gebhart/patrepeval huggingface dataset:
Failure of human immunodeficiency virus entry and infection in CD4-positive human brain and skin cells (1990)

CD4 molecules on human cells function as a major receptor for human immunodeficiency virus (HIV); however, certain CD4-negative cell types may also be susceptible to infection. Therefore, we attempted to quantitate the relationship between HIV infection and CD4 expression on human cell lines before and after introduction of the CD4 gene by using a retrovirus vector. Prior to introduction of the CD4 expression vector, low levels of HIV infection were detected by a sensitive focal immunoassay on all three cell types studied. With several HIV strains in clones of human cervical carcinoma (HeLa) cells expressing different levels of CD4, HIV titer increased with increasing CD4 expression. In contrast, in squamous cell carcinoma cells (SCL1) and astroglial cells (U87MG), even high levels of CD4 expression failed to augment HIV infection. The CD4 protein expressed in these two cell lines had the expected molecular weight and was capable of binding HIV virions. However, in contrast to CD4-positive HeLa cells, CD4-positive U87MG and SCL1 cells were unable to form syncytia when cultured with cells expressing HIV envelope protein. Thus, the inability of HIV to infect these cells appeared to be due to lack of fusion between HIV virion envelope proteins and CD4-positive cell membranes. This block is infectivity was overcome when cells were infected with HIV which was pseudotyped with the envelope protein of amphotropic murine leukemia virus. Thus, in addition to CD4, other cell surface molecules appear to be required for successful HIV entry into and infection of these two human cell lines.
Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma (2005)

We have shown that the proteasome inhibitor bortezomib (formerly known as PS-341) triggers significant antitumor activity in multiple myeloma (MM) in both preclinical models and patients with relapsed refractory disease. Recent studies have shown that unfolded and misfolded ubiquitinated proteins are degraded not only by proteasomes, but also by aggresomes, dependent on histone deacetylase 6 (HDAC6) activity. We therefore hypothesized that inhibition of both mechanisms of protein catabolism could induce accumulation of ubiquitinated proteins followed by significant cell stress and cytotoxicity in MM cells. To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively. Tubacin specifically triggers acetylation of alpha-tubulin as a result of HDAC6 inhibition in a dose- and time-dependent fashion. It induces cytotoxicity in MM cells at 72 h with an IC50 of 5-20 microM, which is mediated by caspase-dependent apoptosis; no toxicity is observed in normal peripheral blood mononuclear cells. Tubacin inhibits the interaction of HDAC6 with dynein and induces marked accumulation of ubiquitinated proteins. It synergistically augments bortezomib-induced cytotoxicity by c-Jun NH2-terminal kinase/caspase activation. Importantly, this combination also induces significant cytotoxicity in plasma cells isolated from MM patient bone marrow. Finally, adherence of MM cells to bone marrow stromal cells confers growth and resistance to conventional treatments; in contrast, the combination of tubacin and bortezomib triggers toxicity even in adherent MM cells. Our studies therefore demonstrate that tubacin combined with bortezomib mediates significant anti-MM activity, providing the framework for clinical evaluation of combined therapy to improve patient outcome in MM.
Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer (2012)

The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.
Not So Different After All: A Comparison of Methods for Detecting Amino Acid Sites Under Selection (2005)

We consider three approaches for estimating the rates of nonsynonymous and synonymous changes at each site in a sequence alignment in order to identify sites under positive or negative selection: (1) a suite of fast likelihood-based "counting methods" that employ either a single most likely ancestral reconstruction, weighting across all possible ancestral reconstructions, or sampling from ancestral reconstructions; (2) a random effects likelihood (REL) approach, which models variation in nonsynonymous and synonymous rates across sites according to a predefined distribution, with the selection pressure at an individual site inferred using an empirical Bayes approach; and (3) a fixed effects likelihood (FEL) method that directly estimates nonsynonymous and synonymous substitution rates at each site. All three methods incorporate flexible models of nucleotide substitution bias and variation in both nonsynonymous and synonymous substitution rates across sites, facilitating the comparison between the methods. We demonstrate that the results obtained using these approaches show broad agreement in levels of Type I and Type II error and in estimates of substitution rates. Counting methods are well suited for large alignments, for which there is high power to detect positive and negative selection, but appear to underestimate the substitution rate. A REL approach, which is more computationally intensive than counting methods, has higher power than counting methods to detect selection in data sets of intermediate size but may suffer from higher rates of false positives for small data sets. A FEL approach appears to capture the pattern of rate variation better than counting methods or random effects models, does not suffer from as many false positives as random effects models for data sets comprising few sequences, and can be efficiently parallelized. Our results suggest that previously reported differences between results obtained by counting methods and random effects models arise due to a combination of the conservative nature of counting-based methods, the failure of current random effects models to allow for variation in synonymous substitution rates, and the naive application of random effects models to extremely sparse data sets. We demonstrate our methods on sequence data from the human immunodeficiency virus type 1 env and pol genes and simulated alignments.
Specific Recognition of Disaccharides in Water by an Artificial Bicyclic Carbohydrate Receptor (2007)

Abstract We present the synthesis of a peptide‐based bicyclic carbohydrate receptor capable of carbohydrate recognition in 10 % deuterated acetic acid in water. The binding constants were estimated by using NMR spectroscopy, and furthermore, a series of carbohydrate complexes were studied with the use of MS (ESI) of the complex. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2007)
Interactions between the Protein-tyrosine Kinase ZAP-70, the Proto-oncoprotein Vav, and Tubulin in Jurkat T Cells (1995)

Two molecules involved in signal transduction via the T cell antigen receptor, namely the protein-tyrosine kinase ZAP-70 and the proto-oncoprotein Vav, were found to be constitutively associated with tubulin in Jurkat T cells. Both were able to bind to tubulin independently of one another, as determined by transient transfection into COS-7 cells. The ZAP-70 associated with tubulin was preferentially tyrosine-phosphorylated after T cell antigen receptor stimulation of Jurkat T cells, suggesting that this interaction was functionally significant. Vav was also found to co-immunoprecipitate with ZAP-70 from cell extracts depleted of tubulin. This raised the possibility that Vav might be a substrate for ZAP-70 protein-tyrosine kinase activity. However, tyrosine phosphorylation of Vav preceded that of ZAP-70, indicating that Vav was unlikely to be a downstream target of ZAP-70. The association of ZAP-70 and Vav with tubulin implies that the microtubules may be involved in the signaling function of these two molecules, perhaps by targeting them to their appropriate intracellular location.
Canonical and Non-Canonical Barriers Facing AntimiR Cancer Therapeutics (2013)

Once considered genetic "oddities", microRNAs (miRNAs) are now recognized as key epigenetic regulators of numerous biological processes, including some with a causal link to the pathogenesis, maintenance, and treatment of cancer. The crux of small RNA-based therapeutics lies in the antagonism of potent cellular targets; the main shortcoming of the field in general, lies in ineffective delivery. Inhibition of oncogenic miRNAs is a relatively nascent therapeutic concept, but as with predecessor RNA-based therapies, success hinges on delivery efficacy. This review will describes the canonical (e.g. pharmacokinetics and clearance, cellular uptake, endosome escape, etc.) and non-canonical (e.g. spatial localization and accessibility of miRNA, technical limitations of miRNA inhibition, off-target impacts, etc.) challenges to the delivery of antisense-based anti-miRNA therapeutics (i.e. antimiRs) for the treatment of cancer. Emphasis will be placed on how the current leading antimiR platforms-ranging from naked chemically modified oligonucleotides to nanoscale delivery vehicles-are affected by and overcome these barriers. The perplexity of antimiR delivery presents both engineering and biological hurdles that must be overcome in order to capitalize on the extensive pharmacological benefits of antagonizing tumor-associated miRNAs.
Outage evaluation for slow frequency-hopping mobile radio systems (1999)

In a shadowing-free environment, the improvement introduced by slow frequency-hopping (SFH) on a time-division multiple-access based mobile radio system can be taken into account by redefining the minimum carrier-to-interference ratio. This protection ratio, with SFH, is dependent on the transmission system, channel model, traffic, and frequency reuse parameters. In this paper, the above-mentioned analysis is used in order to investigate the capacity of a SFH mobile radio system, with reference to both the uplink and downlink, by taking into account a complete scenario, i.e., shadowing, fast fading, power control, antenna diversity, discontinuous transmission, and forward error correction with nonideal interleaving and sectorization. Outage probability is evaluated by a completely analytical methodology for the uplink, whereas the downlink requires a semianalytical approach to take users' positions into account. Comparison with a pure simulative approach is used to validate the results.
EFFECT OF INTRAVITREAL METHOTREXATE AND AQUEOUS HUMOR CYTOKINE LEVELS IN REFRACTORY RETINAL VASCULITIS IN BEHCET DISEASE (2011)

Increased intraocular levels of IL-6, IL-8, vascular endothelial growth factor, and monocyte chemotactic protein 1 may be responsible for refractory retinal vasculitis in Behcet disease. Intravitreal MTX was associated with a significant reduction of IL-6 and IL-8 levels and was effective and well tolerated even in steroid responders with refractory retinal vasculitis due to Behcet disease.
Application of Full-Order and Simplified EKFs to Sensorless PM Brushless AC Machines (2005)

This paper employs an extended Kalman filter (EKF) to estimate the rotor position and speed of a vector controlled surface-mounted permanent magnet (PM) brushless AC (BLAC) motor from measured terminal voltages and currents only. Both full-order and simplified EKFs are employed and their simulated performance capabilities are compared. Excellent agreement is achieved between estimated and commanded results. The EKF is also employed to identify the stator flux-linkage due to the PMs, which is influenced by temperature variation and magnetic saturation.
Bordetella adenylate cyclase: a genus specific protective antigen and virulence factor. (1985)

Most of the adenylate cyclase (AC) present in Bordetella species is localized in the outer membrane, partly exposed to the cell surface. An isolation procedure to obtain the cell-bound enzyme was applied to Bordetella bronchiseptica, Bordetella pertussis and Bordetella parapertussis. Passive transfer of B. bronchiseptica anti-AC antibody, either in the form of monoclonal antibody or antibody transferred to offspring from female mice previously immunized with immunopurified B. bronchiseptica AC, prevented both death and the development of "atrophic rhinitis" in mice infected by an aerosol of virulent B. bronchiseptica. Immunopurified AC from both B. bronchiseptica and B. pertussis protected mice against intracerebral challenge with strain 18323, although five to six times more protein of B. bronchiseptica was necessary to produce the same level of protection as with B. pertussis-derived protein. The AC of Bordetella species differ in molecular weight and, despite sharing at least two common non-overlapping epitopes (BB05, BB07), antigenic differences are likely: sera from piglets artificially infected with virulent B. bronchiseptica developed high ELISA titers against AC from B. bronchiseptica but low titers against B. pertussis-derived antigen. Strains of B. bronchiseptica which did not induce "atrophic rhinitis" in pigs were found to be AC-less variants. When tested in our laboratory model, such a strain was also unable to induce "atrophic rhinitis" in mice. We conclude that AC is a mandatory component of any future subcellular vaccine against Bordetella species.
Essential role of Gas6 for glomerular injury in nephrotoxic nephritis (2002)

Growth-arrest specific gene 6 (Gas6) is a vitamin K–dependent growth factor for mesangial and epithelial cells. To investigate whether Gas6 is essential for progressive glomerular injury, we constructed Gas6–/– mice and examined the role of Gas6 in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis. We found less mortality and proteinuria in Gas6–/– mice than in wild-type mice following injection of nephrotoxic serum. Glomerular cell proliferation, glomerular sclerosis, crescent formation, and deposition of fibrin/fibrinogen in glomeruli were also reduced in Gas6–/– mice. Furthermore, administering Gas6–/– mice recombinant wild-type Gas6, but not Gas6 lacking a previously characterized N-terminal γ-carboxyl group, induced massive proteinuria, glomerular cell proliferation, and glomerulosclerosis, comparable to responses seen in wild-type mice. These data indicate that Gas6 induces glomerular cell proliferation in NTN and suggest that this factor contributes to glomerular injury and the progression of chronic nephritis.
Immunochemical characterization of and isolation of the gene for a Borrelia burgdorferi immunodominant 60-kilodalton antigen common to a wide range of bacteria (1988)

By crossed immunoelectrophoresis and Western blotting (immunoblotting), it was shown that Borrelia burgdorferi expresses the 60-kilodalton Common Antigen (CA) that is cross-reactive with an equivalent antigen in a wide range of remotely related bacteria. B. burgdorferi CA is strongly immunogenic. A B. burgdorferi genomic library was constructed by using a plasmid cloning system. Escherichia coli recombinants were screened for expression of immunodominant B. burgdorferi antigens. One of the recombinant clones expressed the 60-kilodalton CA of B. burgdorferi. The DNA region encoding B. burgdorferi CA was localized on a 2.3-kilobase fragment of the plasmid pKH1. CA may have pathogenetic implications in Lyme borreliosis, since the CA of mycobacteria recently has been shown to play a role in the etiology of experimental autoimmune arthritis. The extensive cross-reactivity of this antigen may account for the low diagnostic specificity of the currently used serological tests in Lyme borreliosis.
Isotope Dilution Gas Chromatographic-Mass Spectrometric Measurement of Tricyclic Antidepressant Drugs. Utility of the 4-Carbethoxyhexafluorobutyryl Derivatives of Secondary Amines (1998)

Stable isotope dilution gas chromatographic-mass spectrometric (GC-MS) measurement of tricyclic antidepressants (TCA) is a useful alternative to high-performance liquid chromatography (HPLC) methods when interfering substances prevent accurate quantitation by HPLC. For satisfactory GC-MS analysis, secondary amine TCA must be derivatized. Commonly employed trifluoroacetyl and heptafluorobutyryl derivatives are relatively unstable and cause rapid deterioration of capillary GC columns. Therefore we examined 4-carbethoxyhexafluorobutyryl chloride (CHFB-CI) as an alternative derivatizing agent and developed a stable isotope dilution GC-MS method employing ring-labeled [2H4]-desipramine and [2H4]-imipramine internal standards, which permits measurement of desipramine, nortriptyline, imipramine, and amitriptyline in plasma samples containing one or all of these analytes. The GC-MS assay is linear for each analyte from the lower limit of quantitation (25 ng/mL) up to 1500 ng/mL and correlates well with HPLC measurements. The GC-MS analytic coefficient of variation was 9.7 +/- 1.3% for all analytes considered together. Although interferences are observed in the HPLC assay, thioridazine, perphenazine, cyclobenzaprine, and norcyclobenzaprine do not interfere with GC-MS measurements of the TCA examined here. The stability of the CHFB derivative of secondary amine TCA was found to be superior to that of the trifluoroacetyl derivatives of these compounds.
Characterization of the Pf3 single-stranded DNA binding protein by circular dichroism spectroscopy (1993)

We have used circular dichroism (CD) spectroscopy and gel electrophoresis to characterize the single-strand DNA binding protein (ssDBP) of the bacteriophage Pf3 and its complexes with Pf3 DNA and various DNA and RNA homopolymers. The secondary structure of Pf3 ssDBP had < 1% alpha-helix and therefore was probably a beta-sheet structure like the fd gene 5 protein (g5p). From CD titrations, the binding stoichiometry of Pf3 ssDBP was two nucleotides per protein monomer (n = 2) for complexes formed with all of the nucleic acids except poly[r(U)], for which n = 3 (in a buffer of 10 mM Tris-HCl and 70 mM NaCl, pH 8.2). Evidence of an additional binding mode of n = 4 for complexes formed with Pf3 DNA was found by gel electrophoresis experiments. Pf3 ssDBP showed a marked sequence dependence in binding affinities similar to that known for the fd g5p.
Dynamics of internalization and sequestration of guanylyl cyclase/atrial natriuretic peptide receptor-A (2001)

The guanylyl cyclase/natriuretic peptide receptor-A (NPRA), also referred to as GC-A, is a single polypeptide molecule. In its mature form, NPRA resides in the plasma membrane and consists of an extracellular ligand-binding domain, a single transmembrane-spanning region, and intracellular cytoplasmic domain that contains a protein kinase-like homology domain (KHD) and a guanylyl cyclase (GC) catalytic active site. The binding of atrial natriuretic peptide (ANP) to NPRA occurs at the plasma membrane; the receptor is synthesized on the polyribosomes of the endoplasmic reticulum, and is presumably degraded within the lysosomes. It is apparent that NPRA is a dynamic cellular macromolecule that traverses through different compartments of the cell through its lifetime. This review describes the experiments addressing the interaction of ANP with the NPRA, the receptor-mediated internalization and stoichiometric distribution of ANP-NPRA complexes from cell surface to cell interior, and its release into culture media. It is hypothesized that after internalization, the ligand-receptor complexes dissociate inside the cell and a population of NPRA recycles back to plasma membrane. Subsequently, some of the dissociated ligand molecules escape the lysosomal degradative pathway and are released intact into culture media, which reenter the cell by retroendocytotic mechanisms. By utilizing the pharmacologic and physiologic perturbants, the emphasis has been placed on the cellular regulation and processing of ligand-receptor complexes in intact cells. I conclude the discussion by examining the data available on the utilization of deletion mutations of NPRA cDNA, which has afforded experimental insights into the mechanisms the cell utilizes in modulating the expression and functioning of NPRA.
Unique glycoprotein-proteoglycan complex defined by monoclonal antibody on human melanoma cells. (1982)

A monoclonal antibody, 9.2.27, with a high specificity for human melanoma cell surfaces has been utilized for biosynthetic studies in M21 human melanoma cells to define a unique antigenic complex consisting of a 250-kilodalton N-linked glycoprotein and a high molecular weight proteoglycan component larger than 400 kilodaltons. The 250-kilodalton glycoprotein has endoglycosidase H-sensitive precursors and shows a lower apparent molecular weight after treatment with neuraminidase. The biosynthesis of the proteoglycan component is inhibited by exposure of M21 cells to the monovalent ionophore monensin, this component can be labeled biosynthetically with 35SO4, is sensitive to beta-elimination in dilute base, and is degraded by both chondroitinase AC and ABC lyases, suggesting that it is a chondroitin sulfate proteoglycan. These data demonstrate that the antigenic determinant recognized by monoclonal antibody 9.2.27 is located on a glycoprotein-proteoglycan complex which may have unique implications for the interaction of glycoconjugates at the human melanoma tumor cell surface.
146. The constitutions of eremophilone, hydroxyeremophilone, and hydroxydihydroeremophilone. Part II (1938)

A. E. Bradfield, N. Hellström, A. R. Penfold and J. L. Simonsen, J. Chem. Soc., 1938, 767 DOI: 10.1039/JR9380000767
Hearing preservation in cochlear implantation for electric acoustic stimulation (2004)

Preservation of low-frequency hearing in cochlear implantation is possible in patients implanted because of profound high-frequency deafness. With the development of new, more atraumatic electrode designs, preservation of residual hearing should be further improved.
Interactions among the subunits of the G protein involved in Saccharomyces cerevisiae mating. (1993)

The SCG1 (GPA1), STE4, and STE18 genes of Saccharomyces cerevisiae encode mating-pathway components whose amino acid sequences are similar to those of the alpha, beta, and gamma subunits, respectively, of mammalian G proteins. Genetic evidence suggests that the STE4 and STE18 gene products interact. The mating defects of a set of ste4 mutants were partially suppressed by the overexpression of STE18, and, moreover, a combination of partially defective ste4 and ste18 alleles created a totally sterile phenotype, whereas such synthetic sterility was not observed when the ste18 allele was combined with a weakly sterile ste11 allele. Others have provided genetic evidence consistent with an interaction between the SCG1 (GPA1) and STE4 gene products. We have examined the physical interactions of these subunits by using an in vivo protein association assay. The STE4 and STE18 gene products associated with each other, and this association was disrupted by a mutation in the STE4 gene product whose phenotype was partially suppressed by overexpression of STE18. The STE4 and SCG1 (GPA1) gene products also interacted in the assay, whereas we detected no association of the SCG1 (GPA1) and STE18 gene products.