gebhart/patrepeval huggingface dataset:
Effects of Melagatran, a New Low-molecular-weight Thrombin Inhibitor, on Thrombin and Fibrinolytic Enzymes (1998)

Melagatran, a new, competitive and rapid inhibitor of thrombin with a molecular mass of 429 Da is described. Melagatran is well tolerated when administered in very high doses, and the oral bioavailability in the dog is relatively high. The aim of the study was to determine, in the preclinical setting, the degree of selectivity against the fibrinolytic system required for entering the clinical development phase. Melagatran was compared with two structurally similar thrombin inhibitors, inogatran and H 317/86. The potent inhibition of thrombin by melagatran was demonstrated by a low inhibition constant (Ki) for thrombin (0.002 micromol/l) and prolongation of clotting time to twice the control value in coagulation assays at low concentrations (0.010, 0.59 and 2.2 micromol/l for thrombin time, activated partial thromboplastin time and prothrombin time, respectively). Furthermore, thrombin-induced platelet aggregation was inhibited at the same concentration (IC50-value 0.002 micromol/l) as the Ki-value for thrombin. In two assays of global fibrinolysis, inhibition was observed at a concentration of 1.1 micromol/l in a euglobulin plasma fraction model, while no inhibition was observed at a concentration of < or = 10 micromol/l in a plasma model. In an in vivo model of endogenous fibrinolysis in the rat, inhibition of fibrinolysis was observed at > or = 1.0 micromol/l. In all assays, except the Ki-ratio determinations, the compounds could be graded with regard to selectivity against the fibrinolytic system: inogatran > melagatran > H 317/86. For melagatran, inhibition of fibrinolysis was not observed at concentrations below the upper limit of the proposed therapeutic plasma concentration interval (< 0.5 micromol/l). Thus, melagatran seems to have a sufficient selectivity against the fibrinolytic system, while H 317/86 was considered to be insufficient for clinical development.
Meta-programming for the real world (2004)

JeeWiz is a commercial tool for model-driven generation of enterprise-level systems. It can automate any part of the development process where repetitive work is required by meta-programming. JeeWiz is universal - being based on a meta modelling approach, it can describe and generate any software technology. It is used for both system-level generation (multi-tier J2EE,.NET, SOA systems) and design-level transformation (XMI to WSDL/XML Schema, and back). The most difficult problem we have confronted is the complexity of mapping from rich, high-level logical models to the detailed artifacts required in real-life systems. Some of the features JeeWiz provides to address this are: reusable architecture and technology layers; local flexibility and cross-tier patterns; and strategies for shielding application programmers from the complexity of infrastructures.
Preparation and Optical Properties of Novel 3-Alkoxycarbonyl Aza- and Diazacoumarins (2010)

International audience
Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation (2015)

Although anti-retroviral therapy (ART) is highly effective in suppressing HIV replication, it fails to eradicate the virus from HIV-infected individuals. Stable latent HIV reservoirs are rapidly established early after HIV infection. Therefore, effective strategies for eradication of the HIV reservoirs are urgently needed. We report that ingenol-3-angelate (PEP005), the only active component in a previously FDA approved drug (PICATO) for the topical treatment of precancerous actinic keratosis, can effectively reactivate latent HIV in vitro and ex vivo with relatively low cellular toxicity. Biochemical analysis showed that PEP005 reactivated latent HIV through the induction of the pS643/S676-PKCδ/θ-IκBα/ε-NF-κB signaling pathway. Importantly, PEP005 alone was sufficient to induce expression of fully elongated and processed HIV RNAs in primary CD4+ T cells from HIV infected individuals receiving suppressive ART. Furthermore, PEP005 and the P-TEFb agonist, JQ1, exhibited synergism in reactivation of latent HIV with a combined effect that is 7.5-fold higher than the effect of PEP005 alone. Conversely, PEP005 suppressed HIV infection of primary CD4+ T cells through down-modulation of cell surface expression of HIV co-receptors. This anti-cancer compound is a potential candidate for advancing HIV eradication strategies.
STAT3 mRNA and protein expression in colorectal cancer: effects on STAT3-inducible targets linked to cell survival and proliferation (2007)

Both inactive (UP-STAT3) and active (P-STAT3) STAT3 proteins are markedly increased in invasive CRCs. This is associated with Bcl-xl and survivin induction, increased proliferation and lymph node metastasis. This study therefore provides the basis for further examination of the prognostic or predictive value of these molecular markers in CRC.
Inhibitory receptors abound? (1997)

Receptor biologists have traditionally focused on receptors that are physiologically coupled to inductive responses such as gene expression, cytokinesis, secretion, or entry into the cell cycle. It has generally been assumed that such inductive responses were terminated by ligand decay or receptor desensitization, which lead to cessation of signaling. While such mechanisms are clearly operative, a number of recent experiments have demonstrated that inhibitory receptors exist that function to attenuate inductive signals and further indicate that these receptors play a very important regulatory role in biology. Relatively few inhibitory receptors have been defined in part because the effects of these receptors can only be detected against the backdrop of an inductive signal. However, this situation is rapidly changing as recent pioneering studies have provided new approaches to isolation of such receptors. Three reports published in recent months (1–3), one by Kubagawa et al. in the Proceedings (1), have identified two new extended families of cell surface proteins that may function as inhibitory receptors. These findings are discussed below in the context of known inhibitory receptors and their mode of action (Table 1).
Effect of a multiple-site intensive care unit telemedicine program on clinical and economic outcomes: An alternative paradigm for intensivist staffing* (2004)

The addition of a supplemental, telemedicine-based, remote intensivist program was associated with improved clinical outcomes and hospital financial performance. The magnitude of the improvements was similar to those reported in studies examining the impact of implementing on-site dedicated intensivist staffing models; however, factors other than the introduction of off-site intensivist staffing may have contributed to the observed results, including the introduction of computer-based tools and the increased focus on ICU performance. Although further studies are needed, the apparent success of this on-going multiple-site program, implemented with commercially available equipment, suggests that telemedicine may provide a means for hospitals to achieve quality improvements associated with intensivist care using fewer intensivists.
Development of a broad-host-range phage cocktail for biocontrol (2011)

The aims of this study were to investigate the incidence of different resistance mechanisms to phage K in a bank of Irish Staph aureus hospital strains; and to develop a broad host-range phage cocktail with enhanced lytic activity against those strains which were previously phage resistant. A bank of 180 Staph aureus strains, which included all the sequence types currently in existence in Ireland, were tested for sensitivity to phage K. Twenty nine strains were identified, which did not permit plaque formation. The phage resistance systems in the 29 strain were investigated and it was found that restriction modification (r-m) was evident in 24, an adsorption inhibition mechanism was evident in three, while two were resistant by an unidentified mechanism. Seventeen modified derivatives of phage K were developed which could circumvent all the r-m systems. Nevertheless, six of the modified phage were considered superior in terms of their individual host ranges. These six were pooled as a cocktail with phage K, which then lysed 24 of the 29 resistant strains (97.2% of the entire staphylococcal bank). In conclusion, phage resistant systems affecting phage K are common in Staph. aureus but it is possible to significantly broaden the host-range of this phage for biocontrol applications.
Synthesis and Evaluation of Iron Chelators with Masked Hydrophilic Moieties (2002)

Synthetic iron chelators based on the natural siderophore ferrichrome have previously been shown to bind Fe(III) with high affinity (pKf > 27) and have shown no toxicity to mammalian cell cultures in vitro. A new class of lipophilic ferrichrome analogues carrying acetoxymethyl ester moieties has been synthesized. We have shown that these molecules penetrate rapidly through cell membranes and turn highly hydrophilic while inside the cells, upon esterase mediated hydrolysis of the lipophilic termini. The intracellular retention was visualized by labeling these analogues with a fluorescent naphthalic diimide probe. The prohydrophilic iron chelators have been shown to inhibit the metal-catalyzed intracellular formation of reactive oxygen species with high effectivity, and preliminary results suggest these molecules to be potent antimalarial agents.
Perineural Invasion, Mucinous Fibroplasia, and Glomerulations (1999)

The diagnosis of prostate cancer on needle biopsy is based on a constellation of histologic features. There are, however, three histologic findings that are diagnostic of prostate carcinoma: perineural invasion (PNI), mucinous fibroplasia, and glomerulations. We prospectively identified core needle biopsies during a 5-month period in which one of these three entities was the key diagnostic feature of carcinoma within the biopsy specimen. Of 1480 consult cases reviewed, the following were key features to the diagnosis of very limited carcinoma: PNI (n = 9; 0.6%), mucinous fibroplasia (n = 2; 0.1%), and glomerulations (n = 0). To assess the incidence of PNI as the key feature, we also analyzed reports from Dianon during a 1-year period. Of approximately 16,300 Dianon needle biopsies with cancer, 12(0.07%) cases had PNI as the key diagnostic feature. Six of these 12 cases were also consult cases. Of the total of 15 cases with PNI, cancer was limited with 11 of the cases showing involvement of only one nerve. The median number of glands per nerve was five (range, 1-15). In addition to PNI, malignant cytologic features included amphophilic cytoplasm in 11 of 11 assessable cases and nuclear enlargement and hyperchromasia in 11 of 15 cases. Other malignant features were limited. Twelve cases showed rare to no visible nucleoli. Two cases had eosinophilic intraluminal debris. Blue mucin, crystalloids, and mitoses were absent in all cases. Nine of the 15 cases of PNI and the two cases of mucinous fibroplasia were verified as carcinoma with immunohistochemistry using high molecular weight cytokeratin. In rare cases, PNI is virtually the sole finding necessary to establish the diagnosis of carcinoma on needle biopsy. Although mucinous fibroplasia and glomerulations are also considered diagnostic of carcinoma, their occurrence alone without more conventional forms of carcinoma is even more rare.
Identification of two distinct NADH oxidases corresponding to H2O2-forming oxidase and H2O-forming oxidase induced in Streptococcus mutans (1993)

Two distinct NADH oxidases, corresponding to H2O2-forming and H2O-forming enzymes were purified to homogeneity from Streptococcus mutans and their basic properties determined. The H2O2-forming enzyme was a tetramer with a subunit molecular mass of about 56 kDa and required flavin adenine dinucleotide (FAD) for full activity. The enzyme had an isoelectric point of 6.6 and exhibited optimal activity at pH 6.0. The H2O-forming enzyme was a monomer with a molecular mass of 50 kDa and activity independent of exogenously added flavin. The enzyme had an isoelectric point of 4.8 and exhibited optimal activity between pH 7.0 and 7.5. Both enzymes oxidized NADH (Km 0.05 and 0.025 mM for the H2O2- and H2O-forming enzyme, respectively) but not NADPH and contained 1 mol of FAD per monomer. Spectra of the oxidized enzymes exhibited maxima at 271, 383 and 449 nm for the H2O2-forming enzyme and 271, 375 and 447 nm for the H2O-forming enzyme. Antibodies raised against the H2O2-forming enzyme or the H2O-forming enzyme reacted with their corresponding antigen, but did not cross-react. The amino-terminal regions of the two enzymes had completely different amino acid sequences.
MRMOGA: parallel evolutionary multiobjective optimization using multiple resolutions (2005)

Whereas multiobjective evolutionary algorithms have reached certain effectiveness in solving many real-world problems efficiency still remains as an open problem. One choice to reduce the execution time of the multiobjective evolutionary algorithms is their parallelization. This paper introduces a parallel MOEA which is based on the island model with heterogeneous nodes. This algorithm is characterized by encoding the solutions using a different resolution for each island. In this way, the search space is divided into well-defined overlapped regions in decision variable space.
Integration of Calcium and Cyclic AMP Signaling Pathways by 14-3-3 (2000)

Calcium-stimulated nuclear factor of activated T cells (NFAT) transcription activity at the interleukin-2 promoter is negatively regulated by cyclic AMP (cAMP). This effect of cAMP is mediated, in part, by protein kinase A phosphorylation of NFAT. The mechanism of regulation involves the creation of a phosphorylation-dependent binding site for 14-3-3. Decreased NFAT phosphorylation caused by the calcium-stimulated phosphatase calcineurin, or mutation of the PKA phosphorylation sites, disrupted 14-3-3 binding and increased NFAT transcription activity. In contrast, NFAT phosphorylation caused by cAMP increased 14-3-3 binding and reduced NFAT transcription activity. The regulated interaction between NFAT and 14-3-3 provides a mechanism for the integration of calcium and cAMP signaling pathways.
Compact multimode fiber beam-shaping system based on GPU accelerated digital holography (2015)

Real-time, on-demand, beam shaping at the end of the multimode fiber has recently been made possible by exploiting the computational power of rapidly evolving graphics processing unit (GPU) technology [Opt. Express 22, 2933 (2014)]. However, the current state-of-the-art system requires the presence of an acousto-optic deflector (AOD) to produce images at the end of the fiber without interference effects between neighboring output points. Here, we present a system free from the AOD complexity where we achieve the removal of the undesired interference effects computationally using GPU implemented Gerchberg-Saxton and Yang-Gu algorithms. The GPU implementation is two orders of magnitude faster than the CPU implementation which allows video-rate image control at the distal end of the fiber virtually free of interference effects.
The Role of Lipoproteins in Steroidogenesis and Cholesterol Metabolism in Steroidogenic Glands* (1982)

Cholesterol is an obligate intermediate in steroidogenesis. It may be synthesized by steroidogenic cells or taken up from circulating lipoproteins. In the adrenal, ovary, placenta, and possibly the testes of many species, including man, lipoprotein cholesterol is the major source of steroidogenic substrate. Lipoprotein cholesterol uptake is hormonally regulated in these tissues, with the exception of the placenta, and coordinated with intracellular cholesterol synthesis and mobilization of cholesteryl esters to ensure a continuous supply of free cholesterol for steroid synthesis. When the rate of cholesterol uptake exceeds the rate of steroidogenesis, intracellular cholesterol synthesis is suppressed and cholesterol in excess of cellular needs is esterified and stored for future use. During the last decade the mechanisms and regulation of lipoprotein cholesterol uptake by steroidogenic tissues have been elucidated. Two distinct lipoprotein-specific, hormonally regulated mechanisms for taking up extracellular cholesterol have been found in steroidogenic cells. Not all steroidogenic tissues possess both mechanisms. It is our purpose to review these findings.
INCIDENCE, PROGRESSION AND FUNCTIONAL SIGNIFICANCE OF CARDIAC ALLOGRAFT VASCULOPATHY AFTER HEART TRANSPLANTATION1 (2000)

The study confirms the high incidence of intimal thickening after heart transplantation as assessed by intravascular ultrasound. Impaired exercise-induced vasodilatation suggests diminished bioavailability of endothelium-derived nitric oxide to physiological stimulation but the lack of relationship between coronary wall changes and this functional impairment suggests intermittent and presumably reversible endothelial injury in graft atherosclerosis.
Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma (2011)

The methylthioadenosine phosphorylase (MTAP) gene is located on 9p21 telomeric to the CDKN2A tumor suppressor gene. Loss of MTAP gene is frequently associated with CDKN2A homozygous deletion. Although the homozygous deletion of MTAP has been reported in various human cancers, its function in gastric carcinogenesis is unknown. Here, we determined the status of the MTAP gene by using a combination of array-based comparative genomic hybridization and oligonucleotide microarray. It was found that MTAP was deleted and downregulated in 2 of 10 gastric cancer cell lines. Of the 494 primary gastric carcinomas examined, MTAP expression at the protein level was reduced in 59 (11.9%). Furthermore, a lack of MTAP expression was found to be associated with poor survival (P = 0.038). The genomic loss of MTAP and CDKN2A in gastric carcinomas was investigated by quantitative real-time PCR. Among 20 gastric carcinomas, two cases showed deletion of both MTAP and CDKN2A, and three samples showed homozygous deletion of MTAP, but not of CDKN2A. An analysis of gastric carcinomas revealed that reduced MTAP expression correlated significantly with a genomic deletion. Furthermore, functional assays by transfecting the siRNA or the expressional cDNA into gastric cancer cell lines demonstrated that MTAP regulates cell growth and invasion. The present study suggests that MTAP plays an important role in the regulation of gastric carcinogenesis and, in particular, that MTAP loss is implicated in some way with tumor growth via the modulation of cellular properties, which, in turn, suggests that MTAP has therapeutic applications.
Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1 (2010)

Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy.
Characterization of a Saccharomyces cerevisiae NADP(H)‐dependent alcohol dehydrogenase (ADHVII), a member of the cinnamyl alcohol dehydrogenase family (2002)

A new NADP(H)-dependent alcohol dehydrogenase (the YCR105W gene product, ADHVII) has been identified in Saccharomyces cerevisiae. The enzyme has been purified to homogeneity and found to be a homodimer of 40 kDa subunits and a pI of 6.2-6.4. ADHVII shows a broad substrate specificity similar to the recently characterized ADHVI (64% identity), although they show some differences in kinetic properties. ADHVI and ADHVII are the only members of the cinnamyl alcohol dehydrogenase family in yeast. Simultaneous deletion of ADH6 and ADH7 was not lethal for the yeast. Both enzymes could participate in the synthesis of fusel alcohols, ligninolysis and NADP(H) homeostasis.
Systematic Modulation of Michael-Type Reactivity of Thiols through the Use of Charged Amino Acids (2001)

A quantitative structure-reactivity relationship for the Michael-type addition of thiols onto acrylates was determined. Several thiol-containing peptides were investigated by examining the correlation between the second-order rate constant of their addition onto PEG-diacrylate and the pK(a) of the thiols within a peptide. By introducing charged amino acids in close proximity to a cysteine, the pK(a) of the thiol was systematically modulated by electrostatic interactions. Positive charges from the amino acid arginine decreased the pK(a) of the thiol and accelerated the reaction with acrylates while negative charges from aspartic acids showed the opposite effect. A linear correlation between thiolate concentrations and kinetic constants was found, confirming the role of thiolates as the reactive species in this Michael-type reaction. The relevant factors influencing the reactivity were the sign and the number of the neighboring charges, while the position of these charges had little effect on reactivity. These results provide a basis for the rational design of peptides, where the kinetics and thus selectivity of protein/peptide conjugation with polymeric structures via Michael-type addition reactions can be controlled.
STEM CELL NICHE: Structure and Function (2005)

Adult tissue-specific stem cells have the capacity to self-renew and generate functional differentiated cells that replenish lost cells throughout an organism's lifetime. Studies on stem cells from diverse systems have shown that stem cell function is controlled by extracellular cues from the niche and by intrinsic genetic programs within the stem cell. Here, we review the remarkable progress recently made in research regarding the stem cell niche. We compare the differences and commonalities of different stem cell niches in Drosophila ovary/testis and Caenorhabditis elegans distal tip, as well as in mammalian bone marrow, skin/hair follicle, intestine, brain, and testis. On the basis of this comparison, we summarize the common features, structure, and functions of the stem cell niche and highlight important niche signals that are conserved from Drosophila to mammals. We hope this comparative summary defines the basic elements of the stem cell niche, providing guiding principles for identification of the niche in other systems and pointing to areas for future studies.
Viral DNA Polymerases (1996)

Because many viruses are readily amenable to molecular, genetic, and biochemical analyses, and because the replication of certain viruses has been the target of antiviral drug development, a wealth of information has accumulated regarding the structure, functions, properties, and regulation of eukaryotic viral DNA polymerases. Viral DNA polymerases have interesting similarities with eukaryotic cellular DNA polymerases (Wang, this volume) and fascinating differences, both of which shed light on mechanisms of polymerase function.