gebhart/patrepeval huggingface dataset:
The refined 1.9‐Å X‐ray crystal structure of d‐Phe‐Pro‐Arg chloromethylketone‐inhibited human α‐thrombin: Structure analysis, overall structure, electrostatic properties, detailed active‐site geometry, and structure‐function relationships (1992)

Thrombin is a multifunctional serine proteinase that plays a key role in coagulation while exhibiting several other key cellular bioregulatory functions. The X-ray crystal structure of human alpha-thrombin was determined in its complex with the specific thrombin inhibitor D-Phe-Pro-Arg chloromethylketone (PPACK) using Patterson search methods and a search model derived from trypsinlike proteinases of known spatial structure (Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S.R., & Hofsteenge, J., 1989, EMBO J. 8, 3467-3475). The crystallographic refinement of the PPACK-thrombin model has now been completed at an R value of 0.156 (8 to 1.92 A); in particular, the amino- and the carboxy-termini of the thrombin A-chain are now defined and all side-chain atoms localized; only proline 37 was found to be in a cis-peptidyl conformation. The thrombin B-chain exhibits the characteristic polypeptide fold of trypsinlike serine proteinases; 195 residues occupy topologically equivalent positions with residues in bovine trypsin and 190 with those in bovine chymotrypsin with a root-mean-square (r.m.s.) deviation of 0.8 A for their alpha-carbon atoms. Most of the inserted residues constitute novel surface loops. A chymotrypsinogen numbering is suggested for thrombin based on the topological equivalences. The thrombin A-chain is arranged in a boomeranglike shape against the B-chain globule opposite to the active site; it resembles somewhat the propeptide of chymotrypsin(ogen) and is similarly not involved in substrate and inhibitor binding. Thrombin possesses an exceptionally large proportion of charged residues. The negatively and positively charged residues are not distributed uniformly over the whole molecule, but are clustered to form a sandwichlike electrostatic potential; in particular, two extended patches of mainly positively charged residues occur close to the carboxy-terminal B-chain helix (forming the presumed heparin-binding site) and on the surface of loop segment 70-80 (the fibrin[ogen] secondary binding exosite), respectively; the negatively charged residues are more clustered in the ringlike region between both poles, particularly around the active site. Several of the charged residues are involved in salt bridges; most are on the surface, but 10 charged protein groups form completely buried salt bridges and clusters. These electrostatic interactions play a particularly important role in the intrachain stabilization of the A-chain, in the coherence between the A- and the B-chain, and in the surface structure of the fibrin(ogen) secondary binding exosite (loop segment 67-80).(ABSTRACT TRUNCATED AT 400 WORDS)
Dual-subtype FIV vaccine protects cats against in vivo swarms of both homologous and heterologous subtype FIV isolates (2001)

Dual-subtype vaccinated cats developed broad-spectrum humoral and cellular immunity which protected cats against in vivo-derived inocula of homologous and heterologous FIV subtypes. Thus, multi-subtype antigen vaccines may be an effective strategy against AIDS viruses.
Targeting Vascular and Avascular Compartments of Tumors withC. novyi-NTand Anti-microtubule Agents (2004)

Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that C. novyi-NT in combination with anti-microtubule agents can cause the destruction of both the vascular and avascular compartments of tumors. The two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis, such as HTI-286 and vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with C. novyi-NT. In contrast, agents that stabilized microtubules, such as the taxanes docetaxel and MAC-321, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by C. novyi-NT. Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which C. novyi-NT spores could germinate. A single intravenous injection of C. novyi-NT plus selected anti-microtubule agents was able to cause regressions of several human tumor xenografts in nude mice in the absence of excessive toxicity.
Stimulatory effect of zinc-releasing calcium phosphate implant on bone formation in rabbit femora (2000)

Although hydroxyapatite (HAP) and tricalcium phosphate (TCP) are currently used as bone graft substitutes or coatings on metallic prostheses because of their excellent biocompatibility and osteoconductivity, they do not stimulate bone formation or inhibit bone resorption. Zinc, an essential trace element in many animals, has a direct specific proliferative effect on osteoblastic cells and has a potent and selective inhibitory effect on osteoclastic bone resorption in vitro. Therefore, zinc-containing beta-tricalcium phosphate (ZnTCP) ceramics and composite ceramics of ZnTCP and HAP (ZnTCP/HAP) were implanted in the femora of New Zealand White rabbits for 4 weeks to promote bone formation. The implants were sintered ceramics with zinc contents of 0 (control), 0.063, 0.316 and 0.633 wt %. Histological and histomorphometrical investigation of the undecalcified sections revealed an increase by 51% (p =.0509) in the area of newly formed bone around the ZnTCP/HAP implants of 0. 316 Zn wt % compared with the control. Plasma zinc concentration was unchanged. An increased bone resorption on the endosteal surface was observed when ZnTCP and ZnTCP/HAP of 0.633 Zn wt % were implanted. To promote bone formation, the optimum zinc content of the calcium phosphate ceramics was therefore 0.316 wt %.
Ownership questions can stymie development of coalbed methane (1990)

Although the technology exists for commercial recovery of coalbed methane, production has been hindered because of the legal quandary as to ownership. The author discusses how claims to ownership of coalbed methane can and have been made by the coal owner or lessee, the oil and gas owner or lessee, the surface owner, or any combination thereof. The federal perspective on this question of ownership is described and several state rulings are assessed.
Enzymatic Methods for the Determination of Small Quantities of Isomeric Chondroitin Sulfates (1968)

Micromethods have been developed for the measurement of as little as 3 µg of chondroitin sulfate A, B, or C in mixtures with other mucopolysaccharides by the use of chondroitinase-ABC, chondroitinase-AC, chondro-4-sulfatase, and chondro-6-sulfatase. With these methods, 35S-labeled chondroitin sulfates A, B, and C in a given mixture have been precisely and rapidly determined by measuring radioactivity alone. The methods have also been utilized to determine chondroitin sulfates A, B, and C in as little as 4 ml of normal urine.
Betadoublet: de novo design, synthesis, and characterization of a beta-sandwich protein. (1994)

How an amino acid sequence encodes the information necessary for a protein to adopt a unique tertiary structure remains unresolved. We are addressing this problem by designing "from scratch" protein molecules that will adopt predetermined three-dimensional structures. Based on this strategy, two identical four-stranded beta-sheets were designed to dimerize and form a beta-sandwich protein, called betadoublet. A synthetic gene encoding half the beta-sandwich protein was expressed in Escherichia coli, and the protein was purified to homogeneity. Biophysical characterization of betadoublet in aqueous solution demonstrated that the disulfide formed between the two sheets and that the dimer was a compact unaggregated globular protein, consisting predominantly of beta-sheet and stable to thermal denaturation. It has some backbone amide protons whose exchange is slow enough to be measured by NMR but binds more of the dye 1-anilinonaphthalene-8-sulfonate than a well-folded protein.
Client/server database design with SYBASE : a high-performance and fine-tuning guide (1996)

System 10 architecture system 11 architecture hardware performance tuning memory I/O CPU design and indexing locking and concurrency tuning long-running jobs tuning inthe client/server environment transaction processing and error handling tuning transact-SQL stored procedures triggers cursors housekeeping.
Histone H2B ubiquitin ligase RNF20 is required for MLL -rearranged leukemia (2013)

Mixed-lineage leukemia (MLL) fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here, we identify the histone H2B E3 ubiquitin ligase ring finger protein 20 (RNF20) as an additional chromatin regulator that is necessary for MLL-fusion-mediated leukemogenesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation, under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, effects resembling Dot1l inhibition. Using ChIP-seq, we found that H2B ubiquitination is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, Rnf20 is required to maintain local levels of H3K79 methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby cotranscriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program.
HspR Mutations Are Naturally Selected in Bifidobacterium longum When Successive Heat Shock Treatments Are Applied (2009)

ABSTRACT The development of molecular tools allowed light to be shed on several widespread genetic mechanisms aiming at limiting the effect of molecular damage on bacterial survival. For some bacterial taxa, there are limited tools in the genetic toolbox, which restricts the possibilities to investigate the molecular basis of their stress response. In that case, an alternative strategy is to study genetic variants of a strain under stress conditions. The comparative study of the genetic determinants responsible for their phenotypes, e.g., an improved tolerance to stress, offers precious clues on the molecular mechanisms effective in this bacterial taxon. We applied this approach and isolated two heat shock-tolerant strains derived from Bifidobacterium longum NCC2705. A global analysis of their transcriptomes revealed that the dnaK operon and the clpB gene were overexpressed in both heat shock-tolerant strains. We sequenced the hspR gene coding for the negative regulator of dnaK and clpB and found point mutations affecting protein domains likely responsible for the binding of the regulators to the promoter DNA. Complementation of the mutant strains by the wild-type regulator hspR restored its heat sensitivity and thus demonstrated that these mutations were responsible for the observed heat tolerance phenotype.
Experimental study of time-resolved measurements on turbid media: determination of optical properties and fluorescent inclusions characterization (2005)

Among the different existing techniques in optical molecular imaging, time-domain approaches can supply information on the probe concentration or localization, in case of specific fluorescent labelling. We present an experimental validation of an analytical solution to the time-domain fluorescence diffusion equation in an infinite medium. A fitting method issued from frequency domain calculations is also presented. The instrumentation employs a pulsed laser diode as light source, optical fibres, and a photomultiplier as the detector in a time correlated single photon counting (TCSPC) system. Measurements were performed on tissue simulating phantoms containing a small fluorescent inclusion, with the fibres either imbedded deep within the volume or placed at the surface, above the inclusion. Good adequacy was found between the simulations and the within medium measurements. We also demonstrate good performances of the method to recover the fluorophore localization.
Free Radical-Mediated Postischemic Injury in Renal Transplantation (1992)

Oxygen free radicals are generated during reperfusion of ischemic organs. Studies employing several species of laboratory animal (rat, dog, pig, rabbit, mouse) have documented protective effects of a variety of free-radical scavengers and antioxidants when administered before or immediately preceding reperfusion of ischemic kidneys. These protective agents include superoxide dismutase, dimethylthiorea, dimethyl sulfoxide, alpha-tocopherol, glutathione, the iron chelator deferoxamine, probucol, allopurinol and oxypurinol, and the spin-trapping agent PBN. Furthermore, deficiency of antioxidants (selenium, alpha-tocopherol, or catalase) exacerbates postischemic renal injury. These findings have been applied to renal transplantation in an attempt to decrease the incidence of posttransplantation acute renal failure. This is important because acute renal failure results in morbidity, increases hospital stay and the cost of transplantation, and complicates the use of cyclosporine. In porcine and in canine kidney transplantation, superoxide dismutase and allopurinol have provided renal protection. Transplantation is complicated because there may be prolonged hypoperfusion before harvesting plus a brief period of total ischemia during harvesting, followed by a prolonged period of cold ischemia and/or reperfusion, then followed by another brief period of ischemia and reperfusion during transplantation. Injury may occur at each of these phases by different mechanisms.
Response of a Protein Structure to Cavity-Creating Mutations and Its Relation to the Hydrophobic Effect (1992)

Six "cavity-creating" mutants, Leu46----Ala (L46A), L99A, L118A, L121A, L133A, and Phe153----Ala (F153A), were constructed within the hydrophobic core of phage T4 lysozyme. The substitutions decreased the stability of the protein at pH 3.0 by different amounts, ranging from 2.7 kilocalories per mole (kcal mol-1) for L46A and L121A to 5.0 kcal mol-1 for L99A. The double mutant L99A/F153A was also constructed and decreased in stability by 8.3 kcal mol-1. The x-ray structures of all of the variants were determined at high resolution. In every case, removal of the wild-type side chain allowed some of the surrounding atoms to move toward the vacated space but a cavity always remained, which ranged in volume from 24 cubic angstroms (A3) for L46A to 150 A3 for L99A. No solvent molecules were observed in any of these cavities. The destabilization of the mutant Leu----Ala proteins relative to wild type can be approximated by a constant term (approximately 2.0 kcal mol-1) plus a term that increases in proportion to the size of the cavity. The constant term is approximately equal to the transfer free energy of leucine relative to alanine as determined from partitioning between aqueous and organic solvents. The energy term that increases with the size of the cavity can be expressed either in terms of the cavity volume (24 to 33 cal mol-1 A-3) or in terms of the cavity surface area (20 cal mol-1 A-2). The results suggest how to reconcile a number of conflicting reports concerning the strength of the hydrophobic effect in proteins.
Interferon-lnduced Indoleamine 2,3-Dioxygenase Activity in Human Mononuclear Phagocytes (1989)

Interferon (IFN)-induced tryptophan degradation, catalyzed by indoleamine 2,3-dioxygenase (IDO), has been shown to mediate antimicrobial activity in epithelial cells. IDO activity has also been augmented in peripheral blood mononuclear cells (PBMC) treated with IFN or interleukin-2 (IL-2). The effector cells in this population have now been further characterized. PBMCs were isolated from normal donors, separated into monocyte and lymphocyte populations by plastic adherence, treated with IFN or IL-2, and cultivated in medium supplemented with [3H]tryptophan. Culture supernatants were collected after a 48-h incubation and fractionated by high-performance liquid chromatography; radioactivity was determined in fractions corresponding to tryptophan and its metabolites. IFN-gamma and IFN-beta induced IDO activity only in monocytes (plastic-adherent, nonspecific esterase-positive PBMCs). The induction of IDO activity by IL-2 required both monocytes and lymphocytes. Interaction was required between these populations for induction of IDO by IL-2, due to production of IFN-gamma by T lymphocytes, with subsequent IFN-gamma-mediated induction of IDO in monocytes. A number of myeloid cell lines as well as monocyte-derived macrophages were also tested for their ability to be induced to degrade tryptophan in response to IFN treatment. Monocyte-derived macrophages were found to retain their capacity to be induced by IFN-gamma and IFN-beta to degrade tryptophan after differentiation, and to possess seven times more IDO activity per cell than IFN-induced monocytes. However, the presence of lipopolysaccharide (LPS) in the culture medium was required for the maximum induction of IDO activity by IFN-beta. Furthermore, higher concentrations of LPS were sufficient to induce IDO activity in macrophages in the absence of exogenous IFN.
Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation (2012)

Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for antioxidant and anti-inflammation enzymes that binds to its endogenous inhibitor protein, Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1, in the cytoplasm under normal conditions. Various endogenous or environmental oxidative stresses, such as ionizing radiation (IR), can disrupt the Nrf2-Kelch-like ECH-associated protein 1 complex. This allows Nrf2 to translocate from the cytoplasm into the nucleus to induce transcription of heme oxygenase-1 and other cytoprotective enzymes through binding to antioxidant responsive elements. However, how Nrf2 protects cells from IR-induced damage remains unclear. Here, we report that Nrf2 activation by the synthetic triterpenoids, bardoxolone methyl (BARD) and 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-ethyl amide, protects colonic epithelial cells against IR-induced damage, in part, by enhancing signaling of the DNA damage response. Pretreatment with BARD reduced the frequency of both G1 and S/G2 chromosome aberrations and enhanced the disappearance of repairosomes (C-terminal binding protein interacting protein, Rad51, and p53 binding protein-1 foci) after IR. BARD protected cells from IR toxicity in a Nrf2-dependent manner. The p53 binding protein-1 promoter contains three antioxidant responsive elements in which Nrf2 directly binds following BARD treatment. In addition, 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-ethyl amide provided before exposure to a lethal dose of whole-body irradiation protected WT mice from DNA damage and acute gastrointestinal toxicity, which resulted in improved overall survival. These results demonstrate that Nrf2 activation by synthetic triterpenoids is a promising candidate target to protect the gastrointestinal tract against acute IR in vitro and in vivo.
ABCG subfamily of human ATP-binding cassette proteins (2002)

Abstract ATP-binding cassette (ABC) proteins form one of the largest known protein families and have been found in all known organisms. Most members of the human ABC protein family are membrane-spanning transporters that use energy derived from the hydrolysis of ATP to transport specific substrates across cell membranes. Mutations in certain human ABC transporters of the subfamilies A, B, C, and D have been shown to cause a wide variety of inherited diseases such as the lung condition cystic fibrosis, the nervous degenerative condition adrenoleukodystrophy (of Lorenzo’s Oil fame), hereditary macular degeneration of the eye (Stargardt’s disease), and inherited deficiency of circulating high-density lipoproteins (Tangier disease or familial hypoalphalipoproteinemia). Very recent studies showed that mutations in two members of the subfamily G of human ABC transporters (ABCG5 and ABCG8) cause a condition called sitosterolemia in which plant sterols accumulate in the body and may be responsible for influencing total body sterol homeostasis. In addition, other members of the subfamily G, namely ABCG1 and ABCG4, have also been shown to be involved in cellular lipid trafficking and are thought to play important roles during foam cell formation of human macrophages. By contrast, ABCG2 is a multidrug resistance transporter. In this review, we focus on the current knowledge and physiological background of the members of the subfamily G. We also present new insights on the evolutionary relationship of human and nonhuman ABCG proteins.
Cross-National Epidemiology of Major Depression and Bipolar Disorder (1996)

There are striking similarities across countries in patterns of major depression and of bipolar disorder. The differences in rates for major depression across countries suggest that cultural differences or different risk factors affect the expression of the disorder.
Antibodies to steroids from a small human naive IgM library (1997)

Human antibodies specific for digoxigenin, estradiol, testosterone and progesterone have been isolated from a small combinatorial IgM repertoire (4 x 10(7)) of single chain antibodies (scFv). The affinities of both the anti-estradiol and antiprogesterone scFv were approximately 10(8) M(-1). Naive IgM genes appeared to be highly represented, since only the heavy chain variable domain of the anti estradiol antibody contained differences to corresponding germline sequences. The light chain variable domain of the progesterone receptor was also identical to a germline sequence, showing that it is possible for completely naive antibodies to bind steroids with affinities comparable to those obtained after a secondary immune response.
The unseen iceberg: plant roots in arctic tundra (2014)

Plant roots play a critical role in ecosystem function in arctic tundra, but root dynamics in these ecosystems are poorly understood. To address this knowledge gap, we synthesized available literature on tundra roots, including their distribution, dynamics and contribution to ecosystem carbon and nutrient fluxes, and highlighted key aspects of their representation in terrestrial biosphere models. Across all tundra ecosystems, belowground plant biomass exceeded aboveground biomass, with the exception of polar desert tundra. Roots were shallowly distributed in the thin layer of soil that thaws annually, and were often found in surface organic soil horizons. Root traits - including distribution, chemistry, anatomy and resource partitioning - play an important role in controlling plant species competition, and therefore ecosystem carbon and nutrient fluxes, under changing climatic conditions, but have only been quantified for a small fraction of tundra plants. Further, the annual production and mortality of fine roots are key components of ecosystem processes in tundra, but extant data are sparse. Tundra root traits and dynamics should be the focus of future research efforts. Better representation of the dynamics and characteristics of tundra roots will improve the utility of models for the evaluation of the responses of tundra ecosystems to changing environmental conditions.