gebhart/patrepeval huggingface dataset:
A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex–mismatched bone marrow transplantation (2002)

The morbidity and mortality associated with sickle cell disease (SCD) is caused by hemolytic anemia, vaso-occlusion, and progressive multiorgan damage. Bone marrow transplantation (BMT) is currently the only curative therapy; however, toxic myeloablative preconditioning and barriers to allotransplantation limit this therapy to children with major SCD complications and HLA-matched donors. In trials of myeloablative BMT designed to yield total marrow replacement with donor stem cells, a subset of patients developed mixed chimerism. Importantly, these patients showed resolution of SCD complications. This implies that less toxic preparative regimens, purposefully yielding mixed chimerism after transplantation, may be sufficient to cure SCD without the risks of myeloablation. To rigorously test this hypothesis, we used a murine model for SCD to investigate whether nonmyeloablative preconditioning coupled with tolerance induction could intentionally create mixed chimerism and a clinical cure. We applied a well-tolerated, nonirradiation-based, allogeneic transplantation protocol using nonmyeloablative preconditioning (low-dose busulfan) and costimulation blockade (CTLA4-Ig and anti-CD40L) to produce mixed chimerism and transplantation tolerance to fully major histocompatibility complex-mismatched donor marrow. Chimeric mice were phenotypically cured of SCD and had normal RBC morphology and hematologic indices (hemoglobin, hematocrit, reticulocyte, and white blood cell counts) without evidence of graft versus host disease. Importantly, they also showed normalization of characteristic spleen and kidney pathology. These experiments demonstrate the ability to produce a phenotypic cure for murine SCD using a nonmyeloablative protocol with fully histocompatibility complex-mismatched donors. They suggest a future treatment strategy for human SCD patients that reduces the toxicity of conventional BMT and expands the use of allotransplantation to non-HLA-matched donors.
A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis1 (2002)

Eight weeks of treatment with balsalazide (6.75 g daily) is significantly more effective than balsalazide (2.25 g daily) and more rapid in onset than mesalamine (2.4 g daily) in improving signs and symptoms of acute ulcerative colitis. Balsalazide (6.75 g daily) is well tolerated, and the safety profile does not differ from that of balsalazide (2.25 g daily) and mesalamine (2.4 g daily).
Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors (2015)

We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).
Acquisition by a Campylobacter-like strain of aphA-1, a kanamycin resistance determinant from members of the family Enterobacteriaceae (1987)

A Campylobacter-like organism, BM2196, resistant to kanamycin and streptomycin-spectinomycin was isolated from the feces of a patient with acute enteritis. The kanamycin and streptomycin-spectinomycin resistances were not transferable to Camplylobacter sp. or to Escherichia coli, and no plasmid DNA was detected in this strain. The resistance genes were therefore tentatively assigned to a chromosomal locality. Analysis by the phosphocellulose paper-binding assay of extracts from BM2196 indicated that resistance to kanamycin and structurally related antibiotics was due to the synthesis of 3'-aminoglycoside phosphotransferase type I [APH(3')-I], an enzyme specific for gram-negative bacteria, and that resistance to streptomycin-spectinomycin was secondary to the presence of a 3",9-aminoglycoside adenylyltransferase. Homology between BM2196 and an APH(3')-I probe was detected by DNA-DNA hybridization. A 2.2-kilobase BM2196 DNA fragment conferring resistance to kanamycin was cloned in E. coli and was sequenced partially. The resistance gene appeared nearly identical to that of Tn903 from E. coli and was adjacent to IS15-delta, an insertion sequence widespread in gram-negative bacteria, thus indicating that Campylobacter species can act as a recipient for genes originating in members of the family Enterobacteriaceae.
Nucleic Acid Sequence-Based Amplification (NASBA™) (2003)

Originally envisaged as an improved diagnostic method for detection of RNA viruses, NASBA™ has been developed into a technology with much wider application.
Liquid polymer nano-PEBBLEs for Cl? analysis and biological applications (2003)

The first nanometer scale anion sensing fluorescent spherical nanosensors, or PEBBLEs (probes encapsulated by biologically localized embedding) have been developed for the intracellular monitoring of chloride. The general scheme for the polymerization and introduction of sensing components creates a matrix that allows for the utilization of the highly selective ionophores used in poly(vinyl chloride) and poly(decyl methacrylate) ion-selective electrodes. We have demonstrated that our previously developed scheme for cation sensors can be utilized to tailoring selective submicron sensors for use in intracellular measurements of biologically relevant anions for which selective enough fluorescent probes do not exist. Three schemes were attempted for the development of chloride sensitive PEBBLEs. The first two used the Chloride ionophore indium(III) octaethylporphyrin chloride (In(OEP)Cl) (1) as an ionophore working in tandem with a chromoionophore and (2) as a chromoionophore with a peak shift generated by chloride mediated breaking of hydroxide ion-bridged porphyrin dimer. The third method used the optically silent Chloride ionophore III (ETH 9033) working in tandem with chromoionophore III (ETH 5350) to indirectly monitor Cl- activity by reporting the H+ coextracted into the matrix. Method 3 gave the most promising results, at a pH of 7.2 these PEBBLEs have a limit of detection of 0.2 mM Cl- with a linear dynamic range of 0.4 mM-190 mM Cl-. These PEBBLEs were delivered into C6 glioma cells, utilizing a gene gun, and intracellular chloride levels were monitored during ion-channel stimulation by kainic acid.
Zadar Airport Maneouvring area development (2009)

U radu je opisano postojece stanje manevarske povrsine zracne luke Zadar. Dane su prognoze vezane za razvoj prometa zrakoplova. Prema ocekivanjima prometa predložen je razvoj manevarske povrsine uzimajuci u obzir i zadovoljavanje uvjeta sigurnosti.
Human Intestinal Permeability (1998)

This review focuses on permeability measurements in humans, briefly discussing different perfusion techniques, the relevance of human Peff values, and various aspects of in vivo transport mechanisms. In addition, human Peff values are compared with corresponding data from three preclinical transport models. The regional human jejunal perfusion technique has been validated in several important ways. One of the most important findings is that there is a good correlation between the measured human effective permeability values and the extent of absorption of drugs in humans determined by pharmacokinetic studies. Estimations of the absorption half-lives from the measured Peff agree very well with the time to maximal amount of the dose absorbed achieved after an oral dose in humans. We have also shown that it is possible to determine the Peff for carrier-mediated transported compounds and to classify them according to the proposed biopharmaceutical classification system (BCS). Furthermore, human in vivo permeabilities can be predicted using preclinical permeability models, such as in situ perfusion of rat jejunum, the Caco-2 model, and excised intestinal segments in the Ussing chamber. The permeability of passively transported compounds can be predicted with a particularly high degree of accuracy. However, special care must be taken for drugs with a carrier-mediated transport mechanism, and a scaling factor has to be used. Finally, the data obtained in vivo in humans emphasize the need for more clinical studies investigating the effect of physiological in vivo factors and molecular mechanisms influencing the transport of drugs across the intestinal and as well as other membrane barriers. It will also be important to study the effect of antitransport mechanisms (multidrug resistance, MDR), such as efflux by P-glycoprotein(s) and gut wall metabolism, for example CYP 3A4, on bioavailability.
A transient definitive erythroid lineage with unique regulation of the β-globin locus in the mammalian embryo (2011)

A transient erythromyeloid wave of definitive hematopoietic progenitors (erythroid/myeloid progenitors [EMPs]) emerges in the yolk sac beginning at embryonic day 8.25 (E8.25) and colonizes the liver by E10.5, before adult-repopulating hematopoietic stem cells. At E11.5, we observe all maturational stages of erythroid precursors in the liver and the first definitive erythrocytes in the circulation. These early fetal liver erythroblasts express predominantly adult β-globins and the definitive erythroid-specific transcriptional modifiers c-myb, Sox6, and Bcl11A. Surprisingly, they also express low levels of "embryonic" βH1-, but not εy-, globin transcripts. Consistent with these results, RNA polymerase and highly modified histones are found associated with βH1- and adult globin, but not εy-globin, genes. E11.5 definitive proerythroblasts from mice transgenic for the human β-globin locus, like human fetal erythroblasts, express predominately human γ-, low β-, and no ε-globin transcripts. Significantly, E9.5 yolk sac-derived EMPs cultured in vitro have similar murine and human transgenic globin expression patterns. Later liver proerythroblasts express low levels of γ-globin, while adult marrow proerythroblasts express only β-globin transcripts. We conclude that yolk sac-derived EMPs, the first of 2 origins of definitive erythropoiesis, express a unique pattern of globin genes as they generate the first definitive erythrocytes in the liver of the mammalian embryo.
Pulmonary Hypertension: New Perspectives (2003)

The World Health Organization symposium offers a new treatment-oriented classification of pulmonary hypertension based on an improved understanding of its pathophysiology. Regardless of the etiology, severe or unrelieved pulmonary hypertension leads to right heart failure. Symptoms and signs of pulmonary hypertension are often subtle and nonspecific. As a result, a significant delay between the onset of symptoms and the diagnosis of pulmonary hypertension is common. Echocardiography with Doppler flow is the most useful study to evaluate patients suspected of having pulmonary hypertension. The suspected diagnosis of pulmonary hypertension should then be confirmed by right heart catheterization. If present, further evaluation may include oxygen assessment, pulmonary function testing, high resolution computed tomography of the chest, and ventilation-perfusion lung scanning. Treatment of pulmonary hypertension requires uncommon expertise. General measures include correction of the underlying cause, reversal of hypoxemia and judicious use of diuretics. Advances in vasodilator therapy have increased treatment options beyond calcium channel blockers and intravenous epoprostenol. Lung transplantation remains an option for select patients with pulmonary hypertension not responding to medical management.
Circulating cytokine levels compared to pain in patients with fibromyalgia -- a prospective longitudinal study over 6 months. (2008)

Our results suggest that proinflammatory cytokines TNF-alpha and IL-8 are involved in FM, but they do not apparently provoke the pain of FM directly. Multidisciplinary pain therapy modified the cytokine profile in patients with FM during the observation period.
Nanoparticles for Heterogeneous Catalysis: New Mechanistic Insights (2012)

Metallic nanoparticles finely dispersed over oxide supports have found use as heterogeneous catalysts in many industries including chemical manufacturing, energy-related applications and environmental remediation. The compositional and structural complexity of such nanosized systems offers many degrees of freedom for tuning their catalytic properties. However, fully rational design of heterogeneous catalysts based on an atomic-level understanding of surface processes remains an unattained goal in catalysis research. Researchers have used surface science methods and metal single crystals to explore elementary processes in heterogeneous catalysis. In this Account, we use more realistic materials that capture part of the complexity inherent to industrial catalysts. We assess the impacts on the overall catalytic performance of characteristics such as finite particle size, particle structure, particle chemical composition, flexibility of atoms in clusters, and metal-support interactions. To prepare these materials, we grew thin oxide films on metal single crystals under ultrahigh vacuum conditions and used these films as supports for metallic nanoparticles. We present four case studies on specifically designed materials with properties that expand our atomic-level understanding of surface chemistry. Specifically, we address (1) the effect of dopants in the oxide support on the growth of metal nanoclusters; (2) the effects of size and structural flexibility of metal clusters on the binding energy of gas-phase adsorbates and their catalytic activity; (3) the role of surface modifiers, such as carbon, on catalytic activity and selectivity; and (4) the structural and compositional changes of the active surface as a result of strong metal-support interaction. Using these examples, we demonstrate how studies of complex nanostructured materials can help revealing atomic processes at the solid-gas interface of heterogeneous catalysts. Among our findings is that doping of oxide materials opens promising routes to alter the morphology and electronic properties of supported metal particles and to induce the direct dissociation and reaction of molecules bound to the oxide surface. Also, the small size and atomic flexibility of metal clusters can have an important influence on gas adsorption and catalytic performance.
Development of an Oligonucleotide Array for Direct Detection of Fungi in Sputum Samples from Patients with Cystic Fibrosis (2008)

Cystic fibrosis (CF) is the most common inherited genetic disease in Caucasian populations. Besides bacteria, many species of fungi may colonize the respiratory tract of these patients, sometimes leading to true respiratory infections. In this study, an oligonucleotide array capable of identifying 20 fungal species was developed to directly detect fungi in the sputum samples of CF patients. Species-specific oligonucleotide probes were designed from the internal transcribed spacer (ITS) regions of the rRNA operon and immobilized on a nylon membrane. The fungal ITS regions were amplified by PCR and hybridized to the array for species identification. The array was validated by testing 182 target strains (strains which we aimed to identify) and 141 nontarget strains (135 species), and a sensitivity of 100% and a specificity of 99.2% were obtained. The validated array was then used for direct detection of fungi in 57 sputum samples from 39 CF patients, and the results were compared to those obtained by culture. For 16 sputum samples, the results obtained by the array corresponded with those obtained by culture. For 33 samples, the array detected more fungal species than culture did, while the reverse was found for eight samples. The accuracy of the array for fungal detection in sputum samples was confirmed (or partially confirmed) in some samples by cloning and resequencing the amplified ITS fragments. The present array is a useful tool for both the simultaneous detection of multiple fungal species present in the sputa of CF patients and the identification of fungi isolated from these patients.
Structure–Activity Relationships in Toll-Like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides (2011)

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C(16)) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.
An excitatory nociceptive cardiac reflex elicited by bradykinin and potentiated by prostaglandins and myocardial ischaemia (1976)

Application of bradykinin to the exposed ventricular surface of the dog heart elicits a reflex cardiovascular response which includes a rise in blood pressure, tachycardia, renal vasoconstriction and muscular vasodilation. The reflex response depends on the dose of bradykinin and is increased by concomitant application of prostaglandin E1 or E2 and reduced by indomethacin. Temporary occlusion of the coronary artery supplying the area of the ventricle under study also sensitized the heart to topical application of bradykinin. Bradykinin and prostaglandins are released by the heart during ischaemia. We suggest, therefore, that bradykinin and prostaglandins acting in concert are the natural stimulus for excitation of the sensory receptors signalling the pain of myocardial ischaemia. We also suggest that the nervous reflex which arises from activation of sympathetic sensory nerve endings is the mechanism subserving the cardiovascular events which accompany anginal attacks.
Environmental and occupational disorders Occupational allergy to bumblebees: Allergens of Bombus terrestris (2001)

Background: With the increase in commercial vegetable production in greenhouses, occupational sensitization to bumblebee venom is becoming more common. Studies using sera from subjects thus sensitized allow evaluation of the allergenic specificity of bumblebee sensitization. Objective: The purposes of this study were to determine the degree of species group specificity of bumblebee venom allergens in sera of allergic patients and to investigate the structural basis of this specificity. Methods: Allergens were purified from bumblebee venom, studied serologically by direct binding and inhibition techniques, and characterized by enzyme analysis and amino acid sequencing. Three-dimensional models of the phospholipases were constructed and analyzed. Results: Bombus terrestris venom contains phospholipase A2, venom protease, hyaluronidase, and acid phosphatase allergens. The protease and phospholipase A2 allergens contain IgE-reactive epitopes that are different from those seen in Bombus pennsylvanicus, a North American species. Bumblebee phospholipase A2 is only 53% identical to honeybee phospholipase A2. The results of 3-dimensional modeling are consistent with the immunologic observations. Conclusions: Patients with primary bumblebee sensitization should be diagnosed and treated with venom from the appropriate species group of bumblebees. Bumblebee venom phospholipase A2 and protease are antigenically distinct from honeybee venom proteins. There are significant species group‐specific epitopes on bumblebee venom proteins. (J Allergy Clin Immunol 2001;108:855-60.)
Kinetic studies on the processing of human beta-lipotropin by bovine pituitary intermediate lobe pro-opiomelanocortin-converting enzyme. (1986)

The kinetics of the previously reported paired basic residue-specific pro-opiomelanocortin-converting enzyme from bovine pituitary intermediate lobe secretory vesicles (Loh, Y. P., Parish, D.C., and Tuteja, R. (1985) J. Biol. Chem. 260, 7194-7205) were studied using human 125I-beta-lipotropin as substrate. The enzyme, at a concentration of 20 ng/100 microliters cleaved human beta-lipotropin to yield gamma-lipotropin, a beta-melanotropin linked to beta-endorphin intermediate and beta-endorphin, whereas at an enzyme concentration of 40 ng/100 microliters, the substrate was completely cleaved to yield beta-endorphin and beta-melanotropin. These products were identified by their immunological properties and size on sodium dodecyl sulfate-polyacrylamide gels. The 125I-beta-endorphin product was further shown by high pressure liquid chromatography to contain two forms; the major form co-eluted with 125I-Arg0-beta h-endorphin and the minor form with 125I-beta h-endorphin. No COOH-terminal shortened forms of beta-endorphin were detected. The products formed indicate cleavages at two of the three pairs of basic residues of human beta-lipotropin, at Lys37-Lys38 and Lys57-Arg58, but not at Lys86-Lys87. The cleavage at Lys57-Arg58 occurred primarily in between these basic residues. The Km values for the cleavage of the Lys37-Lys38 and Lys57-Arg58 pairs were 1.9 and 2.5 microM, respectively. The Vmax values for the cleavage of the Lys37-Lys38 and Lys58-Arg58 pairs were 4.8 nmol/micrograms of enzyme/h and 9.1 nmol/micrograms of enzyme/h, respectively.
Rep/Cap Gene Amplification and High-Yield Production of AAV in an A549 Cell Line Expressing Rep/Cap (2002)

Cell lines stably expressing rep/cap are important tools for studying adeno-associated virus (AAV) biology and producing AAV vectors. Several rep/cap cell lines have been isolated, each of which is based on HeLa cells. Infection of these cell lines with adenovirus for production of AAV vector is associated with substantial amplification of the rep/cap gene. Concerns over the presence of human papilloma viral (HPV) sequences in HeLa cells may limit use of such lines for production of clinical-grade vectors. Here we describe a non-HeLa-derived rep/cap cell line called K209, generated by stable transfection of A549 cells with a plasmid construct containing the P5 rep/cap cassette from AAV2. Infection of K209 cells with adenovirus leads to a 1000-fold amplification of the rep/cap gene with high-yield production of AAV vectors. The multiplicity of infection (MOI) of adenovirus that led to maximum amplification of the rep/cap gene and high-level production of AAV is 10 times higher in the HeLa-based cell line than that required in K209 cells. Our data suggest that papilloma-derived gene products present in HeLa cells are not required for high-yield production of AAV vectors.
Sodium 2-Mercaptoethanesulfonate in Reversible Adduct Formation and Water Solubilization. (1989)

Sodium 2-mercaptoethanesulfonate (MESNA, coenzyme M) forms 1:1 covalent adducts with highly pi-electron deficient heterocycles. The addition is caused by the thiol function, and the adducts become water soluble as sulfonates. 1H NMR spectroscopy has been used to obtain information about electronic and steric effects on the equilibria between 2-pyrimidinones and their 1:1 MESNA adducts. The adducts are potential prodrugs for biologically interesting 2-pyrimidinones.