gebhart/patrepeval huggingface dataset:
The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and –independent mechanisms (2017)

Elotuzumab is a humanized therapeutic monoclonal antibody directed to the surface glycoprotein SLAMF7 (CS1, CRACC, CD319), which is highly expressed on multiple myeloma (MM) tumor cells. Improved clinical outcomes have been observed following treatment of MM patients with elotuzumab in combination with lenalidomide or bortezomib. Previous work showed that elotuzumab stimulates NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), via Fc-domain engagement with FcγRIIIa (CD16). SLAMF7 is also expressed on NK cells, where it can transmit stimulatory signals. We tested whether elotuzumab can directly activate NK cells via ligation with SLAMF7 on NK cells in addition to targeting ADCC through CD16. We show that elotuzumab strongly promoted degranulation and activation of NK cells in a CD16-dependent manner, and a non-fucosylated form of elotuzumab with higher affinity to CD16 exhibited enhanced potency. Using F(ab')<sub>2</sub> or Fc-mutant forms of the antibody, the direct binding of elotuzumab to SLAMF7 alone could not stimulate measurable CD69 expression or degranulation of NK cells. However, the addition of soluble elotuzumab could costimulate calcium signaling responses triggered by multimeric engagement of NKp46 and NKG2D in a CD16-independent manner. Thus, while elotuzumab primarily stimulates NK cells through CD16, it can also transduce effective "trans"-costimulatory signals upon direct engagement with SLAMF7, since these responses did not require direct co-engagement with the activating receptors. Trans-costimulation by elotuzumab has potential to reduce activation thresholds of other NK cell receptors engaging with their ligands on myeloma target cell surfaces, thereby potentially further increasing NK cell responsiveness in patients.
Aromatic alpha-glycosides of mannose are powerful inhibitors of the adherence of type 1 fimbriated Escherichia coli to yeast and intestinal epithelial cells (1987)

Adherence of bacteria via their surface lectins to host epithelial cells is considered an important initial event in bacterial pathogenesis. Mannose-specific (type 1) fimbriae are among the most commonly found lectins in enterobacteria. We studied the effect of aromatic alpha-glycosides of mannose on the agglutination of mannan-containing yeasts by different strains of Escherichia coli and on the adherence of the bacteria to guinea pig ileal epithelial cells. In both systems these compounds were considerably more effective inhibitors than methyl alpha-mannoside, with 4-methylumbelliferyl alpha-mannoside and p-nitro-o-chlorophenyl alpha-mannoside being the strongest inhibitors. Both compounds were approximately 400-times stronger inhibitors of yeast agglutination by E. coli O128 than was methyl alpha-mannoside and 1,000- and 470-fold stronger, respectively, than was methyl alpha-mannoside in inhibiting the adherence of the bacteria to ileal epithelial cells. 4-Methylumbelliferyl alpha-mannoside was 540 to 1,000 times more effective in inhibiting yeast agglutination by four additional strains of mannose-specific E. coli. It was also more efficient than methyl alpha-mannoside in removing adherent E. coli O128 from ileal epithelial cells. Our results provide further evidence that type 1 fimbriae of E. coli possess a hydrophobic region next to the mannose-binding site. The results suggest that 4-methylumbelliferyl alpha-mannoside and p-nitro-o-chlorophenyl alpha-mannoside are good candidates for the design of therapeutic agents that may prevent adherence in vivo and infection by E. coli strains that express type 1 fimbriae.
Yellow Fever Virus Encephalitis: Properties of the Brain-Associated T-Cell Response during Virus Clearance in Normal and Gamma Interferon-Deficient Mice and Requirement for CD4+Lymphocytes (2001)

Viral encephalitis caused by neuroadapted yellow fever 17D virus (PYF) was studied in parental and gamma interferon (IFN-gamma)-deficient (IFN-gamma knockout [GKO]) C57BL/6 mice. The T-cell responses which enter the brain during acute fatal encephalitis of nonimmunized mice, as well as nonfatal encephalitis of immunized mice, were characterized for relative proportions of CD4+ and CD8+ cells, their proliferative responses, and antigen-specific expression of cytokines during stimulation in vitro. Unimmunized mice accumulated only low levels of T cells within the brain during fatal disease, whereas the brains of immunized mice contained higher levels of both T-cell subsets in response to challenge, with CD8+ cells increased relative to the CD4+ subset. The presence of T cells correlated with the time at which virus was cleared from the central nervous system in both parental and GKO mice. Lymphocytes isolated from the brains of challenged immunized mice failed to proliferate in vitro in response to T-cell mitogens or viral antigens; however, IFN-gamma, interleukin 4 (IL-4), and, to a lesser extent, IL-2 were detectable after stimulation. The levels of IFN-gamma, but not IL-2 or IL-4, were augmented in response to viral antigen, and this specificity was detectable in the CD4+ compartment. When tested for the ability to survive both immunization and challenge with PYF virus, GKO and CD8 knockout mice did not differ from parental mice (80 to 85% survival), although GKO mice exhibited a defect in virus clearance. In contrast, CD4 knockout and Igh-6 mice were unable to resist challenge. The data implicate antibody in conjunction with CD4+ lymphocytes bearing a Th1 phenotype as the critical factors involved in virus clearance in this model.
Rituximab-Mediated ADCC Is Augmented by Concomitant Interference with Inhibitory Self-Recognition by Human NK Cells. (2005)

Abstract The anti-CD20 monoclonal antibody, rituximab is widely used in the treatment of non-Hodgkin lymphomas. However, clinical responses to rituximab are variable. It has been demonstrated that rituximab can lead to tumor cell death by engaging the cellular immune system through antibody dependent cellular cytotoxicity (ADCC). NK cells have been shown to play a critical rule in eliminating rituximab coated B-cells, and the efficiency of killing depends on the interaction between the Fc portion of rituximab and the FcγRIII (CD16) activating receptor on NK cells. NK cell function is regulated by a complex balance of inhibitory and activating signals that enable the cells to survey their surrounding and selectively target and kill targets that do not display a “self” ligand (the “missing self hypothesis”). We hypothesized that interference with inhibitory self-recognition would augment rituximab-induced NK cell-mediated ADCC. Initial studies with the 721.221 B51 (HLA Bw4+) CD20+ cell line and NK92.26.5 cells transduced with human CD16 suggested that interference with KIR3DL1 recognition of Bw4 augmented tumor lysis in the presence of rituximab. To further test this hypothesis we employed human NK cells and autologous EBV transformed B cells from normal volunteers, and blocked the KIR3DL1 inhibitory receptor on NK cells using (Fab′)2 fragments of the DX9 antibody, in conjunction with rituximab exposure. Inhibitory blockade promoted rituximab-mediated cytotoxicity by peripheral blood mononuclear cells in three separate HLABw4+, KIR3DL1+ volunteers. These results suggest that manipulating the balance between inhibitory and activating receptors on NK cells might be applied to improve ADCC and ultimately lead to an improvement in response rates to rituximab and related lymphoma-directed antibodies that mediate ADCC. Supported by R01CA50633.
Optimal defocus estimation in individual natural images (2011)

Defocus blur is nearly always present in natural images: Objects at only one distance can be perfectly focused. Images of objects at other distances are blurred by an amount depending on pupil diameter and lens properties. Despite the fact that defocus is of great behavioral, perceptual, and biological importance, it is unknown how biological systems estimate defocus. Given a set of natural scenes and the properties of the vision system, we show from first principles how to optimally estimate defocus at each location in any individual image. We show for the human visual system that high-precision, unbiased estimates are obtainable under natural viewing conditions for patches with detectable contrast. The high quality of the estimates is surprising given the heterogeneity of natural images. Additionally, we quantify the degree to which the sign ambiguity often attributed to defocus is resolved by monochromatic aberrations (other than defocus) and chromatic aberrations; chromatic aberrations fully resolve the sign ambiguity. Finally, we show that simple spatial and spatio-chromatic receptive fields extract the information optimally. The approach can be tailored to any environment-vision system pairing: natural or man-made, animal or machine. Thus, it provides a principled general framework for analyzing the psychophysics and neurophysiology of defocus estimation in species across the animal kingdom and for developing optimal image-based defocus and depth estimation algorithms for computational vision systems.
Sodium bicarbonate ingestion and its effects on anaerobic exercise of various durations (1992)

Four groups of male subjects participated in anaerobic testing on a Repco EX10 cycle ergometer to determine the effectiveness of sodium bicarbonate (0.3 g kg-1 body mass) as an ergogenic aid during exercise of 10, 30, 120 and 240 s duration. Blood was collected 90 min prior to ingestion of sodium bicarbonate (NaHCO3), after ingestion of NaHCO3 and immediately post-exercise from a heated (43-46 degrees C) fingertip and analysed immediately post-collection for pH, base excess, bicarbonate and lactate. The total work undertaken (kJ) and peak power achieved during the tests were also obtained via a Repco Work Monitor Unit. Blood bicarbonate levels were again increased above the control and placebo conditions (P < 0.001) and blood lactate levels were also increased following the bicarbonate trials. The pH levels fell significantly (P < 0.05) below the control and placebo conditions in all trials. The results indicate that NaHCO3 at this dosage has no ergogenic benefit for work of either 10 or 30 s duration, even though blood bicarbonate levels were significantly increased (P < 0.05) following ingestion of NaHCO3. For work periods of 120 and 240 s, performance was significantly increased (P < 0.05) above the control and placebo conditions following NaHCO3 ingestion.
Tissue Engineered Nucleus Pulposus Tissue Formed on a Porous Calcium Polyphosphate Substrate (2004)

Nucleus pulposus-like tissue formed in vitro on the surface of a calcium polyphosphate substrate resembles the native tissue in terms of proteoglycan content and compressive mechanical properties. These studies are the first step toward developing a functional spinal unit in vitro.
Lipid biochemistry: functions of glycerolipids and sphingolipids in cellular signaling (1997)

Products of glycerolipid and sphingolipid metabolism are now known to fulfill second messenger functions in a variety of cellular signaling pathways. Evidence for glycerolipid-derived second messengers was first obtained from the "phosphatidylinositol cycle," which involves a signal-dependent hydrolysis of phosphatidylinositol bisphosphate yielding diacylglycerol and inositol trisphosphate. The role of diacylglycerol in the regulation of protein kinase C activity and its site of interaction with PKC are now well known. Recently, another glycerolipid second messenger, phosphatidic acid, was found to interact with the protooncogenic Raf-1 kinase. In cultured cells, a signal-induced generation of phosphatidic acid was critical for Raf-1 translocation to the cell membrane. Thus, different glycerolipid second messengers appear to regulate distinct targets with exquisite specificity. Analogous to the PI cycle, a "sphingomyelin cycle" was also found to exist, generating sphingolipid second messengers. Ceramide, derived from the agonist-induced hydrolysis of sphingomyelin, is a potent biomolecule with effects in multiple cell signaling pathways. The steroid hormone progesterone stimulated sphingomyelin hydrolysis in Xenopus oocytes. Ceramide, derived from the "sphingomyelin cycle," was sufficient for meiotic cell cycle progression in the oocytes. These results demonstrate the various effects of lipid-derived second messengers and promise exciting discoveries into the roles of lipids in cell signaling.
UV-Absorbing Compounds in the Aqueous Humor from Aquatic Mammals and Various Non-Mammalian Vertebrates (2003)

The UV absorbance of aqueous humor varies considerably from one species to the next, and independent of class. It is noteworthy that the species being at highest risk for high-dose UV exposure, the migrating goose, showed the most red-shifted spectrum.
Rat brain expresses a heterogeneous family of calcium channels. (1990)

We describe the isolation and characterization of several rat brain cDNAs that are homologous to the alpha 1 subunit of heart and skeletal muscle dihydropyridine-sensitive Ca channels. Northern blot analysis of 32 cDNAs shows that they can be grouped into four distinct classes (A, B, C, and D), each corresponding to a distinct hybridization pattern of brain mRNAs. Southern blot and DNA sequencing suggest that each class of cDNA represents a distinct gene or gene family. In the regions sequenced, the rat brain class C and D gene products share approximately 75% amino acid identity with the rabbit skeletal muscle Ca channel. In addition, the class C polypeptide is almost identical to the rabbit cardiac Ca channel (97% identity). In contrast, the rat brain class A and B cDNAs are more distantly related to dihydropyridine-sensitive Ca channels (47-64% amino acid identity) and to the brain class C and D genes (51-55% amino acid identity). To examine the functional significance of the isolated brain cDNAs, hybrid depletion experiments were performed in Xenopus oocytes. Antisense oligonucleotides against class A and B cDNAs each partially inhibited, and a class C oligonucleotide almost fully inhibited, the expression of Ba current in rat brain mRNA injected oocytes; but none of the oligonucleotides affected the expression of voltage-gated Na or K conductances. The clone characterization and sequencing results demonstrate that a number of distinct, yet related, voltage-gated Ca-channel genes are expressed in the brain. The antisense oligonucleotide experiments specifically show that one or several of the Ca-channel classes are related to the Ca channels observed in rat brain mRNA injected oocytes.
Characterization of an interleukin 4 (IL-4) responsive region in the immunoglobulin heavy chain germline epsilon promoter: regulation by NF-IL-4, a C/EBP family member and NF-kappa B/p50. (1995)

A large body of data indicate that antibody class switching is directed by cytokines by inducing or repressing transcription from unrearranged, or germline, CH genes. Interleukin 4 (IL-4) induces transcription of the germline C epsilon genes in activated B cells and subsequently, cells in this population will undergo switch recombination to immunoglobulin E. Furthermore, the data suggest that transcription of germline C epsilon genes is required for class switching. In this paper we define DNA elements required for induction of transcription of the germline C epsilon genes by IL-4. To do this, segments of DNA from the 5' flank of the initiation sites for germline epsilon RNA were ligated to a luciferase reporter gene and transfected into two mouse B cell lines, one of which can be induced to switch to IgE. By analysis of a series of 5' deletion constructs and linker-scanning mutations, we demonstrate that a 46-bp segment (residing at -126/-79 relative to the first RNA initiation site) contains an IL-4 responsive region. By electrophoretic mobility shift assays, we find that this segment binds three transcription factors: the recently described NF-IL4, one or more members of the C/EBP family of transcription factors, and NF-kappa B/p50. Mutation of any of the binding sites for these three factors abolishes or reduces IL-4 inducibility of the epsilon promoter. A 27-bp segment within this IL-4 response region containing binding sites for NF-IL4 and a C/EBP factor is sufficient to transfer IL-4 inducibility to a minimal c-fos promoter.
Statistical Quality Control (1990)

This title is a substantial revision of one of the leading textbooks designed for the statistical quality control course taught in departments of industrial engineering, operations research and statistics . While maintaining its already successful writing style and pedagogy, this title has also incorporated key organizational changes in order to reflect recent trends in the field. The text features large quantity of examples and student problems and a strong introduction to the proper use and misuse of control charts. In this edition several chapters were streamlined, and consolidations and profitability were brought forward in the text. There is new material on experimental design, a reduced emphasis on acceptance sampling, and enhanced attention to the managerial and organizational aspects of quality control. Free SPC expert software is packaged with the text for use as a statistical and graphical tool. Text plus 3.5 diskette.
Placenta Growth Factor and Vascular Endothelial Growth Factor B and C Expression in Microvascular Endothelial Cells and Pericytes (1999)

We have shown previously that vascular endothelial growth factor (VEGF) synthesized by the cellular constituents of small vessels per se, viz. endothelial cells and pericytes, participates in the hypoxia-driven proliferation of both cell types (Nomura, M., Yamagishi, S., Harada, S., Hayashi, Y., Yamashima, T., Yamashita, J., Yamamoto, H. (1995) J. Biol. Chem. 270, 28316-28324; Yamagishi, S., Yonekura, H., Yamamoto, Y., Fujimori, H., Sakurai, S., Tanaka, N., and Yamamoto, H. (1999) Lab. Invest. 79, 501-509). In this study, we examined the expression of the recently isolated VEGF gene family members (placenta growth factor (PlGF), VEGF-B, and VEGF-C) in human dermal microvascular endothelial cells and bovine retinal pericytes cultured under various oxygen tensions. Quantitative reverse transcription-polymerase chain reaction analyses demonstrated that the two cell types possess not only VEGF (VEGF-A) mRNA, but also VEGF-B, VEGF-C, and PlGF mRNAs. Among them, only VEGF-A mRNA was induced under hypoxia. Competitive reverse transcription-polymerase chain reaction showed that, under normoxic conditions, the rank order of mRNA content in endothelial cells was PlGF > VEGF-B > VEGF-C > VEGF-A and that mRNA coding for PlGF was expressed at >100-fold higher levels than VEGF-A mRNA. In pericytes, the rank order was VEGF-C > VEGF-A > VEGF-B > PlGF, and approximately 7-fold higher levels of VEGF-C mRNA compared with VEGF-A mRNA were noted in this cell type. Furthermore, antisense inhibition of PlGF protein production lowered the endothelial cell synthesis of DNA under hypoxic conditions. The results suggest that these VEGF family members may also take active parts in angiogenesis.
‘On-the-fly’ optical encoding of combinatorial peptide libraries for profiling of protease specificity (2009)

Large solid-phase combinatorial libraries currently play an important role in areas such as infectious disease biomarker discovery, profiling of protease specificity and anticancer drug discovery. Because compounds on solid support beads are not positionally-encoded as they are in microarrays, innovative methods of encoding are required. There are many advantages associated with optical encoding and several strategies have been described in the literature to combine fluorescence encoding methods with solid-phase library synthesis. We have previously introduced an alternative fluorescence-based encoding method ("colloidal barcoding"), which involves encoding 10-20 mum support beads during a split-and-mix synthesis with smaller 0.6-0.8 mum silica colloids that contain specific and identifiable combinations of fluorescent dye. The power of this 'on-the-fly' encoding approach lies in the efficient use of a small number of fluorescent dyes to encode millions of compounds. Described herein, for the first time, is the use of a colloid-barcoded library in a biological assay (i.e., protease profiling) combined with the use of confocal microscopy to decode the colloidal barcode. In this proof-of-concept demonstration, a small focussed peptide library was optically-encoded during a combinatorial synthesis, incubated with a protease (trypsin), analysed by flow cytometry and decoded via confocal microscopy. During assay development, a range of parameters were investigated and optimised, including substrate (or probe) loading, barcode stability, characteristics of the peptide-tagging fluorophore, and spacer group configuration. Through successful decoding of the colloidal barcodes, it was confirmed that specific peptide sequences presenting one or two cleavage sites were recognised by trypsin while peptide sequences not cleavable by trypsin remained intact.
Implantable parylene-based wireless intraocular pressure sensor (2008)

This paper presents a novel implantable, wireless, passive pressure sensor for ophthalmic applications. Two sensor designs incorporating surface-micromachined variable capacitor and variable capacitor/inductor are implemented to realize the pressure sensitive components. The sensor is monolithically microfabricated using parylene as a biocompatible structural material in a suitable form factor for increased ease of intraocular implantation. Pressure responses of the microsensor are characterized on-chip to demonstrate its high pressure sensitivity (≫ 7000 ppm/mmHg) with mmHg level resolution. An in vivo animal study verifies the biostability of the sensor implant in the intraocular environment after more than 150 days. This sensor will ultimately be implanted at the pars plana or iris of the eye to fulfill continuous intraocular pressure (IOP) monitoring in glaucoma patients.
Does Trypsin Cut Before Proline? (2007)

Trypsin is the most commonly used enzyme in mass spectrometry for protein digestion with high substrate specificity. Many peptide identification algorithms incorporate these specificity rules as filtering criteria. A generally accepted "Keil rule" is that trypsin cleaves next to arginine or lysine, but not before proline. Since this rule was derived two decades ago based on a small number of experimentally confirmed cleavages, we decided to re-examine it using 14.5 million tandem spectra (2 orders of magnitude increase in the number of observed tryptic cleavages). Our analysis revealed a surprisingly large number of cleavages before proline. We examine several hypotheses to explain these cleavages and argue that trypsin specificity rules used in peptide identification algorithms should be modified to "legitimatize" cleavages before proline. Our approach can be applied to analyze any protease, and we further argue that specificity rules for other enzymes should also be re-evaluated based on statistical evidence derived from large MS/MS data sets.