARP1 inhibitors to kill carcinoma cells. In multiple mammary and ovarian cancer lines SRA737 synergized with the PARP1 inhibitors olaparib and niraparib to cause cell death. The [SRA737 + niraparib] drug combination activated an ATM-AMPK-ULK1-mTOR pathway which resulted in the formation of autophagosomes, temporally followed by autolysosome formation. Phosphorylation of ULK1 S317 was essential for kinase activation against ATG13. The drug combination elevated eIF2α phosphorylation which was causal at increasing Beclin1 and ATG5 expression, reducing MCL-1 and BCL-XL levels, and causing CD95 activation. Knock down of CD95, eIF2α, ATM, AMPKα, ULK1, Beclin1 or ATG5 reduced drug combination lethality. Blockade of either caspase 9 function or that of AIF each partially prevented cell death. Expression of activated mTOR or of c-FLIP-s or of BCL-XL reduced cell killing. In vivo, SRA737 and niraparib interacted in an additive fashion to suppress the growth of mammary tumors. Multiplex analyses revealed that drug combination treated tumors had reduced their plasma levels of sERBB1, sERBB2, sVEGFR1, sVEGFR2, sIL-6R, HGF, PDGFAB/BB and CXCL16 and enhanced the levels of CCL26, IL-8 and MIF. Surviving tumors had activated ERK1/2 and AKT. This finding argues that IL-8/ERK/AKT signaling may be an evolutionary survival response to [SRA737 + niraparib].
Liquid Crystal Electro-Optical Switching Approaches (2000)

Liquid crystals (LCs), a special state of matter, with properties resembling both liquids and crystals has proven to be a commercially viable technology in the flat panel displays arena. For years, LCs have attracted the attention of optical switch designers, hoping to capture and harness their powerful electro-optic properties for routing and controlling light.
Modeling the evolution of discussion topics and communication to improve relational classification (2010)

Textual analysis is one means by which to assess communication type and moderate the influence of network structure in predictive models of individual behavior. However, there are few methods available to incorporate textual content into time-evolving network models. In particular, modeling both the evolution of network topology and textual content change in time-varying communication data poses a difficult challenge. In this work, we propose a Temporally-Evolving Network Classifier (TENC) to incorporate the influence of time-varying edges and temporally-evolving attributes in relational classification models. To facilitate this, we use an evolutionary latent topic approach to automatically discover and label communications between individuals in a network with their corresponding latent topic. The topics of the messages are incorporated into the TENC along with time-varying relationships and temporally-evolving attributes, using weighted, exponential kernel summarization. We evaluate the utility of the TENC on a real-world classification task, where the aim is to predict the effectiveness of a developer in the python open-source developer network. We take advantage of the textual content in developer emails and bug communications, which both evolve over time. The TENC paired with the latent topics significantly improves performance over the baseline classifiers that only take into account the static properties of the topics and communications. The results show that the TENC can be used to accurately model the complete-set of temporal dynamics in time-evolving communication networks.
Inhibition of glycogenolysis in astrocytes interrupts memory consolidation in young chickens (2006)

Glycolysis and glycogenolysis are involved in memory processing in day-old chickens and, aside from the provision of energy for neuronal and astrocytic energy metabolism these pathways enable astrocytes to supply neurones with precursor for transmitter glutamate by glucose-based de novo synthesis. We have previously shown that memory processing for bead discrimination learning is dependent on glycolysis; however, the metabolic inhibitor used, iodoacetate, inhibits pyruvate formation from both glucose and glycogen. At specific time points after training transient reductions in brain glycogen content occur, mirrored by increases in glutamate/glutamine content. In the present study, we used intracerebral injection of a glycogen phosphorylase inhibitor, 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), which does not affect glucose breakdown, to evaluate the role of glycogen metabolism in memory consolidation. Dose-dependent inhibition of learning occurred when DAB was administered at specific time periods in relation to training: (i) 5 min before training, (ii) around 30 min posttraining, and (iii) 55 min posttraining. After injection at either of the two earlier periods, memory disappeared after consolidation 30 min postlearning, and after injection 55 min after learning memory was absent at 70 min. The memory loss caused by early administration could be prevented after training by central injection of the glutamate precursor glutamine or the astrocyte-specific substrate acetate together with aspartate, substituting for pyruvate carboxylation. Thus, glycogenolysis is essential for learning in this paradigm and, aside from energy supply considerations, we suggest that an important role for glycogenolysis is to provide neurones with glutamine as the precursor for neuronal glutamate and GABA.
Coplanar waveguide feeds for phased array antennas (1992)

The design and performance is presented of the following Coplanar Waveguides (CPW) microwave distribution networks for linear as well as circularly polarized microstrip patches and dipole arrays: (1) CPW/Microstrip Line feed; (2) CPW/Balanced Stripline feed; (3) CPW/Slotline feed; (4) Grounded CPW/Balanced coplanar stripline feed; and (5) CPW/Slot coupled feed. Typical measured radiation patterns are presented, and their relative advantages and disadvantages are compared.
Macrophage Endocytosis of Superparamagnetic Iron Oxide Nanoparticles (2003)

Rationale and objectives Superparamagnetic iron oxides (SPIO) used as magnetic resonance (MR) contrast agents undergo specific uptake by macrophages. The purpose of this study was first to determine the mechanism of macrophage uptake for Ferumoxides by using competition experiments with specific ligands of scavenger receptors SR-A (I/II) and second, to evaluate and compare the internalization of 2 different contrast agents, Ferumoxides (SPIO) and Ferumoxtran-10 (USPIO: ultrasmall superparamagnetic iron oxide) using macrophages obtained by chemical activation of human monocytic cells. Methods Ferumoxides and Ferumoxtran-10 are 2 MR contrast agents, composed of dextran-coated iron oxide nanoparticles. The endocytosis pathway of Ferumoxides was studied using competition experiments on mouse peritoneal macrophages in the presence of specific ligands of scavenger receptors SR-A (types I and II): polyinosinic acid and fucoidan. In vitro assays using THP-1 (human promonocyte) cells activated into macrophages were performed in the presence of the 2 superparamagnetic nanoparticles. The cellular uptake was determined by measuring the iron content using ICP-AES (inductively coupled plasma–atomic emission spectrometry) and by Prussian blue staining. Results In the presence of polyinosinic acid or fucoidan, the endocytosis of Ferumoxides by mouse peritoneal macrophages was inhibited. This inhibition was obtained using 10 μg/mL of scavenger receptor ligands at a concentration of 62.5 μg Fe/mL of SPIO, and a dose-dependent relationship was observed. Without competitors, the percentage of uptake of Ferumoxides by mouse peritoneal macrophages ranged between 3 and 8%. On the human activated monocyte THP-1 cell assay, Ferumoxides underwent a higher macrophage uptake (between 1.1 and 3%) compared with Ferumoxtran-10 (between 0.03 and 0.12%). This difference is attributed to the larger size of Ferumoxides nanoparticles. Conclusions Competition experiments indicate that the cellular uptake of Ferumoxides involves scavenger receptor SR-A-mediated endocytosis. The comparison between Ferumoxides and Ferumoxtran-10 confirms that macrophage uptake of iron oxide nanoparticles depends mainly on the size of these contrast agents.
Tetrabenazine in the treatment of hyperkinetic movement disorders (2006)

Tetrabenazine, a dopamine-depleting agent first synthesized half a century ago, was initially developed for the treatment of schizophrenia. Although psychotic disorders have since been treated more successfully with other neuroleptic medications, many studies have shown this drug to be effective in the treatment of hyperkinetic movement disorders (hyperkinesias). Hyperkinesias are neurologic disorders characterized by abnormal involuntary movements such as chorea associated with Huntington's disease, tics in Tourette's syndrome and stereotypies in tardive dyskinesia. Recently, clinical trials investigating tetrabenazine for the treatment of chorea associated with Huntington's disease found the drug to be safe and efficacious, making approval by the US Food and Drug Administration for this indication a distinct possibility.
Effects of nitric oxide and nitrogen dioxide on bacterial growth (1983)

The effects of low concentrations of nitric oxide (NO) and nitrogen dioxide (NO2) on actively dividing cultures of Staphylococcus aureus, Micrococcus luteus, Micrococcus roseus, Serratia marcescens, Bacillus subtilis, Bacillus circulans, Bacillus megaterium, and Bacillus cereus were studied. Fresh cultures of each organism were incubated for 24 h at 25 degrees C on both nutrient agar and mineral salts glucose agar plates under atmospheres containing various low concentrations of NO in air (0 to 1.9 ppm [0 to 2.0 micrograms/g of air]), NO2 in air (0 to 5.5 ppm [0 to 8.8 micrograms/g of air]), or NO and NO2 in air. Bacteria grown under air only were used as controls. After incubation, the colonies that developed on the plates were counted. None of the bacteria tested was affected by NO or NO2 at the indicated concentrations while growing on nutrient agar. Serratia marcescens, B. circulans, B. subtilis, B. megaterium, and B. cereus grown on mineral salts glucose agar were not significantly affected by NO or NO2. Low concentrations (0 to 1.9 ppm) of NO were bacteriostatic to log-phase cultures of M. roseus, M. luteus, and Staphylococcus aureus grown on mineral salts glucose agar. Bacteriostatic activity over a 24-h interval was maximal at an initial NO concentration of 1 ppm. Appreciable amounts of NO2 were produced in 24 h at initial NO concentrations greater than 1 ppm. These results suggest that NO2 may reduce the bacteriostatic activity of NO. Low concentrations (0 to 5.5 ppm) of NO2 in air did not affect any of the bacteria tested. At these low concentrations, NO affected bacterial growth, although NO2, NO2-, and NO3- did not. In addition, it was determined that the bacteriostatic activity observed in this study was not due to an increase in the acidity of the medium.
Legends as a Device for Interacting with Visualizations (2001)

Users and developers of visualization tools must deal with the problem of specifying what information to show and how to represent it. Typically, the user's focus of interest will change over time, and the specifications must change with the user's interests. Techniques for the simple, direct, and intuitive creation and refinement of these specifications can be useful. In this paper we show how legends, a natural element of graphical displays, may be used as a direct and unobstrusive interaction device through which users may interactively specify new visualizations and animations.
Effects of a new mixture of prebiotics on faecal flora and stools in term infants (2003)

A double-blind, randomized, controlled study was performed in 90 full term infants to evaluate dose-related bifidogenic effects of a new synergistic mixture of galacto-oligosaccharides (GOS) and fructo-oligosacharides (FOS). The GOS/FOS mixture showed a dose-dependent stimulatory effect on the intestinal growth of bifidobacteria. Also stool consistency and faecal pH were positively affected.
Isolation of a cDNA cLone Derived from a Blood-Borne Non-A, Non-B Viral Hepatitis Genome (1989)

A random-primed complementary DNA library was constructed from plasma containing the uncharacterized non-A, non-B hepatitis (NANBH) agent and screened with serum from a patient diagnosed with NANBH. A complementary DNA clone was isolated that was shown to encode an antigen associated specifically with NANBH infections. This clone is not derived from host DNA but from an RNA molecule present in NANBH infections that consists of at least 10,000 nucleotides and that is positive-stranded with respect to the encoded NANBH antigen. These data indicate that this clone is derived from the genome of the NANBH agent and are consistent with the agent being similar to the togaviridae or flaviviridae. This molecular approach should be of great value in the isolation and characterization of other unidentified infectious agents.
Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer (2017)

SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1-20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p<0.001), female sex (odds ratio 1.71; p = 0.02), and shorter overall survival than in wild-type SMAD4 cases (median, 29 months versus 56 months; hazard ratio 2.08; p<0.001 [log-rank test]). SMAD4 mutation was not associated with age, stage at presentation, colonic location, distant metastasis, or tumor grade. A subset of patients with metastatic CRC (n = 44) wild-type for KRAS, NRAS, and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 (n = 13) had shorter progression-free survival duration than did patients wild-type for SMAD4 (n = 31) (median, 111 days versus 180 days; p = 0.003 [log-rank test]). Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations. In The Cancer Genome Atlas data, SMAD4 mutation frequently occurred with KRAS, NRAS, and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes. This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy. Further studies are required to validate these findings and the role of SMAD4 mutation in CRC.
Common Cytokine Receptor γ chain (γc)‐Dependent Cytokines: Understanding in vivo Functions by Gene Targeting (1995)

The common cytokine receptor gamma chain (gamma c) plays a critical role in lymphoid development through its participation in the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Absence of gamma c results in abnormal lymphopoiesis and immunodeficiency, as evidence by X-linked severe combined immunodeficiency (SCIDX1) in man, and in the corresponding canine and murine models of SCIDX1. Comparison of the phenotypes of mutant mice made deficient for gamma c-dependent cytokines by gene targeting, allows us to define a hierarchy of gamma c-dependent cytokine function in lymphoid development. The participation of distinct cytokine/receptor interactions in the generation, maintenance and regulation of the immune system suggests that developmental steps may be controlled by individual cytokines. The mechanisms by which different cytokine signaling pathways achieve this process remain to be elucidated.
Development of 11&#946; -HSD1 Inhibitors for the Treatment of Type 2 Diabetes (2008)

Glucocorticoid action is linked to the development of obesity and insulin resistance. Inhibition of 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a strategy to suppress glucocorticoid action in a tissue-specific manner. A large variety of 11β-HSD1 inhibitor classes are under investigation by the pharmaceutical industry to treat type 2 diabetes and obesity.