gebhart/patrepeval huggingface dataset:
Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice (2014)

Mice genetically engineered to be humanized for their Ig genes allow for human antibody responses within a mouse background (HumAb mice), providing a valuable platform for the generation of fully human therapeutic antibodies. Unfortunately, existing HumAb mice do not have fully functional immune systems, perhaps because of the manner in which their genetic humanization was carried out. Heretofore, HumAb mice have been generated by disrupting the endogenous mouse Ig genes and simultaneously introducing human Ig transgenes at a different and random location; KO-plus-transgenic humanization. As we describe in the companion paper, we attempted to make mice that more efficiently use human variable region segments in their humoral responses by precisely replacing 6 Mb of mouse Ig heavy and kappa light variable region germ-line gene segments with their human counterparts while leaving the mouse constant regions intact, using a unique in situ humanization approach. We reasoned the introduced human variable region gene segments would function indistinguishably in their new genetic location, whereas the retained mouse constant regions would allow for optimal interactions and selection of the resulting antibodies within the mouse environment. We show that these mice, termed VelocImmune mice because they were generated using VelociGene technology, efficiently produce human:mouse hybrid antibodies (that are rapidly convertible to fully human antibodies) and have fully functional humoral immune systems indistinguishable from those of WT mice. The efficiency of the VelocImmune approach is confirmed by the rapid progression of 10 different fully human antibodies into human clinical trials.
Entacapone‐Induced Hepatotoxicity and Hepatic Dysfunction (2002)

We describe 2 patients with Parkinson's disease who developed hepatotoxicity associated with the use of entacapone, a novel, mainly peripheral acting inhibitor of catechol-D-methyltransferase. Hepatotoxicity resolved rapidly with discontinuation of the drug. Analysis of causality in a further case initially linked to entacapone exposure was confounded by conflicting serial adverse reaction reports.
Interferon γ (IFN-γ) Is Necessary for the Genesis of Acetylcholine Receptor–induced Clinical Experimental Autoimmune Myasthenia gravis in Mice (1997)

Experimental autoimmune myasthenia gravis (EAMG) is an animal model of human myasthenia gravis (MG). In mice, EAMG is induced by immunization with Torpedo californica acetylcholine receptor (AChR) in complete Freund's adjuvant (CFA). However, the role of cytokines in the pathogenesis of EAMG is not clear. Because EAMG is an antibody-mediated disease, it is of the prevailing notion that Th2 but not Th1 cytokines play a role in the pathogenesis of this disease. To test the hypothesis that the Th1 cytokine, interferon (IFN)-gamma, plays a role in the development of EAMG, we immunized IFN-gamma knockout (IFN-gko) (-/-) mice and wild-type (WT) (+/+) mice of H-2(b) haplotype with AChR in CFA. We observed that AChR-primed lymph node cells from IFN-gko mice proliferated normally to AChR and to its dominant pathogenic alpha146-162 sequence when compared with these cells from the WT mice. However, the IFN-gko mice had no signs of muscle weakness and remained resistant to clinical EAMG at a time when the WT mice exhibited severe muscle weakness and some died. The resistance of IFN-gko mice was associated with greatly reduced levels of circulating anti-AChR antibody levels compared with those in the WT mice. Comparatively, immune sera from IFN-gko mice showed a dramatic reduction in mouse AChR-specific IgG1 and IgG2a antibodies. However, keyhole limpet hemocyanin (KLH)-priming of IFN-gko mice readily elicited both T cell and antibody responses, suggesting that IFN-gamma regulates the humoral immune response distinctly to self (AChR) versus foreign (KLH) antigens. We conclude that IFN-gamma is required for the generation of a pathogenic anti-AChR humoral immune response and for conferring susceptibility of mice to clinical EAMG.
Oriented Immobilization of C-Reactive Protein on Solid Surface for Biosensor Applications (2006)

An attempt of surface modification with receptor layers to achieve a maximal signal from antigen-antibody interaction on the solid surface has been undertaken. Interaction of C-reactive protein (CRP) with monoclonal anti-CRP has been investigated by comparative study by chemical cross-linking or electrostatic interaction in the framework of Layer-by-Layer approach. The processes of gold surface modification have been monitored by a wavelength interrogation-based surface plasmon resonance (SPR) sensor. Atomic force microscopy has been used for visualization of the surfaces modified with protein layers. The influence of biotinylated protein G-streptavidin (bPG/STV) complex on the SPR signal shift by antigen-antibody interaction has been studied. The influence of different cross-linking chemicals, such as di(N-succinimidyl)-3,3′-dithiodipropionate, 3-(2-pyridyldithio)-propionic acid N-hydroxysuccinimide ester, and N-hydroxysuccinimide/N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide on antigen immobilization of anti-CRP/bPG/STV system has been also examined. The film morphology of the first immobilized layer is very important for protein interactions. Maximum SPR-shift by CRP coupling with anti-CRP has been observed on the surface modified by streptavidin and di(N-succinimidyl)-3,3′-dithiodipropionate. AFM method can be used to directly monitor CRP/anti-CRP interaction on polyelectrolyte support.
Identification of Effective Constituents of Influenza Vaccine by Immunization with Plasmid DNAs Encoding Viral Proteins (2001)

The use of plasmid DNA encoding influenza viral proteins to vaccinate animals constitutes a promising approach to the development of effective subunit vaccines. This review describes the results obtained by the immunization of mice with such plasmid DNAs. (i) Both hemagglutinin (HA)- and neuraminidase (NA)-expressing DNAs for the surface glycoproteins from A/PR/8/34 (H1N1) or B/Ibaraki/2/85 virus can provide the most effective protection against influenza A-type or B-type virus infection among the various viral protein-expressing DNAs tested in BALB/c mice. (ii) A mixture of plasmid DNAs encoding HA and NA can provide more effective protection against virus challenge than plasmid DNA encoding HA or NA alone in BALB/c mice. (iii) NA-DNA can provide protection against infection not only by homologous virus but also by drift viruses. (iv) HA-DNA from A/PR/8/34 (H1N1) virus provides significant protection only in BALB/c (H-2(b)) mice, whereas HA-DNA from B/Ibaraki/2/85 virus affords significant protection in BALB/c, B10 (H-2(d)), and C3H (H-2(k)) mice. NA-DNA from both A-type and B-type viruses provides significant protection in the three strains of mice. These results suggest that both HA and NA molecules should be used as vaccine components to provide effective protection against influenza A-type and B-type virus infection in genetically heterogeneous humans.
The Myb DNA-binding domain is highly conserved in Dictyostelium discoideum. (1992)

The c-myb proto-oncogene encodes a protein that is highly conserved among birds and mammals. The amino-terminal domain of c-Myb contains three imperfect tandem repeats of approximately 50 amino acids each. This domain is required for DNA binding and has also been conserved to varying degrees in invertebrates, plants and yeast. Given that myb-related genes appear to control cellular differentiation in a variety of eucaryotic systems, the presence of a myb gene in the cellular slime mold Dictyostelium discoideum might provide a tractable system for studying the role of myb in differentiation. Degenerate oligonucleotide primers encoding regions that are highly conserved in the vertebrate and Drosophila Myb DNA-binding domains were used to amplify a related domain from Dictyostelium genomic DNA, which was then used to isolate a genomic clone. The putative DNA-binding domain of Dictyostelium Myb is as closely related to vertebrate c-Myb as is Drosophila Myb (65% identity), whereas the known Myb-related proteins of plants and yeast are more distantly related. The conserved domain of Dictyostelium Myb is capable of binding to the same DNA sequence as the vertebrate and Drosophila Myb proteins. The remainder of the deduced amino acid sequence of Dictyostelium Myb shows no homology to the divergent domains of the known animal, plant and yeast Myb-related proteins. Evolutionary analysis implies that the duplications that generated the repeats of the Myb DNA-binding domain began prior to the divergence of animals, plants, cellular slime molds and yeast.
MPEG-L/MRP: Adaptive Streaming of MPEG Videos for Interactive Internet Applications (2000)

Continuous delivery of media streams like video over IP networks so far is mainly handled by commercial approaches delivering streams forward-oriented in their own proprietary format. Though some existing streaming technologies are able to adapt to varying bandwidths, they do not provide smooth reactions to user interactions with the continuous stream.
Protein Kinase Cσ-specific Phosphorylation of the Elongation Factor eEF-1α and an eEF-1α Peptide at Threonine 431 (1995)

Two cytosolic proteins of murine epidermis or porcine spleen with molecular masses of 37 kDa (p37) and 50 kDa (p50) are differentially phosphorylated in vitro by the purified protein kinase C (PKC) isoenzymes alpha, beta, gamma (cPKC) and PKC delta. p37, identified as annexin I, is preferentially phosphorylated by cPKC, whereas p50, identified as elongation factor eEF-1 alpha, is phosphorylated with much greater efficacy by PKC delta than by cPKC. Using the recombinant PKC isoenzymes alpha, beta, gamma, delta, epsilon, eta, and zeta, we could show that purified eEF-1 alpha is indeed a specific substrate of PKC delta. It is not significantly phosphorylated by PKC epsilon, -eta, and -zeta and only slightly by PKC alpha, -beta, and -gamma. PKC delta phosphorylates eEF-1 alpha at Thr-431 (based on the murine amino acid sequence). The peptide RFAVRDMRQTVAVGVIKAVDKK with a sequence corresponding to that of 422-443 from murine eEF-1 alpha and containing Thr-431 is an absolutely specific substrate for the delta-type of PKC. The single basic amino acid close to Thr-431 (Arg-429) is essential for recognition of the peptide as a substrate by PKC delta and for the selectivity of this recognition. Substitution of Arg-429 by alanine abolishes the ability of PKC delta to phosphorylate the peptide, and insertion of additional basic amino acids in the vicinity of Thr-431 causes a complete loss of selectivity.
Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children's Oncology Group (COG) Phase II Study (2010)

Patients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma.
Acetylcholinesterase and butyrylcholinesterase activity in the human term placenta: implications for fetal cocaine exposure. (1994)

The characterization of the enzymes responsible for drug metabolism in the human placenta is of great importance in determining the possible role the placenta plays in protecting the fetus from potentially fetotoxic drugs. We speculate that the placenta metabolizes cocaine, serving to protect the fetus from the drug's ill effects. Cholinesterase, the principle enzyme that metabolizes cocaine, has been hypothesized to be present yet is not well characterized in the human placenta. The purpose of this study was to quantify human placental acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. Human placentas were obtained from elective cesarean sections, and several lobules were thoroughly perfused with cold buffer to ensure minimal contamination from erythrocyte AChE. Subcellular fractions were then prepared from these lobules by using standard differential centrifugation techniques. Microsomes and cytosol were assayed for AChE and BChE activity by using a spectrophotometric assay. BChE activity was found in the cytosolic fraction of the placental villous tissue, whereas AChE activity was measured in the microsomal fraction. By demonstrating that BChE activity is present in human term placenta we have shown that this organ has the capacity to metabolize cocaine and may therefore serve as a metabolic barrier to fetal exposure to cocaine.
Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma (2015)

Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA's mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt's lymphoma cell lines. Phagocytosis contributed to DARA's anti-tumor activity in vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model. Finally, DARA was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression. In summary, we demonstrate that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of DARA in multiple myeloma and potentially other hematological tumors.
The stability of the heme-globin linkage in some normal, mutant, and chemically modified hemoglobins. (1990)

The rates and equilibria of heme exchange between methemoglobin and serum albumin were measured using a simple new spectrophotometric method. It is based on the large difference between the spectrum of methemoglobin and that of methemealbumin at pH 8-9. The rate of heme exchange was found to be independent of the albumin concentration and inversely proportional to the hemoglobin (Hb) concentration. Taken together with the finding that the rate was 10 times greater for Hb Rothschild, which is completely dissociated into alpha beta dimers and 10 times smaller for two cross-linked hemoglobins, the subunits of which cannot dissociate, this showed that the rate of dissociation of heme from alpha beta dimers is very much greater than from tetramers. Conditions were found for the attainment of an equilibrium distribution of hemes between beta globin and albumin. The equilibrium distribution ratio, R = methemealbumin/albumin/methemoglobin/apohemoglobin, for hemoglobin A was 3.4 with human and 0.005 with bovine serum albumin. Both the rates of exchange and the R values of HbS and HbF were the same as that for HbA. The equilibrium distribution ratio for Hb Rothschild was 7 times greater than that for HbA whereas that of one but not the other of the cross-linked hemoglobins was 10 times smaller. The structural bases for these differences are analyzed.
An Inherited Abnormality of Neutrophil Adhesion (1980)

Neutrophils from a five-year-old boy with recurrent bacterial infections failed to spread on surfaces, leading to a severe defect in chemotaxis and a mild impairment in phagocytosis. Failure to spread was also seen in a fraction of the neutrophils from the patient's mother and sister, but cells from his father and brother were normal. Gel electrophoresis revealed that a protein with a molecular weight of 110,000 daltons (designated gp 110) present in the particulate fraction of normal neutrophils was absent from the patient's cells, and that its levels were below normal in cells from his mother and sister but normal in neutrophils from his father and brother. These findings suggest that gp 110 is necessary for the spreading of neutrophils onto surfaces, that the functional abnormality in the patient's cells is caused by its absence, and that deficiency of gp 110 is an X-linked congenital disease.
Synthetic investigations of molybdenum pyrrolide and related complexes (2010)

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2010.
Human Type II Receptor for Bone Morphogenic Proteins (BMPs): Extension of the Two-Kinase Receptor Model to the BMPs (1995)

Bone morphogenic proteins (BMPs) are universal regulators of animal development. We report the identification and cloning of the BMP type II receptor (BMPR-II), a missing component of this receptor system in vertebrates. BMPR-II is a transmembrane serine/threonine kinase that binds BMP-2 and BMP-7 in association with multiple type I receptors, including BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor. Cloning of BMPR-II resulted from a strong interaction of its cytoplasmic domain with diverse transforming growth factor beta family type I receptor cytoplasmic domains in a yeast two-hybrid system. In mammalian cells, however, the interaction of BMPR-II is restricted to BMP type I receptors and is ligand dependent. BMPR-II binds BMP-2 and -7 on its own, but binding is enhanced by coexpression of type I BMP receptors. BMP-2 and BMP-7 can induce a transcriptional response when added to cells coexpressing ActR-I and BMPR-II but not to cells expressing either receptor alone. The kinase activity of both receptors is essential for signaling. Thus, despite their ability to bind to type I and II receptors receptors separately, BMPs appear to require the cooperation of these two receptors for optimal binding and for signal transduction. The combinatorial nature of these receptors and their capacity to crosstalk with the activin receptor system may underlie the multifunctional nature of their ligands.
Sex differences in physiological cardiac hypertrophy are associated with exercise-mediated changes in energy substrate availability (2011)

Exercise-induced cardiac hypertrophy has been recently identified to be regulated in a sex-specific manner. In parallel, women exhibit enhanced exercise-mediated lipolysis compared with men, which might be linked to cardiac responses. The aim of the present study was to assess if previously reported sex-dependent differences in the cardiac hypertrophic response during exercise are associated with differences in cardiac energy substrate availability/utilization. Female and male C57BL/6J mice were challenged with active treadmill running for 1.5 h/day (0.25 m/s) over 4 wk. Mice underwent cardiac and metabolic phenotyping including echocardiography, small-animal PET, peri-exercise indirect calorimetry, and analysis of adipose tissue (AT) lipolysis and cardiac gene expression. Female mice exhibited increased cardiac hypertrophic responses to exercise compared with male mice, measured by echocardiography [percent increase in left ventricular mass (LVM): female: 22.2 ± 0.8%, male: 9.0 ± 0.2%; P < 0.05]. This was associated with increased plasma free fatty acid (FFA) levels and augmented AT lipolysis in female mice after training, whereas FFA levels from male mice decreased. The respiratory quotient during exercise was significantly lower in female mice indicative for preferential utilization of fatty acids. In parallel, myocardial glucose uptake was reduced in female mice after exercise, analyzed by PET {injection dose (ID)/LVM [%ID/g]: 36.8 ± 3.5 female sedentary vs. 28.3 ± 4.3 female training; P < 0.05}, whereas cardiac glucose uptake was unaltered after exercise in male counterparts. Cardiac genes involved in fatty acid uptake/oxidation in females were increased compared with male mice. Collectively, our data demonstrate that sex differences in exercise-induced cardiac hypertrophy are associated with changes in cardiac substrate availability and utilization.
A low-cost, high-yield fabrication method for producing optimized biomimetic dry adhesives (2009)

We present a low-cost, large-scale method of fabricating biomimetic dry adhesives. This process is useful because it uses all photosensitive polymers with minimum fabrication costs or complexity to produce molds for silicone-based dry adhesives. A thick-film lift-off process is used to define molds using AZ 9260 photoresist, with a slow acting, deep UV sensitive material, PMGI, used as both an adhesion promoter for the AZ 9260 photoresist and as an undercutting material to produce mushroom-shaped fibers. The benefits to this process are ease of fabrication, wide range of potential layer thicknesses, no special surface treatment requirements to demold silicone adhesives and easy stripping of the full mold if process failure does occur. Sylgard® 184 silicone is used to cast full sheets of biomimetic dry adhesives off 4" diameter wafers, and different fiber geometries are tested for normal adhesion properties. Additionally, failure modes of the adhesive during fabrication are noted and strategies for avoiding these failures are discussed. We use this fabrication method to produce different fiber geometries with varying cap diameters and test them for normal adhesion strengths. The results indicate that the cap diameters relative to post diameters for mushroom-shaped fibers dominate the adhesion properties.
Three-dimensional integration: technology, use, and issues for mixed-signal applications (2003)

Three-dimensional (3-D) integration provides opportunities in large-scale integration of mixed-signal and general system-on-chip applications with improved performance, through increased density and mixing of different active and passive technologies. This paper reports a novel low-thermal-budget 3-D fabrication technique-multilayers with buried structures (MLBS) and an analysis of its applicability to mixed-signal integration. The MLBS technique uses a low temperature of 450/spl deg/C to transfer a single-crystal silicon layer over a processed wafer consisting of buried in-plane and out-of-plane interconnects obtained through a dual Damascene process. Devices can continue to be processed on this transferred layer. Electrical characteristics of MOS capacitors (D/sub it/=4.7/spl times/10/sup 10/ cm/sup -2/ eV/sup -1/) and 3-D integrated planar CMOS transistors (3-D CMOS), fabricated using MLBS, are consistent with integration requirements. Our analog analysis includes an investigation of thermal effects important to analog applications with continuous operation of transistors in forward active bias, as well as of the coupling isolation derived from use of a ground-plane. Use of high density local interconnectivity improves the thermal properties of 3-D CMOS over that of silicon-on-insulator, and use of a ground plane is shown to lead to an improvement of better than 8 dB in coupling isolation.