gebhart/patrepeval huggingface dataset:
CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling (2007)

Lysophosphatidic acid receptors stimulate a Galpha(12/13)/RhoA-dependent gene transcription program involving the serum response factor (SRF) and its coactivator and oncogene, megakaryoblastic leukemia 1 (MKL1). Inhibitors of this pathway could serve as useful biological probes and potential cancer therapeutic agents. Through a transcription-based high-throughput serum response element-luciferase screening assay, we identified two small-molecule inhibitors of this pathway. Mechanistic studies on the more potent CCG-1423 show that it acts downstream of Rho because it blocks SRE.L-driven transcription stimulated by Galpha(12)Q231L, Galpha(13)Q226L, RhoA-G14V, and RhoC-G14V. The ability of CCG-1423 to block transcription activated by MKL1, but not that induced by SRF-VP16 or GAL4-VP16, suggests a mechanism targeting MKL/SRF-dependent transcriptional activation that does not involve alterations in DNA binding. Consistent with its role as a Rho/SRF pathway inhibitor, CCG-1423 displays activity in several in vitro cancer cell functional assays. CCG-1423 potently (<1 mumol/L) inhibits lysophosphatidic acid-induced DNA synthesis in PC-3 prostate cancer cells, and whereas it inhibits the growth of RhoC-overexpressing melanoma lines (A375M2 and SK-Mel-147) at nanomolar concentrations, it is less active on related lines (A375 and SK-Mel-28) that express lower levels of Rho. Similarly, CCG-1423 selectively stimulates apoptosis of the metastasis-prone, RhoC-overexpressing melanoma cell line (A375M2) compared with the parental cell line (A375). CCG-1423 inhibited Rho-dependent invasion by PC-3 prostate cancer cells, whereas it did not affect the Galpha(i)-dependent invasion by the SKOV-3 ovarian cancer cell line. Thus, based on its profile, CCG-1423 is a promising lead compound for the development of novel pharmacologic tools to disrupt transcriptional responses of the Rho pathway in cancer.
Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors (1994)

Since activated factor X (FXa) is a coagulant enzyme that generates thrombin and participates in both intrinsic and extrinsic coagulation pathways, inhibition of FXa may be more effective than inactivation of thrombin for interrupting blood coagulation. To assess the possible effectiveness of FXa inhibition as an anticoagulant, we designed and synthesized 3-(amidinoaryl)-2-[4-[(3S)-3-pyrrolidinyloxy]phenyl]propanoi c acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selective anti-FXa activity in vitro and anticoagulant activity on oral administration. The most promising compound, (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]- 3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4,DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 microM, doubled plasma recalcification time (PRCT) at 0.5 microM, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 100 mg/kg on oral administration. In contrast with FXa inhibition, 4 showed no activity against thrombin (IC50 > 2000 microM).
The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance. (2000)

Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.
On the automatic modularization of software systems using the Bunch tool (2006)

Since modern software systems are large and complex, appropriate abstractions of their structure are needed to make them more understandable and, thus, easier to maintain. Software clustering techniques are useful to support the creation of these abstractions by producing architectural-level views of a system's structure directly from its source code. This paper examines the Bunch clustering system which, unlike other software clustering tools, uses search techniques to perform clustering. Bunch produces a subsystem decomposition by partitioning a graph of the entities (e.g., classes) and relations (e.g., function calls) in the source code. Bunch uses a fitness function to evaluate the quality of graph partitions and uses search algorithms to find a satisfactory solution. This paper presents a case study to demonstrate how Bunch can be used to create views of the structure of significant software systems. This paper also outlines research to evaluate the software clustering results produced by Bunch.
A rapid direct fluorescent assay for cell-free DNA quantification in biological fluids (2009)

The direct SYBR Gold assay proved to be an accurate and simple technique for measuring CFD in biological fluids.
Genome scale analysis of diffusible signal factor regulon in Xanthomonas campestris pv. campestris: identification of novel cell–cell communication‐dependent genes and functions (2005)

The bacterial pathogen Xanthomonas campestris pv. campestris (Xcc) recruits a diffusible signal factor (DSF), which has recently been structurally characterized as cis-11-methyl-2-dodecenoic acid, as a cell-cell communication signal to synchronize virulence gene expression and biofilm dispersal. In this study, we showed that despite the existance of phenotype variations in different Xcc isolates, the DSF-mediated functions were in general conserved. To investigate the genomic profiles of DSF regulation, we designed and conducted oligomicroarray analysis by comparison of the gene expression patterns of wild-type strain XC1 and its DSF-deficient mutant XC1dF, as well as those of XC1dF in the presence or absence of DSF signals. The analyses led to identification of 165 genes, whose expression was significantly influenced by DSF signals. These genes encode proteins and enzymes belonging to at least 12 functional groups. In addition to those previously known DSF-dependent activities such as production of extracellular enzymes and extracellular polysaccharides, microarray analyses also revealed new functions mediated by DSF, such as flagellum synthesis, resistance to toxins and oxidative stress, and aerobic respiration. Phenotype analyses confirmed that DSF signalling contributed to resistance to toxin acriflavin and hydrogen peroxide, and to the survival of bacterial cells at different temperatures. We conclude that DSF cell-cell signalling is not only essential for co-ordinating the expression of virulence genes but also plays a vital role in keeping up the general competence of the pathogen in ecosystems.
Metal–organic frameworks with designed chiral recognition sites (2010)

Linking struts containing Cram-like bisbinaphthyl[22]crown-6 with Zn(4)O(CO(2))(6) joints affords metal-organic frameworks with chiral recognition sites that are highly designed, ordered and placed in a precise manner throughout the entire crystal.
The epidemiology of surgically treated acute subdural and epidural hematomas in patients with head injuries: a population-based study. (2008)

Acute post-traumatic EDHs and/or SDHs are relatively rare (0.83/100,000 population per annum) and are generally associated with good outcomes. Death was more likely among older, more severely injured patients and among those who required surgery for SDH rather than EDH.
Enzymatic Polymerization of High Molecular Weight DNA Amphiphiles That Self‐Assemble into Star‐Like Micelles (2014)

High molecular weight ssDNA amphiphiles are synthesized by enzymatic polymerization. These highly asymmetric diblock DNA copolymers self-assemble into "hairy", star-like micelles, shown in the AFM image and the DPD snapshot.
Signaling microdomains in T cells (2010)

Sub-micron scale signaling domains induced in the plasma membrane of cells are thought to play important roles in signal transduction. In T cells, agonist MHC-peptide complexes induce small diffraction-limited domains enriched in T cell receptor (TCR) and signaling molecules. These microclusters serve as transient platforms for signal initiation and are required for sustained signaling in T cells, although each microcluster functions for only a couple of minutes. How they are formed, and what mechanisms promote and regulate signaling within TCR microclusters is largely unknown, although it is clear that TCR engagement and dynamic reorganization of cortical actin are involved. Here, we review current understanding of signaling within microclusters in T cells, and speculate on how these structures may form, initiate biochemical signals, and serve as sites of both signal integration and amplification, while also facilitating appropriate termination of TCR and related signaling.
Structure of eltoprazine (1992)

Crystal data: P2 1 2 1 2 1 , a=7.315, b=7.941, c=21.393 A, R=0.069. The piperazine ring adopts an almost perfect chair conformation and the dihydro-1,4-dioxine ring a half-chair conformation.
Mesenchymal Stem Cells Instruct Oligodendrogenic Fate Decision on Adult Neural Stem Cells (2006)

Adult stem cells reside in different tissues and organs of the adult organism. Among these cells are MSCs that are located in the adult bone marrow and NSCs that exist in the adult central nervous system (CNS). In transplantation experiments, MSCs demonstrated neuroprotective and neuroregenerative effects that were associated with functional improvements. The underlying mechanisms are largely unidentified. Here, we reveal that the interactions between adult MSCs and NSCs, mediated by soluble factors, induce oligodendrogenic fate decision in NSCs at the expense of astrogenesis. This was demonstrated (a) by an increase in the percentage of cells expressing the oligodendrocyte markers GalC and myelin basic protein, (b) by a reduction in the percentage of glial fibrillary acidic protein (GFAP)-expressing cells, and (c) by the expression pattern of cell fate determinants specific for oligodendrogenic differentiation. Thus, it involved enhanced expression of the oligodendrogenic transcription factors Olig1, Olig2, and Nkx2.2 and diminished expression of Id2, an inhibitor of oligodendrogenic differentiation. Results of (a) 5-bromo-2'-deoxyuridine pulse-labeling of cells, (b) cell fate analysis, and (c) cell death/survival analysis suggested an inductive mechanism and excluded a selection process. A candidate factor screen excluded a number of growth factors, cytokines, and neurotrophins that have previously been shown to influence neurogenesis and neural differentiation from the oligodendrogenic activity derived from the MSCs. This work might have major implications for the development of future transplantation strategies for the treatment of degenerative diseases in the CNS.
Arginine vasopressin receptor gene-based single-nucleotide polymorphism analysis in attention deficit hyperactivity disorder (2009)

van West, Dirka c d e; Del-Favero, Jurgena c; Deboutte, Dirkd e; Van Broeckhoven, Christineb c; Claes, Stephana c f Author Information
Differential Responses of the Nrf2-Keap1 System to Laminar and Oscillatory Shear Stresses in Endothelial Cells (2005)

The Nrf2-Keap1 system coordinately regulates cytoprotective gene expression via the antioxidant responsive element (ARE). The expression of several ARE-regulated genes was found to be up-regulated in endothelial cells by laminar shear stress, suggesting that Nrf2 contributes to the anti-atherosclerosis response via the ARE. To gain further insight into the roles that Nrf2 plays in the development of atherosclerosis, we examined how Nrf2 regulates gene expression in response to anti-atherogenic laminar flow (L-flow) or pro-atherogenic oscillatory flow (O-flow). Exposure of human aortic endothelial cells (HAECs) to L-flow, but not to O-flow, induced the expression of cytoprotective genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1) by 5-fold and heme oxygenase-1 by 8-fold. The critical contribution of Nrf2 to the expression induced by L-flow was ascertained in siRNA-mediated knock-down experiments. Two cyclooxygenase-2 (COX-2) specific inhibitors attenuated Nrf2 nuclear accumulation in the acute phase of L-flow exposure. A downstream product of COX-2, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), activated the Nrf2 regulatory pathway in HAECs through binding to the cysteines of Keap1. These results demonstrate that 15d-PGJ2 is essential for L-flow to activate Nrf2 and induce anti-atherosclerotic gene expression. Whereas both L-flow and O-flow induced the nuclear accumulation of Nrf2 to comparable levels, chromatin immunoprecipitation analysis revealed that Nrf2 binding to the NQO1 ARE was significantly diminished in the case of O-flow compared with that of L-flow. These results suggest that O-flow inhibits Nrf2 activity at the DNA binding step, thereby suppressing athero-protective gene expression and hence predisposing the blood vessels to the formation of atherosclerosis.
Rectilinear block placement using B*-trees (2002)

Due to the layout complexity in deep sub-micron technology, integrated circuit blocks are often not rectangular. However, literature on general rectilinear block placement is still quite limited. In this paper, we present approaches for handling the placement for arbitrarily shaped rectilinear blocks, based on a newly developed data structure called B*-trees. Experimental results show that our algorithm achieves optimal or near optimal block placement for benchmarks with multiple shaped blocks.
Albumin‐Coated Amberlite XAD‐7 Resin for Hemoperfusion in Acute Liver Failure: Part I: Adsorption Studies (1979)

Platelets adhere to most foreign surfaces. As a result, polymers and albumin have been suggested as possible coatings to improve the blood compatibility of such surfaces. Amberlite XAD-7 has a high affinity for human serum albumin (HSA) and several protein-bound toxic metabolites. In the present study it is shown that HSA can be tightly bound to Amberlite XAD-7 without the use of chemical coupling agents. Optimal binding was achieved at pH 5.0 and the adsorption conforms to Langmuir's isotherm. Theoretical analysis of data and absence of a residual surface coating visible with scanning electron microscopy suggest a monolayer of albumin. The amount of HSA eluted from the resin under severe flow conditions was negligible (approximately 1%). Furthermore, in stirred batch studies with human plasma, the HSA coating did not decrease the adsorptive capacity of XAD-7 for bile acids and bilirubin.
Mammography Screening (1994)

Five experienced screeners independently and blindly reviewed mammograms from the first screening round of 46 healthy women, and of 74 women who had histologically proven breast cancers in the first screening round or later. The films were reviewed first as one-view screening and later as two-view screening. Fifty-one breast cancers were detected by at least one of the screeners on either one-view or two-view screening. The mean increase in sensitivity by using two views, instead of one, was 2%. The median of the proportional increase in detected cancers as the result of independent double reading was 14.5% with one-view screening and 12% with two-view screening. Two screeners using one-view screening detected about 10% more cancers than one screener using two-view screening.
Comparative analysis of discrete exosome fractions obtained by differential centrifugation (2014)

Specific g-force/k factor usage during differential centrifugation greatly influences the purity and yield of exosomes. The vesicle sedimentation profile differed between the 2 cell lines.
Antisense suppression of phospholipase D alpha retards abscisic acid- and ethylene-promoted senescence of postharvest Arabidopsis leaves. (1997)

Membrane disruption has been proposed to be a key event in plant senescence, and phospholipase D (PLD; EC 3.1.4.4) has been thought to play an important role in membrane deterioration. We recently cloned and biochemically characterized three different PLDs from Arabidopsis. In this study, we investigated the role of the most prevalent phospholipid-hydrolyzing enzyme, PLD alpha, in membrane degradation and senescence in Arabidopsis. The expression of PLD alpha was suppressed by introducing a PLD alpha antisense cDNA fragment into Arabidopsis. When incubated with abscisic acid and ethylene, leaves detached from the PLD alpha-deficient transgenic plants showed a slower rate of senescence than did those from wild-type and transgenic control plants. The retardation of senescence was demonstrated by delayed leaf yellowing, lower ion leakage, greater photosynthetic activity, and higher content of chlorophyll and phospholipids in the PLD alpha antisense leaves than in those of the wild type. Treatment of detached leaves with abscisic acid and ethylene stimulated PLD alpha expression, as indicated by increases in PLD alpha mRNA, protein, and activity. In the absence of abscisic acid and ethylene, however, detached leaves from the PLD alpha-deficient and wild-type plants showed a similar rate of senescence. In addition, the suppression of PLD alpha did not alter natural plant growth and development. These data suggest that PLD alpha is an important mediator in phytohormone-promoted senescence in detached leaves but is not a direct promoter of natural senescence. The physiological relevance of these findings is discussed.
Retention of imprinting of the human apoptosis-related gene TSSC3 in human brain tumors (2000)

Genomic imprinting is the result of a gamete-specific modification leading to parental origin-specific gene expression in somatic cells of the offspring. Several embryonal tumors show loss of imprinting of genes clustered in human chromosome 11p15.5, an important tumor suppressor gene region, harboring several normally imprinted genes. TSSC3, a gene homologous to mouse TDAG51, implicated in Fas-mediated apoptosis, is also located in this region between hNAP2 and p57 (KIP2). TSSC3 is the first apoptosis-related gene found to be imprinted in placenta, liver and fetal tissues where it is expressed from the maternal allele in normal human development. This study investigated the imprinting status of TSSC3 in human normal, adult brain and in human neuroblastomas, medulloblastomas and glioblastomas. A polymorphism in exon 1 at position 54 was used to analyze the allelic expression of the TSSC3 gene by a primer oligo base extension (PROBE) assay using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). We found that the TSSC3 gene is not imprinted in human normal, adult brain and blood. In contrast, strong allelic bias resembling imprinting could be detected in most examined tumor specimens. The results demonstrate for the first time that the tumors under investigation are associated with a retention of imprinting of a potential growth inhibitory gene.
Etanercept-induced systemic lupus erythematosus (2003)

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Etanercept (Enbrel; Immunex Corp., Seattle, WA, USA) is a recombinant soluble fusion protein of TNF-alpha type II receptor and IgG which acts by blocking the action of TNF-alpha. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis. A number of studies report the development of antinuclear and anti-double-stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept-induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.
Characterization of Attenuated Strains of Rift Valley Fever Virus (1988)

The wild-type ZH501 strain of Rift Valley fever (RVF) virus and two small-plaque strains (T1 and T46) derived from it were characterized by plaque size, pathogenicity for hamsters and ability to replicate in Vero cells. Additionally, a mutagenized, attenuated, large-plaque, vaccine-candidate strain of RVF virus (ZH548-M12) was also studied. Infections with either the ZH501 or T46 strain were uniformly fatal to hamsters. In contrast, nearly all hamsters infected with either the T1 or ZH548-M12 strains survived and were immune to challenge with 10(5) LD50 of the ZH501 strain. Both of these attenuated strains failed to replicate in Vero cells maintained at 41 degrees C, whereas the more virulent strains (ZH501 and T46) replicated at this temperature. The low virulence and ability to induce protection against lethal RVF virus challenge that is associated with the T1 and ZH548-M12 strains make them potential vaccine candidates.
In Vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse (1999)

Delivery of therapeutic proteins into tissues and across the blood-brain barrier is severely limited by the size and biochemical properties of the proteins. Here it is shown that intraperitoneal injection of the 120-kilodalton beta-galactosidase protein, fused to the protein transduction domain from the human immunodeficiency virus TAT protein, results in delivery of the biologically active fusion protein to all tissues in mice, including the brain. These results open new possibilities for direct delivery of proteins into patients in the context of protein therapy, as well as for epigenetic experimentation with model organisms.