gebhart/patrepeval huggingface dataset:
Exploiting Chemical Diversity for Drug Discovery (2006)

Conceptual and technological advances in chemistry and biology have transformed the drug discovery process. Evolutionary pressure among the diverse scientific and engineering disciplines that contribute to the identification of biologically active compounds has resulted in synergistic improvements at every step in the process. Exploiting Chemical Diversity for Drug Discovery encompasses the many components of this transformation and presents the current state-of-the-art of this critical endeavour. From the theoretical and operational considerations in generating a collection of compounds to screen, to the design and implementation of high-capacity and high-quality assays that provide the most useful biological information, this book provides a comprehensive overview of modern approaches to lead identification. Beginning with an introductory overview, subsequent chapters address topics that include the design of chemical libraries and methods for optimizing their diversity; automated and accelerated chemistry; high throughput assay design and detection techniques; and strategies for data analysis and property optimization. Written by experts in the field, both academic and industrial, and illustrated in full colour, this book provides an excellent overview for current practitioners and will also serve as a stimulating resource for future generations. Researchers in organic and medicinal chemistry, the biological and pharmacological sciences, as well as those interested in allied computational and engineering disciplines will value the comprehensive and up-to-date coverage.
Galacto-oligosaccharides and long-chain fructo-oligosaccharides as prebiotics in infant formulas: A review (2005)

Experimental evidence demonstrates that the prebiotic mixture employed in these studies modulates the intestinal flora and modulates the immune system as human milk does. There are sufficient experimental data to put forward the hypothesis that substances like the prebiotic mixture under study will substantially contribute to the improvement of the protective properties of infant formulas.
Nature of the active site of a subunit of the first component of human complement (1969)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNature of the active site of a subunit of the first component of human complementDavid H. BingCite this: Biochemistry 1969, 8, 11, 4503–4510Publication Date (Print):November 1, 1969Publication History Published online1 May 2002Published inissue 1 November 1969https://doi.org/10.1021/bi00839a042RIGHTS & PERMISSIONSArticle Views28Altmetric-Citations45LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (761 KB) Get e-Alerts Get e-Alerts
Bit-interleaved coded modulation (1998)

It has been recognized by Zehavi (1992) that the performance of coded modulation over a Rayleigh fading channel can be improved by bit-wise interleaving at the encoder output, and by using an appropriate soft-decision metric as an input to a Viterbi (1990) decoder. The paper presents in a comprehensive fashion the theory underlying bit-interleaved coded modulation, provides tools for evaluating its performance, and gives guidelines for its design.
Direct measurements improve estimates of dairy greenhouse-gas emissions (2008)

California is the leading dairy state in the United States, producing 21% of the nation's milk supply. The state's highest concentration of dairies is in the San Joaquin Valley, a region that violates federal limits for ozone and particulate matter in the air. Volatile organic compounds and greenhouse-gas emissions from dairies contribute to regional air-quality challenges and also play a role in climate change. We used an environmentally controlled chamber to monitor greenhouse-gas emissions from dairy cattle over a 24-hour period, and we measured the emissions from waste slurry using a simulated dairy waste lagoon. This research helps to quantify emissions from dairies in California and suggests possible approaches for their mitigation.
Immunotoxins: a clinical review of their use in the treatment of malignancies. (1989)

Immunotoxins are a new class of antitumor agents consisting of tumor-selective ligands (generally monoclonal antibodies [MoAbs]) linked to highly toxic protein molecules that have been modified to remove their normal tissue-binding domains. These immuno-conjugates combine the potency of the parent toxin with the specificity of the attached ligand. Toxins used in the construction of immunotoxins belong to a group of peptides that catalytically inhibit the elongation step of protein synthesis, and include ricin, abrin, pokeweed antiviral protein, gelonin, Pseudomonas exotoxin A, diptheria toxin, and alpha-sarcin. To synthesize immunotoxins, the normal cell-binding function must be removed by chemical cleavage or modification, or in the case of toxins that have been cloned, genetic engineering used to delete amino acids critical to cell binding. Covalent linkage of toxin to ligand generally involves a disulfide or thioether bond, though recently, recombinant toxin molecules with ligands that are genetically engineered into the protein have been made. The most successful clinical application of immunotoxins has been in the depletion of T cells from allogeneic bone marrow grafts to prevent graft-versus-host disease (GVHD). Clinical trials have been conducted using immunotoxins for the systemic treatment of chronic lymphocytic leukemia (CLL), GVHD, and selected solid tumors. With the possible exception of GVHD, responses have been limited. Obstacles have included rapid systemic clearance, poor delivery to extravascular tumor deposits, and humoral immune responses to the immunotoxin. Research to overcome these problems is in progress and should lead to a better definition of the role of immunotoxins in the therapy of malignancies.
Neuropeptide Y, Tyrosine Hydroxylase and Vasoactive Intestinal Polypeptide-Immunoreactive Nerve Fibers in the Vertebral Bodies, Discs, Dura Mater, and Spinal Ligaments of the Rat Lumbar Spine (1993)

The occurrence of autonomic nerves in the lumbar spine of rats was investigated by immunohistochemical technique. Both peptidergic nerves, represented by immunoreactivity to neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), and noradrenergic nerves as reflected by tyrosine hydroxylase (TH) immunoreactivity, were identified. NPY- and TH-positive nerves were predominantly found in the blood vessels walls. They occurred in the bone and periosteum of the vertebral body, disc, dura mater, and in the spinal ligaments. They were particularly numerous along the growth plate and in the outer layers of the intervertebral discs. VIP-positive fibers were predominantly nonvascular. They occurred in all tissues analyzed, but were most abundant in the vertebral bone marrow and periosteum. The VIP-immunoreactive fibers in the outer fibrous layers of the disc and the spinal ligaments were occasionally observed in blood vessel walls. No immunoreactivity could be detected in the nucleus pulposus. In the dura mater, NPY-, TH- and VIP-positive fibers were found both in the ventral and dorsal portion. In view of the vasoconstrictive properties of both NPY and noradrenaline, it may be assumed that the abundance of NPY- and TH-immunoreactive nerves fibers in blood vessel walls reflects a vasoregulatory activity. The predominance of nonvascular VIP-positive fibers in the vertebral bone marrow and periosteum may represent an involvement in local bone physiology.
Invariant Feature Extraction and Classification in Kernel Spaces (1999)

We incorporate prior knowledge to construct nonlinear algorithms for invariant feature extraction and discrimination. Employing a unified framework in terms of a nonlinear variant of the Rayleigh coefficient, we propose non-linear generalizations of Fisher&amp;apos;s discriminant and oriented PCA using Support Vector kernel functions. Extensive simulations show the utility of our approach.
Oligonucleotide micro-arrays for identification of unknown mutations: how far from reality? (1997)

The present review examines critically what has been published on oligonucleotide micro-arrays, from the point of view of detection of unknown mutations. We will first demonstrate the theoretical power of this new technique, and then argue that it is experimentally realistic. However, technical difficulties remain, and the proposed solutions for controlling the hybridisation specificity and for manufacturing the micro-arrays will be reviewed. Some are promising, but a complete integration of several of these solutions must be achieved before oligonucleotide micro-arrays become a universal tool for routine detection of unknown mutations. Nevertheless, sequence specific arrays should be available in the short term for the most frequently studied genes.
Palladium-Catalyzed Fluorination of Carbon−Hydrogen Bonds (2006)

This communication describes the development of a new Pd-catalyzed method for the fluorination of carbon-hydrogen bonds. A key step of these transformations involves palladium-mediated carbon-fluorine coupling-a much sought after, but previously unprecedented, transformation. These reactions were successfully achieved under oxidative conditions using electrophilic N-fluoropyridinium reagents. Microwave irradiation in the presence of catalytic palladium acetate served as optimal conditions for the fluorination of C-H bonds in a variety of substituted 2-arylpyridine and 8-methylquinoline derivatives.
Cloning and characterization of DST2, the gene for DNA strand transfer protein beta from Saccharomyces cerevisiae. (1991)

The gene encoding the 180-kDa DNA strand transfer protein beta from the yeast Saccharomyces cerevisiae was identified and sequenced. This gene, DST2 (DNA strand transferase 2), was located on chromosome VII. dst2 gene disruption mutants exhibited temperature-sensitive sporulation and a 50% longer generation time during vegetative growth than did the wild type. Spontaneous mitotic recombination in the mutants was reduced severalfold for both intrachromosomal recombination and intragenic gene conversion. The mutants also had reduced levels of the intragenic recombination that is induced during meiosis. Meiotic recombinants were, however, somewhat unstable in the mutants, with a decrease in recombinants and survival upon prolonged incubation in sporulation media. spo13 or spo13 rad50 mutations did not relieve the sporulation defect of dst2 mutations. A dst1 dst2 double mutant has the same phenotype as a dst2 single mutant. All phenotypes associated with the dst2 mutations could be complemented by a plasmid containing DST2.
Identification, expression, and characterization of the highly conserved d-xylose isomerase in animals (2009)

D-xylose is a necessary sugar for animals. The xylanase from a mollusk, Ampullaria crossean, was previously reported by our laboratory. This xylanase can degrade the xylan into D-xylose. But there is still a gap in our knowledge on its metabolic pathway. The question is how does the xylose enter the pentose pathway? With the help of genomic databases and bioinformatic tools, we found that some animals, such as bacteria, have a highly conserved D-xylose isomerase (EC 5.3.1.5). The xylose isomerase from a sea squirt, Ciona intestinali, was heterogeneously expressed in Escherichia coli and purified to confirm its function. The recombinant enzyme had good thermal stability in the presence of Mg(2+). At the optimum temperature and optimum pH environment, its specific activity on D-xylose was 0.331 micromol/mg/min. This enzyme exists broadly in many animals, but it disappeared in the genome of Amphibia-like Xenopus laevis. Its sequence was highly conserved. The xylose isomerases from animals are very interesting proteins for the study of evolution.
Requirement for the von Hippel-Lindau tumor suppressor gene for functional epidermal growth factor receptor blockade by monoclonal antibody C225 in renal cell carcinoma. (2000)

Renal cell carcinoma (RCC) is a cytologically and histologically diverse disease in which a spectrum of distinct molecular alterations occurs, including the inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which is specific for the clear cell variant of RCC. The prognosis for RCC is poor, and, to date, no effective systemic treatment is available for this cancer. In the present study, we assessed the extent to which the transforming growth factor alpha-epidermal growth factor receptor (EGFR) autocrine loop could be used as a potential therapeutic target for RCC. Northern blot analysis of transforming growth factor alpha and EGFR revealed variable but consistent expression of these transcripts in cell lines derived from both clear cell and non-clear cell RCC variants, indicating the potential for this autocrine loop in both tumor types. The therapeutic utility of interruption of this feedback loop was determined by examining growth inhibition after the exposure of these cell lines to a humanized anti-EGFR monoclonal antibody, C225. In vitro treatment of clear cell RCC-derived cell lines lacking VHL resulted in only a modest decrease in growth rate. In contrast, non-clear cell RCC-derived cell lines that retained VHL responded significantly to C225 treatment. Transfection of VHL into VHL-negative RCC cell lines restored responsiveness to C225, indicating that this tumor suppressor gene is required for effective EGFR blockade. Growth inhibition by C225 in VHL-positive cells was linked to a requirement for VHL to up-regulate p27 in response to C225. These data provide compelling evidence that treatment modalities for RCC are likely to be strongly influenced by the molecular etiology of this phenotypically diverse cancer.
Structural requirements for thymosin β4 in its contact with actin (2000)

We examined the conformational preferences of mutants of thymosin beta4, an actin monomer sequestering protein by NMR spectroscopy in 60% (v/v) trifluoroethanol. Under these conditions, the wild-type thymosin beta4 conformation consists of an alpha-helix (helix I) extending from residues 5-16 with a more stable fragment from lysine 11 to lysine 16 and a second alpha-helix (helix II) encompassing residues 31-39. The point mutations studied here are located in helix I or in the LKKTET segment (residues 17-22) that form the two main entities of interaction with the actin molecule. The alpha-1H conformational shifts allow us to investigate the helicity of the polypeptides at the residue level and to correlate these structures with their biological activity. We determine that an extension of helix I at its C-terminal end over the LKK-segment results in loss of activity. The correct termination of this helix is connected to a specific orientation of the polypeptide essential for a cooperative action of the thymosin beta4 binding entities required for full activity.
Applying a Compensated Pulsed Alternator to a flashlamp load for NOVA (1979)

The Compensated Pulsed Alternator (CPA) is a large rotating machine that will convert mechanical, rotationally stored energy into a single electrical impulse of very high power. It is being optimized for driving flashlamps in the very large NOVA Nd:glass laser system. The machine is a rotary flux compression device, and for maximum performance, it requires start-up current. We report upon a circuit that will provide this current and that will also assist in triggering the flashlamps. This circuit has been tested with a 200 kilojoule capacitor bank and it is now being tested with a small 200 kilojoule CPA. Large Nove-size machines will require output energies in excess of 5 megajoules. We also present empirically tested formulae that will assist in matching the Nova flashlamp load to any given size CPA machine.
A method for reproducing apparent continuous depth in a stereoscopic display using “Depth‐Fused 3D” technology (2006)

Abstract— A new method that can present fine depth increments in a stereoscopic display is proposed. In typical stereoscopic displays, depth can be presented by binocular disparity, but binocular disparity of less than one pixel cannot be displayed because, in general, electronic displays have discrete pixels. We combined binocular disparity and modulation of the edge luminance in DFD (depth‐fused 3D) displays. In an experiment, the perceived depth could be continuously changed by modulating the edge luminance only. Therefore, continuous depth can be produced by combining binocular disparity and modulation of edge luminance distribution.
Long-term repopulation of irradiated mice with limiting numbers of purified hematopoietic stem cells: in vivo expansion of stem cell phenotype but not function (1995)

Hematopoietic stem cells were isolated from normal adult mouse bone marrow based on surface antigen expression (Thy-1.1(low)Lin(neg)Ly-6A/E+) and further selected for low retention of rhodamine 123. This population of cells (Rh-123low) could mediate radioprotection and long-term (greater than 12 months) repopulation after transplantation of as few as 25 cells. Transfer of five genetically marked Rh-123low cells in the presence of 10(5) normal bone marrow cells resulted in reconstitution of peripheral blood by greater than 10% donor cells in 64% (30 of 47) of recipient mice. Of 46 animals surviving after 24 weeks, 10 had over 50% donor-derived cells in peripheral blood. Two general patterns of long-term reconstitution were observed: one in which many donor-derived cells were observed 5 to 6 weeks after reconstitution and another in which donor-derived cells were rare initially but expanded with time. This result suggests that two classes of long-term repopulating hematopoietic stem cells exist, differing in their ability to function early in the course of transplantation. Alternatively, distinct anatomic sites of engraftment may dictate these two outcomes from a single type of cell. As an approach to measure the extent of self-renewal by the injected cells, recipients of five or 200 stem cells were killed 8 to 13 months after the transplants, and Thy-1.1(low)Lin(neg)Ly-6A/E+ progeny of the original injected cells were isolated for a second transplant. While a numerical expansion of cells expressing the cell surface phenotype of stem cells was observed, along with activity in the colony-forming unit-spleen assay, the expanded cells were vastly inferior in radioprotection and long-term reconstitution assays when compared with cells freshly isolated from normal animals. This result demonstrates that in stem cell expansion experiments, cell surface antigen expression is not an appropriate indicator of stem cell function.
Electron Cryo‐Crystallography of a Recombinant Cardiac Gap Junction Channel (2007)

Gap junctions in the heart play an important functional role by electrically coupling cells, thereby organizing the pattern of current flow to allow co-ordinated muscle contraction. Cardiac gap junctions are therefore intimately involved in normal conduction as well as the genesis of potentially lethal arrhythmias. We recently utilized electron cryo-microscopy and image analysis to examine frozen-hydrated 2D crystals of a recombinant, C-terminal truncated form of connexin 43 (Cx43; alpha 1), the principal cardiac gap junction protein. The projection map at 7 A resolution revealed that each 30 kDa connexin subunit has a transmembrane alpha-helix that lines the aqueous pore and a second alpha-helix in close contact with the membrane lipids. The distribution of densities allowed us to propose a model in which the two apposing connexons that form the channel are staggered by approximately 30 degrees. We are now recording images of tilted, frozen-hydrated 2D crystals, and a preliminary 3D map has been computed at an in-plane resolution of approximately 7.5 A and a vertical resolution of approximately 25 A. As predicted by our model, the two apposing connexons that form the channel are staggered with respect to each other for certain connexin molecular boundaries within the hexamer. Within the membrane interior each connexin subunit displays four rods of density, which are consistent with an alpha-helical conformation for the four transmembrane domains. Preliminary studies of BHK hamster cells that express the truncated Cx43 designated alpha 1 Cx263T demonstrate that oleamide, a sleep inducing lipid, blocks in vivo dye transfer, suggesting that oleamide causes closure of alpha 1 Cx263T channels. The comparison of the 3D structures in the presence and absence of oleamide may provide an opportunity to explore the conformational changes that are associated with oleamide-induced blockage of dye transfer. The structural details revealed by our analysis will be essential for delineating the molecular basis for intercellular current flow in the heart, as well as the general molecular design and functional properties of this important class of channel proteins.
Prostate cancer detection by laser induced autofluorescence and multicomponent spectroscopy (2007)

Laser-Induced-Autofluorescence (LIAF), White-Light-Remission (WLR) and Electrical-Impedance-Measurement (EIM) in combination with principal component analysis were used at first time for differentiation benign from malignant prostatic tissue in vitro. The used complex statistical processing of the data has shown a differentiation of benign and malignant prostatic tissue with a sensitivity of 93.8% and a specificity of 92.4%.
Demonstration of the Iron-regulated Surface Determinant (Isd) Heme Transfer Pathway in Staphylococcus aureus (2008)

In this study, we report experimental results that provide the first complete challenge of a proposed model for heme acquisition by Staphylococcus aureus via the Isd pathway first put forth by Mazmanian, S. K., Skaar, E. P., Gaspar, A. H., Humayun, M., Gornicki, P., Jelenska, J., Joachmiak, A., Missiakas, D. M., and Schneewind, O. (2003) Science 299, 906-909. The heme-binding NEAT domains of Isd proteins IsdA, IsdB (domain 2), IsdC, and HarA/IsdH (domain 3), and the heme-binding IsdE protein, were overexpressed and purified in apo (heme-free) form. Absorption and magnetic circular dichroism spectral data, together with electrospray ionization mass spectrometry were used to unambiguously identify that heme transfers from NEAT-A through NEAT-C to IsdE. Heme transfer was demonstrated to occur in a unidirectional fashion in the sequence NEAT-B2 --> NEAT-A --> NEAT-C --> IsdE or, alternatively, initiating from NEAT-H3 instead of NEAT-B2: NEAT-H3 --> NEAT-A --> NEAT-C --> IsdE. Under the conditions of our experiments, only NEAT-H3 and NEAT-B2 could transfer bidirectionally, which is in the reverse direction as well, and only with each other. Whereas apo-IsdE readily accepted heme from holo-NEAT-C, it would not accept heme from holo-NEAT-A. Heme transfer to IsdE requires the presence of holo-NEAT-C, in agreement with the proposal that IsdC serves as the central conduit of the heme transfer pathway. These experimental findings corroborate the heme transfer model first proposed by the Schneewind group. Our data show that heme transport from the wall-anchored IsdH/IsdB proteins proceeds directly to IsdE at the membrane and, for this to occur, we propose that specific protein-protein interactions must take place.