gebhart/patrepeval huggingface dataset:
Delineation of putative mechanisms involved in antibody-mediated clearance of rabies virus from the central nervous system. (1992)

The in vitro biological activities of several rabies virus-neutralizing monoclonal antibodies (mAbs) were compared with their ability to prevent a lethal rabies virus encephalomyelitis. The protective activity of a particular mAb in vivo did not correlate with its virus-neutralizing activity in vitro; rather it was related to the mAb's ability to inhibit virus spread from cell to cell and to restrict rabies virus RNA transcription. Since treatment of rabies virus-infected cells with virus-neutralizing mAbs results in an endocytosis of the antibody, we hypothesize that an antibody may exert its inhibitory activity even after uptake by the cell. Post-exposure treatment of rats with a mAb that inhibited both virus spread and virus RNA transcription in vitro resulted in viral clearance from the central nervous system and protected the animals against a lethal rabies virus infection.
BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance (2006)

Mutations in the BCR/ABL kinase domain play a major role in resistance to imatinib mesylate (IM). We report here that BCR/ABL kinase stimulates reactive oxygen species (ROS), which causes oxidative DNA damage, resulting in mutations in the kinase domain. The majority of mutations involved A/T-->G/C and G/C-->A/T transitions, a phenotype detected previously in patients, which encoded clinically relevant amino acid substitutions, causing IM resistance. This effect was reduced in cells expressing BCR/ABL(Y177F) mutant, which does not elevate ROS. Inhibition of ROS in leukemia cells by the antioxidants pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine (NAC), and vitamin E (VE) decreased the mutagenesis rate and frequency of IM resistance. Simultaneous administration of IM and an antioxidant exerted better antimutagenic effect than an antioxidant alone. Therefore, inhibition of ROS should diminish mutagenesis and enhance the effectiveness of IM.
Antiestrogen-Binding Sites Distinct from the Estrogen Receptor: Subcellular Localization, Ligand Specificity, and Distribution in Tissues of the Rat* (1983)

Antiestrogens are known to interact with the estrogen receptor system of target cells. In addition, it is possible that recently identified estrogen-noncompetable, antiestrogenspecific binding sites may be of importance in mediating and/or modulating the actions of antiestrogens, and hence, we have examined their nature and properties. We find these sites to fractionate with what is likely the microsomal fraction of rat uterus with only very small amounts in high speed cytosol. Antiestrogen-specific binding sites are present in the 800 ×g × 10 min or 12,000 or 20,000 × g × 30 min supernatants, but are pelleted upon centrifugation at 100,000 or 180,000 × g × 60 min. These sites are present in the 12,000 × g supernatant fraction of almost all rat tissues examined. They are highest in concentration in the liver, uterus, esophagus, ovary, brain, and kidney; lower levels are found in lung and spleen, and negligible amounts are seen in muscle, heart, and serum. Hence, these sites are not localized exclusively or primarily in estrogen target tissues and their level does not parallel that of the estrogen receptor, which is high only in the uterus and ovary and at lower levels in liver and kidney. Affinity for this binding site follows the order trans-tamoxifen (1-[4-(2-dimethylaminoethoxy) phenyl]-l,2-diphenylbut-l(Z)-ene) (set at 100%) ≥ cis-tamoxifen > CI628 (α-{p-[2-(l-pyrrolidino)ethoxy]phenyl)-4-methoxy-α′-nitrostilbene) (50%) > trans-hydroxytamoxifen (l,4-(2-dimethylaminoethoxy)phenyl-l-(4-hydroxyphenyl)-2-phenylbut-1(Z)-ene) (40%) > CI628M (α-(p-[2-(l-pyrrolidino) ethoxy]phenylj-4-hydroxy-α′&-nitrostilbene) (20%) > LY117018 (6-hydroxy-2-(p-hydroxyphenyl)benzo[b]thien-3-yl p-[2-(l-pyrrolidinyl)ethoxy]phenyl ketone) (2%). Triphenylethylene antiestrogens lacking the amine side chain do not bind to these antiestrogen-specific sites, but several tamoxifen analogs with altered basic side chains have affinities for these sites 4- to 10-fold greater than that of tamoxifen. Hence, the affinity of different antiestrogens for this site does not parallel the potency of these compounds as antiestrogens or their affinity for the estrogen receptor. Antiestrogen-specific binding sites and estrogen receptor sites differ in their thermal stability, pH stability, and protease sensitivity, and in their pattern of depletion from the 12,000 × g supernatant fraction following the administration of estradiol. From these findings, we believe that these sites may not be directly involved in mediation of the classically recognized estrogen antagonism of antiestrogens. Nevertheless, the high affinity (dissociation constant of 1–3 nM) and wide distribution of these sites suggest that they might influence the action of antiestrogens in vivo, possibly in a passive manner, by altering the apparent distribution volume of antiestrogens and, hence, their biological potency and pharmacokinetics.
Spacecraft-generated plasma interaction with high voltage solar array (1978)

Calculations are made of the effect of interactions of spacecraft-generated plasmas and high voltage solar array components on an advanced Solar Electric Propulsion system. The plasma consists of mercury ions and electrons resulting from the operation of ion thrusters and associated hollow cathode neutralizers. Because large areas of the solar array are at high potential and not completely insulated from the surrounding plasma, the array can, under some conditions, collect excessive electron currents. Results are given for the parasitic currents collected by the solar arrays and means for reducing these currents are considered.
Growth factor receptors: Structure, mechanism, and drug discovery (1997)

The focus of this review is the relationship between the three-dimensional structure of ligands of the various members of the growth factor receptor tyrosine kinase superfamily and their interaction with the cognate receptor. Particular attention is given to the transforming growth factor-alpha, epidermal growth factor (EGF); nerve growth factor, neurotrophin; and insulin-like growth factor-1 (IGF-1), insulin systems since these have been extensively studied in recent years. The three receptor types, which bind these ligands, are the epidermal growth factor receptor family (erb B receptors), the neurotrophin or Trk receptor family, and IGF-1/insulin receptors, respectively, and represent three distinct members of the tyrosine kinase superfamily. For each of these, formation of the ligand-receptor complex initiates the signal transduction cascade through autophosphorylation by the intracellular tyrosine kinase domain. The extracellular portion of the receptor that contains the ligand binding domain in these systems varies significantly in organization in each case. For the EGF receptor system, ligand binding induces homo- and heterodimerization of the receptor leading to activation of the intracellular kinase. For the Trk receptor system, homodimerization of receptors has been shown to occur, although a second receptor, p75, is also required for high affinity binding of neurotrophins and for enhanced sensitivity of tyrosine kinase activation at low ligand concentrations. The IGF-1 and insulin receptors exist as covalent cross-linked dimers where each monomer is composed of two subunits. The aim of this review is also to discuss the mechanism of ligand-receptor interaction for each of these cases; however, since no structural information is yet available for the ligand-receptor complex, the discussion will largely be centered on the molecular requirements of ligand binding. As these receptors are activated through the ligand binding site on the extracellular domain, this represents a possible target for pharmacological intervention by inhibition or stimulation of this portion of the receptor. Thus from a drug design perspective, the focus of this review is to discuss progress in the development of agonists or antagonists of the ligand for these receptors.
Ultrashort pulse generation by intracavity spectral shaping and phase compensation of external-cavity modelocked semiconductor lasers (2000)

Intracavity spectral shaping and external chirp compensation techniques were employed to generate nearly transform-limited optical pulses with a temporal duration of 250 fs from an external-cavity modelocked semiconductor laser. It was also demonstrated that intracavity spectral shaping techniques can be used for artificially tailoring the chirp of the output pulses.
Essential role of urease in pathogenesis of gastritis induced by Helicobacter pylori in gnotobiotic piglets (1991)

A mutant strain of Helicobacter pylori with weak urease activity was created by using N-methyl-N'-nitro-N-nitrosoguanidine. The urease activity of the mutant (0.036 +/- 0.009 nmol of urea per micrograms of bacterial protein per min) was 0.4% of that of the parental strain (8.20 +/- 2.30 nmol of urea per micrograms of bacterial protein per min). The mutant was otherwise indistinguishable from the parental strain. Both demonstrated prominent catalase and oxidase activities, and both produced vacuolating cytotoxin. Restriction endonuclease and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) patterns and ultrastructure were identical for the two strains. The mutant was fully motile, as evaluated by spreading in soft agar and by direct microscopic examination. Growth rate and colony size and morphology were identical for the mutant and parental strains. Seventeen gnotobiotic piglets were challenged with either the mutant or the parental strain and sacrificed 3 or 21 days after challenge. Gastric tissue was examined histologically and cultured for H. pylori. Of seven piglets challenged with the parental strain, all became infected. H. pylori was not recovered from any of 10 piglets challenged with the urease-negative strain. Lymphofollicular gastritis was present in all seven piglets challenged with the parental strain but in none of the piglets challenged with the urease-negative strain. These results suggest that prominent urease activity is essential for colonization by H. pylori.
Cochlear Function and Transgene Expression in the Guinea Pig Cochlea, Using Adenovirus- and Adeno-Associated Virus-Directed Gene Transfer (2001)

Development of a viral vector that can infect hair cells of the cochlea without producing viral-associated ototoxic effects is crucial for utilizing gene replacement therapy as a treatment for certain forms of hereditary deafness. In the present study, cochlear function was monitored using distortion-product otoacoustic emissions (DPOAEs) in guinea pigs that received infusions of either (E1-, E3-) adenovirus, or adeno-associated virus (AAV), directly into the scala tympani. Replication-deficient (E1-, E3-) adenovirus-directed gene transfer, using the cytomegalovirus (CMV) promoter, drove transgene expression to inner hair cells and pillar cells of the cochlea. AAV transduction was tested with several promoters, such as platelet-derived growth factor (PDGF), neuron-specific enolase (NSE), and elongation factor 1α (EF-1α) promoters; which drove transgene expression to cochlear blood vessels, nerve fibers, and certain spiral limbus cells, respectively. AAV transgene expression was visualized by green fluorescent protein immunostaining. Immunocytochemistry to heparan sulfate confirmed the absence of proteoglycans in guinea pig hair cells, indicating that the receptor for AAV was not present on these cells. However, the heparan sulfate proteoglycan expression pattern mimicked the AAV transduction pattern. An overall finding was that cochlear function was not altered throughout the infection period using AAV titers as high as 5 × 108 IP/infused cochlea. In contrast, cochlear function was severely compromised by 8 days postinfection with adenoviral titers of 5 × 108 PFU/infused cochlea, and outer hair cells were eliminated. Thus, cochlear hair cells are amenable to in vivo gene transfer using a replication-deficient (E1-, E3-) adenovirus. However, replication-defective or gutted adenovirus vectors must be employed to overcome the ototoxic effects of (E1-, E3-) adenovirus vectors.
Development of novel dye-doped silica nanoparticles for biomarker application (2001)

We report the development of novel luminescent nanoparticles composed of inorganic luminescent dye, Tris(2,2'-bipyridyl) dichlororuthenium (II) hexahydrate, doped inside a silica network. These dye doped silica (DDS) nanoparticles have been synthesized using a water-in-oil microemulsion technique in which controlled hydrolysis of the tetraethyl orthosilicate leads to the formation of monodispersed nanoparticles. They are prepared with a variety of sizes: small (5+/-1 nm), medium (63+/-4 nm), and large (400+/-10 nm), which shows the efficiency of the microemulsion technique for the synthesis of uniform nanoparticles. All these nanoparticles are suitable for biomarker application since they are much smaller than cellular dimension. These nanoparticles are highly photostable in comparison to most commonly used organic dyes. These nanoparticles have been characterized by various microscopic and spectroscopic techniques. The amount of dye content in these nanoparticles has been optimized to eliminate self-quenching. It has been observed that maximum luminescence intensity is achieved when the dye content is around 20 wt%. Silica surface of DDS nanoparticles is available for surface modification and bioconjunction. For demonstration as a biomarker, the DDS nanoparticle's surface has been biochemically modified to attach membrane-anchoring groups and applied successfully to stain human leukemia cells.
Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1 (1997)

The chemokine receptor CCR5 is the major fusion coreceptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). To define the structures of CCR5 that can support envelope (Env)-mediated membrane fusion, we analyzed the activity of homologs, chimeras, and mutants of human CCR5 in a sensitive gene reporter cell-cell fusion assay. Simian, but not murine, homologs of CCR5 were fully active as HIV-1 fusion coreceptors. Chimeras between CCR5 and divergent chemokine receptors demonstrated the existence of two distinct regions of CCR5 that could be utilized for Env-mediated fusion, the amino-terminal domain and the extracellular loops. Dual-tropic Env proteins were particularly sensitive to alterations in the CCR5 amino-terminal domain, suggesting that this domain may play a pivotal role in the evolution of coreceptor usage in vivo. We identified individual residues in both functional regions, Asp-11, Lys-197, and Asp-276, that contribute to coreceptor function. Deletion of a highly conserved cytoplasmic motif rendered CCR5 incapable of signaling but did not abrogate its ability to function as a coreceptor, implying the independence of fusion and G-protein-mediated chemokine receptor signaling. Finally, we developed a novel monoclonal antibody to CCR5 to assist in future studies of CCR5 expression.
Determination of the epidemiology and transmission of nontypable Haemophilus influenzae in children with otitis media by comparison of total genomic DNA restriction fingerprints (1989)

It is assumed that the causative bacteria in children suffering from otitis media reach the middle ear via the eustachian tube. The purpose of this investigation was to use endonuclease restriction of bacterial chromosomal DNA to compare isolates of nontypable (NT) Haemophilus influenzae obtained from the nasopharynx and from middle ear (ME) effusions of patients with otitis media. Strains of NT H. influenzae were isolated from the nasopharynx (NP) and affected ME from a group of 13 unrelated children with otitis media with effusion (OME). For 12 of these children, identical strains were isolated from the NP and ME in a first episode of OME. Each of these 12 sets differed from the other 11. Six of these children suffered from a second episode of OME with NT H. influenzae. Five of these children with recurrence again had identical NP and ME strains. These results suggest that at the time of an episode of OME, there is one predominant strain of NT H. influenzae that colonizes both the NP and ME. The strains of NT H. influenzae isolated from all six of the second episodes were different from strains from the first episode, indicating turnover of the predominant strain in the NT H. influenzae population between episodes. When we investigated three siblings with concurrent episodes of OME, we found that they shared several similar strains of NT H. influenzae, thereby demonstrating that within a family, transmission of NT H. influenzae from child to child is possible. These results from DNA fingerprinting were essentially identical when compared with results from outer membrane protein subtyping performed on the same set of strains. The analysis of endonuclease restriction patterns of total genomic DNA provides a sensitive measure of genetic dissimilarity between strains and represents an easily applicable method for epidemiological and transmission studies of bacterial infections associated with NT H. influenzae.
CD2 is involved in maintenance and reversal of human alloantigen-specific clonal anergy. (1994)

Induction and maintenance of a state of T cell unresponsiveness to specific alloantigen would have significant implications for human organ transplantation. Using human histocompatibility leukocyte antigen DR7-specific helper T cell clones, we demonstrate that blockade of the B7 family of costimulatory molecules is sufficient to induce alloantigen-specific T cell clonal anergy. Anergized cells do not respond to alloantigen and a variety of costimulatory molecules, including B7-1, B7-2, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated molecule (LFA)-3. However, after culture in exogenous interleukin (IL)-2 for at least 7 d, anergized cells can respond to alloantigen in the presence of LFA-3. LFA-3 costimulation subsequently restores responsiveness to alloantigen in the presence of previously insufficient costimulatory signals. Expression of CD2R epitope is downregulated on anergic cells and is restored after 7 d of IL-2 culture. The loss of the CD2R is temporally associated with the inability of anergized cells to respond to LFA-3. These results suggest that in addition to blockade of B7 family members, inhibition of CD2 and, potentially, other costimulatory pathways that might reverse anergy will be necessary to maintain prolonged alloantigen-specific tolerance.
A parameterizable SIMD stream processor (2006)

Stream processing is a data processing paradigm in which long sequences of homogeneous data records are passed through one or more computational kernels to produce sequences of processed output data. Applications that fit this model include polygon rendering (computer graphics), matrix multiplication (scientific computing), 2D convolution (media processing), and data encryption (security). Computers that exploit stream computations process data faster than conventional microcomputers because they utilize a memory system and an execution model that increases on-chip bandwidth and delivers high throughput. We have designed a general-purpose, parameterizable, SIMD stream processor that operates on IEEE single-precision floating point data. The system is implemented in VHDL, and consists of a configurable FPU, execution unit array, and memory interface. The FPU supports pipelined operations for multiplication, addition, division, and square root. The data width is configurable. The execution array operates in lock-step with an instruction controller, which issues 32-bit instructions to the execution array. To exploit stream parallelism, the number of execution units as well as the number of interleaved threads is specified as a parameter at compilation time. The memory system allows all execution units to access one element of data from memory in every clock cycle. All memory accesses also pass through a routing network to support conditional reads and writes of stream data. Functional and timing simulations have been performed using a variety of benchmark programs. The system has also been synthesized into an Altera FPGA to verify resource utilization.
Osteopontin and the skin: multiple emerging roles in cutaneous biology and pathology (2009)

Osteopontin (OPN) is a glycoprotein expressed by various tissues and cells. The existence of variant forms of OPN as a secreted (sOPN) and intracellular (iOPN) protein and its modification through post-translational modification and proteolytic cleavage explain its broad range of functions. There is increasing knowledge which receptors OPN isoforms can bind to and which signaling pathways are activated to mediate different OPN functions. sOPN interacts with integrins and CD44, mediates cell adhesion, migration and tumor invasion, and has T helper 1 (Th1) cytokine functions and anti-apoptotic effects. iOPN has been described to regulate macrophage migration and interferon-alpha secretion in plasmacytoid dendritic cells. Both sOPN and iOPN, through complex functions for different dendritic cell subsets, participate in the regulation of Th cell lineages, among them Th17 cells. For skin disease, OPN from immune cells and tumor cells is of pathophysiological relevance. OPN is secreted in autoimmune diseases such as lupus erythematosus, and influences inflammation of immediate and delayed type allergies and granuloma formation. We describe that OPN is overexpressed in psoriasis and propose a model to study OPN function in psoriatic inflammation. Through cytokine functions, OPN supports immune responses against Mycobacteria and viruses such as herpes simplex virus. OPN is also implicated in skin tumor progression. Overexpression of OPN influences invasion and metastasis of melanoma and squamous cell carcinoma cells, and OPN expression in melanoma is a possible prognostic marker. As OPN protein preparations and anti-OPN antibodies may be available in the near future, in-depth knowledge of OPN functions may open new therapeutic approaches for skin diseases.
Directed assembly of cell-laden microgels for fabrication of 3D tissue constructs (2008)

We present a bottom-up approach to direct the assembly of cell-laden microgels to generate tissue constructs with tunable microarchitecture and complexity. This assembly process is driven by the tendency of multiphase liquid-liquid systems to minimize the surface area and the resulting surface free energy between the phases. We demonstrate that shape-controlled microgels spontaneously assemble within multiphase reactor systems into predetermined geometric configurations. Furthermore, we characterize the parameters that influence the assembly process, such as external energy input, surface tension, and microgel dimensions. Finally, we show that multicomponent cell-laden constructs could be generated by assembling microgel building blocks and performing a secondary cross-linking reaction. This bottom-up approach for the directed assembly of cell-laden microgels provides a powerful and highly scalable approach to form biomimetic 3D tissue constructs and opens a paradigm for directing the assembly of mesoscale materials.