gebhart/patrepeval huggingface dataset:
Characterization of a gain of function mutation of integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa). (1992)

Integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa) is a prototype of integrins involved in cellular adhesive functions. As part of a structure-function analysis of this molecule, we constructed a mutant, designated alpha IIb beta 3 (beta 1-2), by replacing 6 amino acids within a putative ligand binding domain of the beta 3 subunit with sequences derived from beta 1. The alteration did not affect the capacity of beta 3(beta 1-2) to combine with transfected alpha IIb, nor did it cause it to combine with endogenous alpha 5. Integrin alpha IIb beta 3(beta 1-2) was in a "resting" state on Chinese hamster ovary cells as judged by minimal binding of an activation-specific anti-alpha IIb beta 3, PAC1. Nevertheless, cells expressing alpha IIb beta 3(beta 1-2) spontaneously bound fibrinogen with low affinity (Ka = (4.85 +/- 0.84) x 10(6) M-1). Activation with an anti-beta 3 antibody (monoclonal antibody 62) resulted in a 10-fold increase in fibrinogen binding affinity (Ka = (4.55 +/- 0.77) x 10(7) M-1), which was 3-fold greater than fibrinogen binding to activated wild type alpha IIb beta 3 (Ka = (1.66 +/- 0.33) x 10(7) M-1, F = 7.46, p = 0.008). The mutant receptor also bound fibrinogen mimetic peptide ligands with enhanced affinity as measured by the conformation-specific antibody, anti-LIBS1. This indicates that the increased affinity for fibrinogen was caused by enhanced interaction of alpha IIb beta 3(beta 1-2) with known recognition sequences in fibrinogen. Thus, this gain of function mutant augments ligand binding function, supporting a role for this region of the beta subunit in ligand binding to integrins.
Ammonium Sulfate Gradients for Efficient and Stable Remote Loading of Amphipathic Weak Bases into Liposomes and Ligandoliposomes. (1994)

The amphipathic anthracycline base doxorubicin (DXR) was accumulated in the aqueous phase of the liposomes where it reached a level as high as 100-fold its concentration in the remote loading medium. Most of the intraliposomal DXR was present in an aggregated state. Efficient (>90%) and stable loading into the liposomes' and ligandoliposomes' aqueous phase was obtained by using gradients of ammonium sulfate in which the ammonium sulfate concentration in the liposomes was higher than its concentration in the extraliposomal medium [(NH4)2SO4)lip. ≫ [(NH4)2SO4)med.]. The “remote” loading is a result of the DXR exchange with ammonia from (NH4)2SO4. Both the ammonium and sulfate contribute to high level and stability of the loading. The ammonium sulfate gradient method differs from most other chemical approaches used for remote loading of liposomes since it neither requires to prepare the liposomes in acidic pH, nor to alkalinize the extraliposomal aqueous phase. Although most of the intraliposomal DXR is present in an aggregated gel-like state, the drug is bioavailable. This approach permits the preparation of DXR-loaded liposomes of a broad spectrum of types, sizes, and composition, including sterically-stabilized liposomes, immunoliposomes, and sterically-stabilized immunoliposomes. Due to the long shelf stability (>6 mo), no “bedside” remote loading is required immediately before patient treatment, and the formulation is ready for injection. The stable encapsulation of the doxorubicin in an aggregated form also permits freezing and lyophilization of the liposomes with only minimal drug release. The loading by ammonium sulfate gradient approach meets all pharmaceutical requirements; it has brought the clinical use of DXR-loaded sterically-stabilized liposomes to reality.
Diagnosis of Down syndrome and other aneuploidies using quantitative polymerase chain reaction and small tandem repeat polymorphisms (1993)

Pregnant women over 35 years of age are routinely offered screening tests and karyotyping to detect Down syndrome and certain other aneuploidies because the risk of these disorders increases exponentially with maternal age. It is, however, only cost-effective to karyotype high-risk pregnancies and a substantial number of remaining aneuploidy cases go undetected. We describe a rapid, inexpensive method to detect trisomy using polymorphic small tandem repeat (STR) markers and the polymerase chain reaction (PCR) to amplify amniocyte DNA. STR patterns obtained on patients with trisomy 21, trisomy 18 and triplo-X syndromes are distinct from controls. Polymorphic trisomy genotypes either show three fragment peaks of equal intensity or two fragments at a 2:1 dosage ratio. In addition, Turner syndrome (45, X0) DNA can be distinguished from normal male DNA because it fails to amplify a Y-chromosome specific PCR marker yet contains only a single dose of X-specific STR markers. Quantitative analysis of peak heights and areas from STR markers show that the two peak patterns separate into completely non-overlapping groups. The high level of heterozygosity of most STR markers result in a predominance of heterozygous controls and trisomy patterns with multiple alleles, the easiest patterns to differentiate. Homozygosity, and hence an uninformative STR pattern, is more common in controls than in trisomy samples. We anticipate as few as three STR markers per chromosome should be over 99% informative.
Antithrombotic Strategies Targeting Thrombin Activities, Thrombin Receptors and Thrombin Generation (1997)

Thrombin mediates acute vascular thrombosis and subsequent vascular lesion formation following mechanical denuding injury or spontaneous atherosclerotic plaque rupture. In the process of generating thrombin Factor VII/VIIa binds avidly with tissue factor (TF) exposed on cellular membranes, and coagulation serine proteases are sequentially cleaved via macromolecular catalytic complexes on phospholipid surfaces. Thrombin activates platelets, blood leukocytes, endothelium and vascular smooth muscle cells (SMCs) by cleaving G protein-coupled thrombin receptors (TRs), leading to SMC intimal proliferation and synthesis of extracellular matrix in the local formation of stenosing neointimal vascular lesions. Therapeutic strategies include inactivation of bound thrombin, inhibition of TR activation by thrombin, and interruption of thrombin generation. In patients having orthopedic surgery, inactivating bound thrombin with direct antithrombins markedly reduces venous thromboembolic events, compared with heparin or its derivatives, without significant impairment of hemostasis. However, acute coronary syndrome patients are not benefitted when given systemic direct antithrombins at safe levels, because interrupting TR-dependent platelet thrombosis demands systemic levels of direct antithrombins that concurrently compromise hemostatic function. Local drug delivery strategies have yet to be explored. In preclinical studies: a) enhancing the formation of endogenous activated Protein C (APC) by Protein C-selective thrombin mutants produces antithrombotic levels of APC; b) inhibiting thrombin activation of TRs abolishes platelet recruitment in arterial thrombogenesis in nonhuman primates, while sparing fibrin formation in hemostatic plugs; and c) preventing thrombin generation by inhibiting precursor serine protease function interrupts the formation of both acute thrombosis and chronic stenotic lesions after denuding vascular damage without significant hemostatic compromise. TF antagonists appear to have a highly favorable efficacy:safety therapeutic relationship for preventing the formation of thrombosis and vascular lesions.
Engineering Agatoxin, a Cystine-Knot Peptide from Spider Venom, as a Molecular Probe for In Vivo Tumor Imaging (2013)

In this study, we demonstrate that AgTx, a knottin from spider venom, can be engineered to bind with high affinity to a tumor-associated receptor target. This work validates AgTx as a viable molecular scaffold for protein engineering, and further demonstrates the promise of using tumor-targeting knottins as probes for in vivo molecular imaging.
Inhibition of Fibronectin Matrix Assembly by the Heparin-binding Domain of Vitronectin (1999)

The deposition of fibronectin into the extracellular matrix is an integrin-dependent, multistep process that is tightly regulated in order to ensure controlled matrix deposition. Reduced fibronectin deposition has been associated with altered embryonic development, tumor cell invasion, and abnormal wound repair. In one of the initial steps of fibronectin matrix assembly, the amino-terminal region of fibronectin binds to cell surface receptors, termed matrix assembly sites. The present study was undertaken to investigate the role of extracellular signals in the regulation of fibronectin deposition. Our data indicate that the interaction of cells with the extracellular glycoprotein, vitronectin, specifically inhibits matrix assembly site expression and fibronectin deposition. The region of vitronectin responsible for the inhibition of fibronectin deposition was localized to the heparin-binding domain. Vitronectin's heparin-binding domain inhibited both beta(1) and non-beta(1) integrin-dependent matrix assembly site expression and could be overcome by treatment of cells with lysophosphatidic acid, an agent that promotes actin polymerization. The interaction of cells with the heparin-binding domain of vitronectin resulted in changes in actin microfilament organization and the subcellular distribution of the actin-associated proteins alpha-actinin and talin. These data suggest a mechanism whereby the heparin-binding domain of vitronectin regulates the deposition of fibronectin into the extracellular matrix through alterations in the organization of the actin cytoskeleton.
Abrogation of the alternative complement pathway by targeted deletion of murine factor B (1997)

To investigate the role of complement protein factor B (Bf) and alternative pathway activity in vivo, and to test the hypothesized potential genetic lethal effect of Bf deficiency, the murine Bf gene was interrupted by exchange of exon 3 through exon 7 (including the factor D cleaving site) with the neor gene. Mice heterozygous for the targeted Bf allele were interbred, yielding Bf-deficient offspring after the F1 generation at a frequency suggesting that Bf deficiency alone has no major effect on fertility or fetal development. However, in the context of one or more genes derived from the 129 mouse strain, offspring homozygous for Bf deficiency were generated at less than expected numbers (P = 0.012). Bf-deficient mice showed no gross phenotypic difference from wild-type littermates. Sera from Bf-deficient mice lacked detectable alternative complement pathway activity; purified mouse Bf overcame the deficit. Classical pathway-dependent total hemolytic activity was lower in Bf-deficient than wild-type mice, possibly reflecting loss of the alternative pathway amplification loop. Lymphoid organ structure and IgG1 antibody response to a T-dependent antigen appeared normal in Bf-deficient mice. Sensitivity to lethal endotoxic shock was not significantly altered in Bf-deficient mice. Thus, deficiency of Bf and alternative complement activation pathway led to a less dramatic phenotype than expected. Nevertheless, these mice provide an excellent model for the assessment of the role of Bf and the alternative pathway in host defense and other functions in vivo.
A direct meta-lithiation route to 1,3-disubstituted ferrocenes (2004)

Ferrocenyl sulfides afford meta-lithiation products with up to 94% regioselectivity on reaction with s-BuLi; the resulting 1,3-disubstituted ferrocenes can then be reacted with a variety of electrophiles.
Reducing the Complexity of Quasi-Maximum-Likelihood Detectors Through Companding for Coded MIMO Systems (2012)

A companding-based transformation method is introduced to quasi-maximum-likelihood (ML) detectors, such as the QR-decomposition-based M-algorithm (QRD-M) and list sphere decoding, for coded multiple-input–multiple-output (MIMO) systems in this paper. The key idea of the proposed companding technique is to compress (i.e., down-weight) the dubious observation of the accumulated branch metric by taking into account its statistical characteristics so that, after companding, the estimation error of the unreliable detected information bits due to insufficient candidate size and/or channel estimation error is significantly mitigated without disproportionate compromise of the reliable information bits. By employing the proposed companding method, the original leptokurtically distributed log-likelihood ratio of the detected information bits becomes more Gaussian distributed. As an illustrative example, the QRD-M detector is employed in this paper. Numerical results show that the QRD-M detector based on the proposed companding paradigm achieves significant performance gain over the conventional method and approaches the performance of the ML detector for a 16-ary quadrature-amplitude-modulated (16-QAM) <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex Notation="TeX">$\hbox{4} \times \hbox{4}$</tex></formula> MIMO multiplexing system with lower-than-linear-detector computational complexity.
Action of 50 Hz magnetic fields on neurite outgrowth in pheochromocytoma cells (1993)

This study tests the capacity of 50 Hz magnetic and electric fields to stimulate neurite outgrowth in PC-12D cells, a cell line which originated from a pheochromocytoma in rat adrenal medulla. The cells were plated on collagen-coated, plastic petri dishes and exposed to sinusoidal 50 Hz magnetic fields for 22 h in a 5% CO2 incubator at 37 degrees C. Two 1,000 turn coils, 20 cm in diameter, were assembled in a Helmholtz configuration to generate a magnetic field in a vertical orientation, thereby inducing a companion electric field in the dish with intensity proportional to radius. A magnetic-field shield housed the control samples in the same incubator. Total cells and number of cells with neurites at least as long as one cell diameter or having a growth cone were counted within a radius of 0.3 cm of the dish center and within an annulus of 1.7-1.8 cm radii in 60 mm dishes, at 3.6 cm radius in 100 mm dishes, and between 1.9 and 2.1 cm radii in the outer well of organ cultured dishes, which are physically separated into two concentric wells. Sham exposure demonstrated no difference in percentage of cells with neurites between the exposed and control locations in the incubator. Exposures were done at 4.0, 8.9, 22, 29, 40, 120, 236, and 400 milliGauss (mG). At dish radii of 1.7-1.8 cm in the 60 mm dishes these magnetic flux densities induced electric fields of 1.1, 2.5, 5.9, 8.1, 11, 33, 65, and 110 microV/m, respectively, while within a radius of 0.3 cm, the induced electric fields were less than 0.2, 0.4, 1.0, 1.5, 1.9, 6.0, 11, and 19 microV/m, respectively. For other dishes, the larger radii produced proportionally larger induced electric fields. At each field strength, there were two control dishes and four to nine exposed dishes; 100 or more cells were counted at each location on the dishes. The results demonstrate that magnetic fields stimulate neurite outgrowth in a flux-density-dependent manner between 22 and 40 mG, reaching an apparent stimulation plateau between 40 and 400 mG; no effects were seen at 8.9 mG or lower. There was no apparent neurite stimulation due to the electric field. Although relatively low intensity (> or = 22 mG) magnetic fields alone can stimulate a morphological response in a cell which is normally stimulated by nerve growth factor molecules binding to membrane receptors, the chemical basis of this response is unknown.
Sinus histiocytosis with massive lymphadenopathy: evidence for its relationship to macrophages and for a cytokine‐related disorder (1999)

We conclude that stimulation of monocytes/macrophages via macrophage colony stimulating factor (M-CSF) leading to immune suppressive macrophages represents a main mechanism for the pathogenesis of SHML. The study further provides evidence for the monocyte/macrophage but not dendritic cell differentiation of SHML histiocytes.
Demethylating Agents in the Treatment of Cancer (2010)

Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of myelodysplastic syndromes (MDS) by the U.S. Food and Drug Administration (FDA), and are now considered the standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitidine and decitabine. We also summarize findings from clinical trials that used these two demethylating agents in the treatment of solid tumors. Lastly, we discuss some limitations in the use of azacitidine and decitabine in cancer therapy.
Topical photodynamic therapy of murine non‐melanoma skin carcinomas with aluminum phthalocyanine chloride and a diode laser: pharmacokinetics, tumor response and cosmetic outcomes (2008)

The results indicate that AlClPc-PDT is an effective treatment for non-melanoma skin carcinomas in experimental mouse models.
The reaction of some heterocyelic thiones with ethyl azidoformate (1976)

A number of heterocyclic thiones react with ethyl azidoformate in boiling carbon tetrachloride to yield the corresponding iminocarboxylic esters. 4-Phenyl-1,2-dithiole-2-thione is an exception and yields both a 1,2,3-dithiazine derivative and a urethane type product. 4-Phenyl-1,2-dithiole-3-one yielded an isothiazolin-3-one product. The mechanisms are discussed briefly.
New Nucleotide Analogues with Enhanced Signal Properties (2010)

We describe synthesis and testing of a novel type of dye-modified nucleotides which we call macromolecular nucleotides (m-Nucs). Macromolecular nucleotides comprise a nucleotide moiety, a macromolecular linear linker, and a large macromolecular ligand carrying multiple fluorescent dyes. With incorporation of the nucleotide moiety into the growing nucleic acid strand during enzymatic synthesis, the macromolecular ligand together with the coupled dyes is bound to the nucleic acid. By the use of this new class of modified nucleotides, signals from multiple dye molecules can be obtained after a single enzymatic incorporation event. The modified nucleotides are considered especially useful in the fields of nanobiotechnology, where signal stability and intensity is a limiting factor.
ISIS: an information-efficient spectral imaging system (1998)

A specialized hyperspectral imager has been developed that preprocesses the spectra from an image before the light reaches the detectors. This 'optical computer' does not allow the flexibility of digital post-processing. However, the processing is done in real time and the system can examine approximately equals 2 X 10<SUP>6</SUP> scene pixels/sec. Therefore, outdoors it could search for pollutants, vegetation types, minerals, or man-made objects. On a high-speed production line it could identify defects in sheet products like plastic wrap or film, or on painted or plastic parts.
Synovial fluid level of aggrecan ARGS fragments is a more sensitive marker of joint disease than glycosaminoglycan or aggrecan levels: a cross-sectional study (2009)

Levels of aggrecan ARGS fragments in human synovial fluid are increased in human arthritis, OA and after knee injury, likely reflecting an enhanced cleavage at the 392Glu-393Ala bond in the IGD by aggrecanase. An assay that specifically quantified these fragments better distinguished samples from joints with pathology than assays monitoring aggrecan or glycosaminoglycan concentrations. The newly developed ARGS fragment assay can be used to monitor aggrecanase activity in human joint disease and experimental models.
Multidrug Efflux Pump AcrAB of Salmonella typhimurium Excretes Only Those β-Lactam Antibiotics Containing Lipophilic Side Chains (1998)

We found that the previously reported SS-B drug-supersusceptible mutant of Salmonella typhimurium (S. Sukupolvi, M. Vaara, I. M. Helander, P. Viljanen, and P. H. Mäkelä, J. Bacteriol. 159:704-712, 1984) had a mutation in the acrAB operon. Comparison of this mutant with its parent strain and with an AcrAB-overproducing strain showed that the activity of the AcrAB efflux pump often produced significant resistance to beta-lactam antibiotics in the complete absence of beta-lactamase. The effect of AcrAB activity on resistance was more pronounced with agents containing more lipophilic side chains, suggesting that such compounds were better substrates for this pump. This correlation is consistent with the hypothesis that only those molecules that become at least partially partitioned into the lipid bilayer of the cytoplasmic membrane are captured by the AcrAB pump. According to this mechanism, the pump successfully excretes even those beta-lactams that fail to traverse the cytoplasmic membrane, because these compounds are likely to become partitioned into the outer leaflet of the bilayer. Even the compounds with lipophilic side chains were shown to penetrate across the outer membrane relatively rapidly, if the pump was inactivated genetically or physiologically. The exclusion of such compounds, exemplified by nafcillin, from cells of the wild-type S. typhimurium was previously interpreted as the result of poor diffusion across the outer membrane (H. Nikaido, Biochim. Biophys. Acta 433:118-132, 1976), but it is now recognized as the consequence of efficient pumping out of entering antibiotics by the active efflux process.
Live Subgroup B Respiratory Syncytial Virus Vaccines that Are Attenuated, Genetically Stable, and Immunogenic in Rodents and Nonhuman Primates (1996)

Optimal immunization of neonates against disease caused by respiratory syncytial virus (RSV) probably will require multiple doses of a vaccine containing viruses of both subgroups A and B. Live subgroup B RSV mutants were generated containing multiple attenuating mutations, ts (temperature-sensitive) and non-ts (host range), that were introduced by prolonged passage in cell culture or by chemical mutagenesis. The cold-passaged (cp)-52 mutant was restricted in replication compared to wild type virus in rodents and nonhuman primates. In addition, the attenuation phenotype of cp-52 was stable after prolonged replication in immunosuppressed rodents. One or two ts mutations were then introduced into the cp-52 mutant to generate additional candidate vaccine strains that were more attenuated in vivo than the cp-52 parental virus. Tests in humans are being done to determine if one or more of the RSV B-1 mutants exhibit a satisfactory balance between attenuation and immunogenicity.