gebhart/patrepeval huggingface dataset:
Complement Depletion in a Porcine Model of Septic Acute Respiratory Disease (1987)

In a porcine model of severe septic acute respiratory failure produced by continuous infusion of live Pseudomonas aeruginosa, the role of the complement system was studied by pretreating animals with cobra venom factor (CVF) to deplete C3. Three groups of spontaneously breathing animals were monitored with Swan-Ganz and arterial thermodilution catheters. Group I was pretreated with 80 U/kg of CVF iv 16–18 hours before testing. Group II received Ps. aeruginosa iv (2 × 108/20 kg/minute). Group III was pretreated with CVF and later given the Pseudomonas infusion. The CH50 as a measure of complement activity was less than 7% of normal level in Groups I and III. No changes in respiratory variables occurred in Group I. In Group II, the mean pulmonary artery pressure doubled, intrapulmonary shunt fraction (Qs/Qt) increased, PaO2 decreased, and extravascular lung water doubled in 4 hours. In Group III, the pulmonary hypertension, hypoxemia, increase in Qs/Qt, and increase in EVLW were all significantly less than in Group II. Neutropenia occurred with the Pseudomonas infusion in Groups II and III.
A Structural Element within the HUWE1 HECT Domain Modulates Self-ubiquitination and Substrate Ubiquitination Activities (2009)

E3 ubiquitin ligases catalyze the final step of ubiquitin conjugation and regulate numerous cellular processes. The HECT class of E3 ubiquitin (Ub) ligases directly transfers Ub from bound E2 enzyme to a myriad of substrates. The catalytic domain of HECT Ub ligases has a bilobal architecture that separates the E2 binding region and catalytic site. An important question regarding HECT domain function is the control of ligase activity and specificity. Here we present a functional analysis of the HECT domain of the E3 ligase HUWE1 based on crystal structures and show that a single N-terminal helix significantly stabilizes the HECT domain. We observe that this element modulates HECT domain activity, as measured by self-ubiquitination induced in the absence of this helix, as distinct from its effects on Ub conjugation of substrate Mcl-1. Such subtle changes to the protein may be at the heart of the vast spectrum of substrate specificities displayed by HECT domain E3 ligases.
Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy (1994)

We studied the cellular distribution of both deleted (delta) and wild-type (wt) mitochondrial DNAs (mtDNAs) in 'normal' and respiration-deficient muscle fibers from four patients with mitochondrial myopathy. PCR-based methods were used to quantitate both relative and absolute amounts of delta- and wt-mtDNAs in microdissected fiber segments. Although delta-mtDNAs were present in normal fibers (31% +/- 26), their percentages were much higher in affected fibers (95% +/- 2). Absolute levels of delta-mtDNA were also increased in affected fibers, whereas levels of wt-mtDNA were significantly reduced in these fibers. These results indicate that a threshold ratio of delta-/wt-mtDNA must be achieved before an impairment of respiration is observed in muscle. Moreover, the marked reduction in wt-mtDNA observed in affected fibers suggests that absolute amounts of mtDNA may play a role in the pathogenesis of mitochondrial myopathies.
Purification, primary structure, and antimicrobial activities of a guinea pig neutrophil defensin (1987)

A broad-spectrum antimicrobial peptide present in guinea pig neutrophils was isolated, characterized biochemically, and assessed for microbicidal range and potency in vitro. The guinea pig neutrophil peptide (GPNP) was purified to homogeneity from a granule-rich subcellular fraction of peritoneal exudate neutrophils by gel filtration and reversed-phase high-performance liquid chromatography. GPNP was microbicidal for selected bacterial, fungal, and viral test organisms at concentrations in the microgram per milliliter range. Composition and primary structure analyses revealed that GPNP was homologous to a recently characterized family of antimicrobial peptides, termed defensins, isolated from rabbit and human neutrophils. The entire amino acid sequence of GPNP was determined, revealing that 8 of 31 residues were among those invariant in six rabbit and three human defensin peptides. The conserved sequence included six disulfide-linked cysteine residues, a common structural feature of defensins. The sequence of GPNP also included three nonconservative substitutions in positions otherwise invariant in the human and rabbit peptides. Characterization of GPNP provides new insight into structural features which may be essential for the broad-spectrum antimicrobial activities of defensins.
A developmentally regulated Streptomyces endoribonuclease resembles ribonuclease E of Escherichia coli (1997)

We report that the Streptomyces species S. lividans and S. coelicolor, morphologically complex gram-positive soil bacteria, contain a developmentally regulated endoribonuclease activity (here named RNase ES) that functionally and immunologically resembles Escherichia coli RNase E. In Streptomyces cells, RNA I - the antisense repressor of replication of ColE1-type plasmids - is cleaved at sites attacked by RNase E. A Mg2+-dependent endonuclease that produces RNase E-like cleavages in RNA I and 9S ribosomal RNA was identified in S. lividans cell extracts. A Streptomyces peptide migrating at 70kDa in SDS/polyacrylamide gels binds to RNase E substrates and reacts with three separate anti-RNase E monoclonal antibodies; the endonucleolytic cleavage activity co-purified with the immunoreactive 70 kDa peptide. We show that RNase ES activity is regulated during the Streptomyces life cycle: activity increased as cells progressed from exponential growth to stationary phase in liquid culture, or from mycelial growth to sporulation on solid media. While mutations that interfere with S. coelicolor development late in its life cycle did not prevent this developmentally associated increase in RNase ES activity, the increase was blocked by a mutation (bldA) that interferes early with both morphological and physiological differentiation.
Irreversible Inhibitors of c-Src Kinase That Target a Nonconserved Cysteine (2012)

We have developed the first irreversible inhibitors of wild-type c-Src kinase. We demonstrate that our irreversible inhibitors display improved potency and selectivity relative to that of their reversible counterparts. Our strategy involves modifying a promiscuous kinase inhibitor with an electrophile to generate covalent inhibitors of c-Src. We applied this methodology to two inhibitor scaffolds that exhibit increased cellular efficacy when rendered irreversible. In addition, we have demonstrated the utility of irreversible inhibitors in studying the conformation of an important loop in kinases that can control inhibitor selectivity and cause drug resistance. Together, we have developed a general and robust framework for generating selective irreversible inhibitors from reversible, promiscuous inhibitor scaffolds.
A score for predicting risk of death from cardiovascular disease in adults with raised blood pressure, based on individual patient data from randomised controlled trials (2001)

The risk score is an objective aid to assessing an individual's risk of cardiovascular disease, including stroke and coronary heart disease. It is useful for physicians when determining an individual's need for antihypertensive treatment and other management strategies for cardiovascular risk.
Synthesis and Partial Biological Evaluation of a Small Library of Differentially-Linked β-C-Disaccharides1 (2003)

The synthesis of a small library of differentially-linked beta-C-disaccharides has been carried out through the use of a radical allylation-RCM strategy. Acids 6 were prepared by Keck allylation of a suitable carbohydrate-based radical precursor, followed by oxidative cleavage of the formed alkene. Dehydrative coupling of these acids with the known olefin alcohol 5 then gave the precursor esters 7 in excellent yield. Methylenation of the esters 7 was followed by RCM and in situ hydroboration-oxidation of the formed glycals to furnish the protected beta-C-disaccharides 10 in good overall yield. Five examples were then deprotected and screened for their efficacy as enzyme inhibitors of beta-glycosidase and against several solid-tumor cell lines for in vitro differential cytotoxicity.
Profiling the immune response in patients with breast cancer by phage-displayed cDNA libraries (2001)

Display on the surface of filamentous phages has been shown to be well suited for the enrichment of serum antibody-binding ligands. Here, we have taken the advantage of this technology to analyze the humoral immune response in patients with cancer. The cDNA repertoires from breast cancer cell lines T47D and MCF-7 were fused to the 3'-end of the filamentous phage M13 gene VI in all three reading frames. When the libraries were biopanned on rabbit polyclonal IgG against the human Bcl-x(L) protein, positive clones were selected, thus confirming the utility of the libraries. Using serum antibodies from patients with breast cancer, we specifically selected IgG-binding phage-encoded cDNA products. Sequence analysis of the selected clones identified important antigens including p53, centromere-F, int-2, pentraxin I, integrin beta5, cathepsin L2 and S3 ribosomal protein. The selected phage-displayed cDNA products were recognized by a significant number of breast cancer sera as compared to sera from normal individuals. Although the human pentraxin I mRNA was reported to be exclusively localized in the nervous system, we found it also expressed by breast cancer cell lines. Four out of 30 patients with breast cancer (13 %) showed reactivity with the recombinant pentraxin expressed in Escherichia coli, while no reactivity was found in normal sera. The obtained results demonstrate that phage display could be a valuable method for the identification of antigens recognized by the humoral immune system in patients with cancer.
The inflammasome NLRP3 plays a protective role against a viral immunopathological lesion (2015)

Herpes simplex 1 infection of the eye can cause blindness with lesions in the corneal stroma largely attributable to inflammatory events that include components of both adaptive and innate immunity. Several innate immune responses are triggered by herpes simplex 1, but it is unclear how such innate events relate to the subsequent development of stromal keratitis. In this study, we compared the outcome of herpes simplex 1 ocular infection in mice unable to express NLRP3 because of gene knockout (NLRP3(-/-)) to that of wild-type mice. The NLRP3(-/-) mice developed more-severe and earlier stromal keratitis lesions and had higher angiogenesis scores than did infected wild-type animals. In addition, NLRP3(-/-) mice generated an increased early immune response with heightened chemokines and cytokines, including interleukin-1β and interleukin-18, and elevated recruitment of neutrophils. Increased numbers of CD4(+) T cells were seen at later stages of the disease in NLRP3(-/-) animals. Reduction in neutrophils prevented early onset of the disease in NLRP3(-/-) animals and lowered levels of bioactive interleukin-1β but did not lower bioactive interleukin-18. In conclusion, our results indicate that NLRP3 has a regulatory and beneficial role in herpetic stromal keratitis pathogenesis.
Inflammatory Mediators and Stroke: New Opportunities for Novel Therapeutics (1999)

Contrary to previous dogmas, it is now well established that brain cells can produce cytokines and chemokines, and can express adhesion molecules that enable an in situ inflammatory reaction. The accumulation of neutrophils early after brain injury is believed to contribute to the degree of brain tissue loss. Support for this hypothesis has been drawn from many studies where neutrophil-depletion blockade of endothelial-leukocyte interactions has been achieved by various techniques. The inflammation reaction is an attractive pharmacologic opportunity, considering its rapid initiation and progression over many hours after stroke and its contribution to evolution of tissue injury. While the expression of inflammatory cytokines that may contribute to ischemic injury has been repeatedly demonstrated, cytokines may also provide "neuroprotection" in certain conditions by promoting growth, repair, and ultimately, enhanced functional recovery. Significant additional basic work is required to understand the dynamic, complex, and time-dependent destructive and protective processes associated with inflammation mediators produced after brain injury. The realization that brain ischemia and trauma elicit robust inflammation in the brain provides fertile ground for discovery of novel therapeutic agents for stroke and neurotrauma. Inhibition of the mitogen-activated protein kinase (MAPK) cascade via cytokine suppressive anti-inflammatory drugs, which block p38 MAPK and hence the production of interleukin-1 and tumor necrosis factor-alpha, are most promising new opportunities. However, spatial and temporal considerations need to be exercised to elucidate the best opportunities for selective inhibitors for specific inflammatory mediators.
The Correlation Between the Expression of Differentiation Markers in Rat Small Intestinal Mucosa and the Transcript Levels of Schlafen 3 (2013)

Taken together with our previous in vitro observations, the results suggest that small intestinal enterocytic epithelial differentiation in rats may be regulated by Slfn3 in vivo, as in vitro, and that these effects may be specific to the small intestinal enterocytic phenotype as opposed to that of the mature colonocyte. Slfn3 human orthologs may be targeted to stimulate intestinal differentiation in patients with short bowel syndrome.
Modeling of real defect outlines for defect size distribution and yield prediction (2002)

For efficient yield, prediction defects are usually modeled by circular disks or squares. A more accurate model is presented. It considers the real outline of physical defects. To utilize this model, only the maximum and the minimum extension of detected defects must be determined. That can be done easily using a checkerboard test structure including a defect localization procedure. The accuracy of the predicted number of defects can be substantially enhanced by modeling real defect outlines with this elliptical model. If the elliptical model of the defect outlines is applied, the defect size distribution implicitly contains information about the physical defect outlines. Hence, for yield prediction the inspection of defect outlines can be omitted.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Changes in alertness are a principal component of variance in the EEG spectrum (1995)

Minute-scale fluctuations in the normalized EEG log spectrum, when correlated with concurrent changes in level of performance on a sustained auditory detection task, showed that a single principal component of EEG spectral variance is linearly related to minute-scale changes in detection performance. The particular EEG frequencies at which this coupling is expressed are similar for most subjects under a range of task conditions, and match those recently reported from analysis of verbal self-reports during drowsiness. The one-dimensional relationship between detection performance and the EEG spectrum confirms quantitatively the intuitive assumption that minute-scale changes in behavioral alertness during drowsiness are predominantly linked to changes in global brain dynamics along a single dimension of psychophysiological arousal.
Glycoprotein IIb/IIIa and P2Y12receptor antagonists yield additive inhibition of platelet aggregation, granule secretion, soluble CD40L release and procoagulant responses (2005)

Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists, including abciximab and tirofiban, are administered concurrently with clopidogrel, a P2Y12 antagonist, and aspirin in some patients undergoing percutaneous coronary intervention. We studied the effects of, and interactions between, abciximab, tirofiban, aspirin and the P2Y12 antagonist cangrelor on platelet aggregation, alpha and dense granule secretion and procoagulant responses in vitro. Blood was obtained from healthy volunteers. Platelet aggregation, dense granule secretion, alpha granule secretion (PAI-1 and soluble CD40 ligand levels) and procoagulant responses (annexin-V and microparticle formation) were assessed using collagen and thrombin receptor activating peptide (TRAP) as agonists. All the antagonists used singularly inhibited collagen-induced responses. Combinations of abciximab or tirofiban with aspirin and/or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor. Cangrelor inhibited TRAP-induced responses and, again, there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor. The GPIIb/IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between GPIIb/IIIa antagonists and inhibitors of both P2Y12 receptor activation and, to a lesser extent, thromboxane A2 generation. These interactions are likely to have important influences on the safety and efficacy of combination anti-platelet therapies.
Synthesis and Comparative Toxicology of a Series of Polyhedral Borane Anion-Substituted Tetraphenyl Porphyrins (2007)

Three structurally similar tetraphenylporphyrins bearing polyhedral borane anions have been synthesized and their toxicological profiles obtained in rats. These conjugates were found to have quite different acute toxicities as manifested at the maximum tolerated dose (MTD). When given at the MTD and observed over 28 days, the most acutely toxic porphyrin was found to be devoid of toxicity, as measured by blood chemistry panels. The remaining two less acutely toxic compounds both elicited significant changes, characterized by moderate to severe thrombocytopenia, failure to gain weight normally and changes in liver enzymes indicative of mild hepatotoxicity. All toxic effects were transient, with platelets rebounding to above normal levels at day 28. We conclude that thrombocytopenia is the dose limiting toxicity for boronated porphyrins in mammals and suggest that these effects may be due to the porphyrin, not the borane or carborane.
Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways (2001)

Lethal factor is a protease, one component of Bacillus anthracis exotoxin, which cleaves many of the mitogen-activated protein kinase kinases (MEKs). Given the importance of MEK signaling in tumorigenesis, we assessed the effects of anthrax lethal toxin (LeTx) on tumor cells. LeTx was very effective in inhibiting mitogen-activated protein kinase activation in V12 H-ras-transformed NIH 3T3 cells. In vitro, treatment of transformed cells with LeTx caused them to revert to a nontransformed morphology, and inhibited their abilities to form colonies in soft agar and to invade Matrigel without markedly affecting cell proliferation. In vivo, LeTx inhibited growth of ras-transformed cells implanted in athymic nude mice (in some cases causing tumor regression) at concentrations that caused no apparent animal toxicity. Unexpectedly, LeTx also greatly decreased tumor neovascularization. These results demonstrate that LeTx potently inhibits ras-mediated tumor growth and is a potential antitumor therapeutic.
MOLECULAR EXECUTORS OF CELL DEATH-DIFFERENTIAL INTRARENAL EXPRESSION OF Fas LIGAND, Fas, GRANZYME B, AND PERFORIN DURING ACUTE AND/OR CHRONIC REJECTION OF HUMAN RENAL ALLOGRAFTS1,2 (1996)

Two distinct cytolytic pathways have been characterized: one in which the interaction between the Fas antigen and its ligand results in apoptosis, and another in which the pore forming protein perforin and the serine protease granzyme B contribute to DNA fragmentation and cell death. We investigated intrarenal expression of these molecular executors of cell death in light of the potential participation of cytolytically active cellular elements in the antiallograft repertory. Reverse transcriptase-polymerase chain reaction was used to identify intrarenal expression of Fas antigen, Fas ligand, granzyme B and perforin in eighty human renal allograft biopsies; mRNA display was correlated with the Banff histological diagnosis of renal allografts. Our studies demonstrate that: (1) intrarenal expression of Fas ligand mRNA and of granzyme B mRNA are correlates of acute but not chronic rejection; (2) Fas ligand mRNA is not detectable in allografts in the absence of rejection; (3) intrarenal coexpression of members of each lytic pathway (Fas ligand and Fas, granzyme B, and perforin) and that of both pathways (e.g., Fas ligand and granzyme B) are correlates of acute rejection; and (4) a direct correlation exists between the histological severity of acute rejection and intrarenal coexpression of mRNA encoding Fas ligand, Fas, granzyme B, and perforin. Our studies identify, for the first time, the differential expression of the two major lytic pathways in acute and chronic allograft rejection and suggest that specific therapy directed at the cytotoxic attack molecules might be efficacious in the prevention and/or treatment of acute rejection.
On the construction of the higher dimensional constellations (2003)

We present a constructive method to generate signal constellations for multidimensional modulation. The multidimensional constellation is then used for information transmission in a WCDMA system.
Molecular Cloning of the Cowpea Leghemoglobin II Gene and Expression of Its cDNA in Escherichia coli (Purification and Characterization of the Recombinant Protein) (1997)

Cowpea (Vigna unguiculata) nodules contain three leghemoglobins (LbI, LbII, and LbIII) that are encoded by at least two genes. We have cloned and sequenced the gene that encodes for LbII (lbII), the most abundant Lb in cowpea nodules, using total DNA as the template for PCR. Primers were designed using the sequence of the soybean lbc gene. The lbII gene is 679 bp in length and codes for a predicted protein of 145 amino acids. Using sequences of the cowpea lbII gene for the synthesis of primers and total nodule RNA as the template, we cloned a cDNA for LbII into a constitutive expression vector (pEMBL19+) and then expressed it in Escherichia coli. Recombinant LbII (rLbII) and native LbII (nLbII) from cowpea nodules were purified to homogeneity using standard techniques. Properties of rLbII were compared with nLbII by partially sequencing the proteins and by sodium dodecyl sulfate- and isoelectric focusing polyacrylamide gel electrophoresis, western-blot analysis using anti-soybean Lba antibodies, tryptic and chymotryptic mapping, and spectrophotometric techniques. The data showed that the structural and spectral characteristics of rLbII and nLbII were similar. The rLbII was reversibly oxygenated/deoxygenated, showing that it is a functional hemoglobin.
Coordinated Reactive Power Control of a Large Wind Farm and a STATCOM Using Heuristic Dynamic Programming (2009)

A novel interface neurocontroller (INC) is proposed for the coordinated reactive power control between a large wind farm equipped with doubly fed induction generators (DFIGs) and a static synchronous compensator (STATCOM). The heuristic dynamic programming (HDP) technique and radial basis function neural networks (RBFNNs) are used to design this INC. It effectively reduces the level of voltage sags as well as the over-currents in the DFIG rotor circuit during grid faults, and therefore, significantly enhances the fault ride-through capability of the wind farm. The INC also acts as a coordinated external damping controller for the wind farm and the STATCOM, and therefore, improves power oscillation damping of the system after grid faults. Simulation studies are carried out in PSCAD/EMTDC and the results are presented to verify the proposed INC.