gebhart/patrepeval huggingface dataset:
Engineered riboswitches: Overview, problems and trends (2008)

The first conditional gene expression system which employed a small molecule binding aptamer was developed several years before the discovery of natural riboswitches. With the discovery of riboswitches it became obvious that nature uses exactly the same principal of direct RNA-ligand interaction to regulate gene expression in a highly efficient, precise and fast way. In the last decade, further engineered riboswitches have been developed to control gene expression in different organisms. The successful development of new engineered riboswitches, however, is not only dependent on an innovative design but also necessitates a two step process: first, an in vitro selection which results in aptamers with high affinity binding to a desired ligand and second, a subsequent screen to identify RNAs with a desired functionality within cells. This review will give an overview of recent reports of engineered riboswitches, highlight recent developments and point out trends and problems in the field.
Spinal Cord Stimulation versus Repeated Lumbosacral Spine Surgery for Chronic Pain: A Randomized, Controlled Trial (2005)

SCS is more effective than reoperation as a treatment for persistent radicular pain after lumbosacral spine surgery, and in the great majority of patients, it obviates the need for reoperation.
Structural basis of the abscess-modulating polysaccharide A2 fromBacteroides fragilis (2000)

Zwitterionic capsular polysaccharides from pathogenic bacteria have peculiar immunological properties. They are capable of eliciting T-cell proliferation and modulating the course of abscess formation. To understand the molecular basis of this characteristic immune response, we are conducting detailed structure-function studies on these polysaccharides. We have identified, purified, and characterized an abscess-modulating polysaccharide, PS A2, from the clinical strain Bacteroides fragilis 638R. Here, we report the elucidation of both the chemical and three-dimensional structures of PS A2 by NMR spectroscopy, chemical methods, gas chromatography-mass spectrometry, and restrained molecular dynamics calculations. PS A2 consists of a pentasaccharide repeating unit containing mannoheptose, N-acetylmannosamine, 3-acetamido-3,6-dideoxyglucose, 2-amino-4-acetamido-2,4,6-trideoxygalactose, fucose, and 3-hydroxybutanoic acid. PS A2 is zwitterionic and carries one cationic free amine and one anionic carboxylate in each repeating unit. It forms an extended right-handed helix with two repeating units per turn and a pitch of 20 A. Positive and negative charges are exposed on the outer surface of the polymer in a regularly spaced pattern, which renders them easily accessible to other molecules. The helix is characterized by repeated large grooves whose lateral boundaries are occupied by the charges. The three-dimensional structure of PS A2 explicitly suggests mechanisms of interaction between zwitterionic polysaccharides and proteins.
Role of κ→λ light-chain constant-domain switch in the structure and functionality of A17 reactibody (2014)

The engineering of catalytic function in antibodies requires precise information on their structure. Here, results are presented that show how the antibody domain structure affects its functionality. The previously designed organophosphate-metabolizing reactibody A17 has been re-engineered by replacing its constant κ light chain by the λ chain (A17λ), and the X-ray structure of A17λ has been determined at 1.95 Å resolution. It was found that compared with A17κ the active centre of A17λ is displaced, stabilized and made more rigid owing to interdomain interactions involving the CDR loops from the VL and VH domains. These VL/VH domains also have lower mobility, as deduced from the atomic displacement parameters of the crystal structure. The antibody elbow angle is decreased to 126° compared with 138° in A17κ. These structural differences account for the subtle changes in catalytic efficiency and thermodynamic parameters determined with two organophosphate ligands, as well as in the affinity for peptide substrates selected from a combinatorial cyclic peptide library, between the A17κ and A17λ variants. The data presented will be of interest and relevance to researchers dealing with the design of antibodies with tailor-made functions.
Isothermal Amplification of Nucleic Acids (2015)

Isothermal amplification of nucleic acids is a simple process that rapidly and efficiently accumulates nucleic acid sequences at constant temperature. Since the early 1990s, various isothermal amplification techniques have been developed as alternatives to polymerase chain reaction (PCR). These isothermal amplification methods have been used for biosensing targets such as DNA, RNA, cells, proteins, small molecules, and ions. The applications of these techniques for in situ or intracellular bioimaging and sequencing have been amply demonstrated. Amplicons produced by isothermal amplification methods have also been utilized to construct versatile nucleic acid nanomaterials for promising applications in biomedicine, bioimaging, and biosensing. The integration of isothermal amplification into microsystems or portable devices improves nucleic acid-based on-site assays and confers high sensitivity. Single-cell and single-molecule analyses have also been implemented based on integrated microfluidic systems. In this review, we provide a comprehensive overview of the isothermal amplification of nucleic acids encompassing work published in the past two decades. First, different isothermal amplification techniques are classified into three types based on reaction kinetics. Then, we summarize the applications of isothermal amplification in bioanalysis, diagnostics, nanotechnology, materials science, and device integration. Finally, several challenges and perspectives in the field are discussed.
Paradoxical toxic and trophic osseous actions of aluminum: potential explanations. (1991)

The osseous effects of aluminum are paradoxical. Aluminum displays toxic effects on bone metabolism in humans but in animal and cell culture models aluminum can exert both toxic and trophic effects. Clinical toxicity to aluminum is typically expressed as vitamin D-resistant osteomalacia and diminished bone remodeling activity. Animal models that mimic these toxic actions of aluminum, however, are difficult to establish. In this regard, aluminum deposition in bone of animals does not necessarily impair mineralization. When aluminum administration to animals results in defective mineralization, cure of osteomalacia can often be achieved by administration of vitamin D. Moreover, aluminum administration has been shown to stimulate de novo bone formation in dogs. Similar disparate actions of aluminum have also been observed in osteoblast culture systems. Aluminum is mitogenic in some and antiproliferative in other osteoblast cell lines. The mechanism(s) underlying these disparate effects of aluminum are unknown. The complexity of the aluminum osseous actions may result from differential responses of preosteoblasts and mature osteoblasts to aluminum and/or modulation of these direct cellular effects by interactions with systemic and/or local factors such as parathyroid hormone, vitamin D and/or other bone growth factors. In addition, differences in speciation of aluminum could contribute to its differential actions on bone. Regardless, understanding the basis for these differential osseous manifestations to aluminum may lead to a better knowledge of aluminum actions which could result in the development of pharmacologic agents to induce neoosteogenesis without adverse consequences as well as development of strategies to limit aluminum toxicity.
Expression of complement alternative pathway proteins by endothelial cells. Differential regulation by interleukin 1 and glucocorticoids (1990)

We have studied the secretion of proteins of the alternative pathway of complement C3, factor B and factor H by human umbilical vein endothelial cells (HUVEC). Results showed that factor H and factor B are quantitatively secreted in abundance whereas C3 could only be detected when the cells are maintained in culture during long periods of time. Interferon-gamma stimulated factor H, factor B and, to a lesser extent, C3 secretions. Interleukin (IL) 1 had a differential effect on spontaneous C3, factor B and factor H secretions. In the presence of IL 1, there was a significant secretion of C3 occurring within a short period of culture. IL 1 also stimulated factor B secretion. There was a synergistic stimulating effect between IL 1 and interferon-gamma to bring C3 and factor B productions by HUVEC to very high levels. In contrast, factor H secretion was consistently inhibited by IL 1. Local increase in C3 and factor B secretions by endothelial cells in the presence of IL 1 may have important implications in the inflammatory reaction. In striking contrast, the glucocorticoid dexamethasone (DXM) had modulatory effects which are consistent with its anti-inflammatory properties. DXM, at therapeutic concentrations, decreased C3 and factor B secretions and increased factor H secretion. Local modulation of complement protein secretion by DXM appears to be a new mechanism by which this glucocorticoid may control inflammation.
Mutational Analysis of the Major Loop of Bacillus1,3-1,4-β-d-Glucan 4-Glucanohydrolases (1997)

The carbohydrate-binding cleft of Bacillus licheniformis 1,3-1, 4-beta-D-glucan 4-glucanohydrolase is partially covered by the surface loop between residues 51 and 67, which is linked to beta-strand-(87-95) of the minor beta-sheet III of the protein core by a single disulfide bond at Cys61-Cys90. An alanine scanning mutagenesis approach has been applied to analyze the role of loop residues from Asp51 to Arg64 in substrate binding and stability by means of equilibrium urea denaturation, enzyme thermotolerance, and kinetics. The DeltaDeltaGU between oxidized and reduced forms is approximately constant for all mutants, with a contribution of 5.3 +/- 0.2 kcal.mol-1 for the disulfide bridge to protein stability. A good correlation is observed between DeltaGU values by reversible unfolding and enzyme thermotolerance. The N57A mutant, however, is more thermotolerant than the wild-type enzyme, whereas it is slightly less stable to reversible urea denaturation. Mutants with a <2-fold increase in Km correspond to mutations at residues not involved in substrate binding, for which the reduction in catalytic efficiency (kcat/Km) is proportional to the loss of stability relative to the wild-type enzyme. Y53A, N55A, F59A, and W63A, on the other hand, show a pronounced effect on catalytic efficiency, with Km > 2-fold and kcat < 5% of the wild-type values. These mutated residues are directly involved in substrate binding or in hydrophobic packing of the loop. Interestingly, the mutation M58A yields an enzyme that is more active than the wild-type enzyme (7-fold increase in kcat), but it is slightly less stable.
Mutagen-directed Attenuation of Rift Valley Fever Virus as a Method for Vaccine Development (1985)

Serial mutagenesis with 5-fluorouracil has been employed to derive an attenuated strain of Rift Valley fever virus for use as a live virus vaccine.
Metabolism of Immunoglobulins (2015)

Publisher Summary Techniques for the study of immunoglobulin metabolism using purified radioiodinated serum proteins helps define the factors controlling the rates of immunoglobulin synthesis, catabolism, and transport. These techniques are important in studying the pathogenesis of the abnormalities of immunoglobulin levels seen in various immunodeficiency diseases. These techniques are of value in the differential diagnosis of immunodeficiency states and in addition provide the information necessary for the rational use of γ-globulin or its subunits as therapeutic tools. The disorders of immunoglobulin pool size and concentration occur secondary to a variety of pathophysiological mechanisms that are associated with a variety of different patterns of immunoglobulin metabolism. At one end of the metabolic processes are the disorders characterized by decreased immunoglobulin synthesis, while on the other end of the metabolic process are disorders characterized by a short survival of immunoglobulin. This short immunoglobulin survival may be caused by excessive loss of immunoglobulins into the urinary or gastrointestinal tracts. Hypogammaglobulinemia may be caused by a disorder of endogenous catabolic pathways that affect a single immunoglobulin class or all immunoglobulin classes.
Isolation and Characterization of cDNAs Corresponding to an Additional Member of the Human Histone Deacetylase Gene Family (1997)

Several human cDNAs encoding a histone deacetylase protein, HDAC3, have been isolated. Analysis of the predicted amino acid sequence of HDAC3 revealed an open reading frame of 428 amino acids with a predicted molecular mass of 49 kDa. The HDAC3 protein is 50% identical in DNA sequence and 53% identical in protein sequence compared with the previously cloned human HDAC1. Comparison of the HDAC3 sequence with human HDAC2 also yielded similar results, with 51% identity in DNA sequence and 52% identity in protein sequence. The expressed HDAC3 protein is functionally active because it possesses histone deacetylase activity, represses transcription when tethered to a promoter, and binds transcription factor YY1. Similar to HDAC1 and HDAC2, HDAC3 is ubiquitously expressed in many different cell types.
Sequence specificity for removal of uracil from U·A pairs and U·G mismatches by uracil‐DNA glycosylase from Escherichia coli, and correlation with mutational hotspots (1995)

The rate of removal of uracil from different positions in double-stranded DNA by uracil-DNA glycosylase from Escherichia coli varied more than 15-fold. Consensus sequences for good and poor removal were 5'-(A/T)UA(A/T)-3' and 5'-(G/C)U(T/G/C)-3', respectively. In general, the sequence context surrounding U was more important for the rate of removal than whether U was present in U.A pairs or U.G mispairs. Rates of removal of U from sites of amber mutations in the lacI gene, where mutation frequencies and deamination rates were known, indicated that the observed variation in removal is biologically significant.
Selective networks capable of representative transformations, limited generalizations, and associative memory. (1982)

Two parallel sets of selective networks composed of intercommunicating neuron-like elements have been connected to produce a new kind of automaton capable of limited recognition of two-dimensional patterns. Salient features of this automaton are (i) preestablished unchanging connectivity, (ii) preassigned connection strengths that are selectively altered according to experience, (iii) local feature detection in one network with simultaneous global feature correlation in the other, and (iv) reentrant interactions between the two networks to generate a new function, associative memory. No forced learning, explicit semantic rules, or a priori instructions are used.
Nucleic acid related compounds. 41. Restricted furanose conformations of 3′,5′-O-(1,1,3,3-tetraisopropyldisilox-1,3-diyl)nucleosides provide a convenient evaluation of anomeric configuration (1983)

Treatment of ribonucleosides (and related furanosyl compounds) with 1.3-dichloro-I , I ,3,3-tetraisopropyldisiloxanc in pyridine gave high yields of 3',5'-0-( 1,1,3,3-tetraisopropyldisilox-I ,3-diyl)nucleosides (3',5'-0-TPDS-nucleosides). The 'H nmr coupling parameters of the sugar backbone of the 6-D-ribofuranosyl anomers of these rrcfrl.,(l .')-fused 8 to 5 membered ring TPDS compounds indicated a remarkably consistent range of furanosc conformations. The data arc compatible with a predominant population of conformers in the general 9 (C3'-endo) range found for a large series of rigidly trarls-fused 6 to 5 membered ring nucleoside cyclic 3',5'-monophosphates. X-ray crystallographic analysis of 3'3'-0-TPDS-cytidinc revealed an almost perfect 'E sugar envelope conformation ( P = 19.7", T,,, = 41.9") in agreement with the 'H nmr solution data. Attachment of two bulky isopropyl groups to each silicon atom and expansion of the Si-0-Si bond angle to 155" gives an essentially planar six atom segment of the 8-membered rlng. Apparently thls demands a distinctly preferred conformation for the fused rlng system. The readily prepared 3',5'-0-TPDS-6-D-r~bofuranosyl derivatives have J I . -? 5 1.5 HZ in most cases. This provides a rapid and convenient evaluation of the HIr-H2' trarl~ configuration in these structures.
Factors affecting the nutritional value of canola meal: A review (1993)

In this review canola meal (CM), its nutritionally significant components and the availability of its nutrients to poultry, pigs and cattle were discussed. Avenues for possible improvement in available energy, protein and lysine were identified. Recent findings on glucosinolates were also discussed with the conclusion that a further reduction of glucosinolates through plant breeding is both possible and desirable. The role of the anti-nutrients sinapine, tannins and phytic acid were also considered. The potential impact of improvements to CM on its economic value was examined using linear program least-cost ration formulations applied to typical market situations. Key words: Canola meal, energy, protein, carbohydrates, anti-nutritional factors, economics
Receptor-Mediated Abeta Amyloid Antibody Targeting to Alzheimer’s Disease Mouse Brain (2010)

The goal of this work is the reduction in the Abeta amyloid peptide burden in brain of Alzheimer's disease (AD) transgenic mice without the concomitant elevation in plasma Abeta amyloid peptide. An anti-Abeta amyloid antibody (AAA) was re-engineered as a fusion protein with a blood-brain barrier (BBB) molecular Trojan horse. The AAA was engineered as a single chain Fv (ScFv) antibody, and the ScFv was fused to the heavy chain of a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), and this fusion protein was designated cTfRMAb-ScFv. The cTfRMAb-ScFv protein penetrates mouse brain from blood via transport on the BBB TfR, and the brain uptake is 3.5% of injected dose/gram brain following an intravenous administration. Double transgenic APPswe,PSEN1dE9 mice were studied at 12 months of age. The mice were shown to have extensive Abeta amyloid plaques in cerebral cortex based on immunocytochemistry. The mice were treated every 3-4 days by intravenous injections of either saline or the cTfRMAb-ScFv fusion protein at an injection dose of 1 mg/kg for 12 consecutive weeks. The brain Aβ¹⁻⁴² concentration was reduced 40% in the fusion protein treated mice, without any elevation in plasma Aβ¹⁻⁴² concentration. No cerebral microhemorrhage was observed in the treated mice. These results show that brain-penetrating antibody pharmaceutics can be developed for brain disorders such as AD following the re-engineering of the antibody as a fusion protein that is transported across the BBB via receptor-mediated transport.
EASTERN SUBTERRANEAN TERMITE (ISOPTERA: RHINOTERMITIDAE) FORAGING TERRITORIES AND POPULATIONS IN TORONTO (1989)

Abstract A mark–release–recapture study was conducted with dye-marked eastern subterranean termites, Reticulitermes flavipes (Kollar), at two sites in metropolitan Toronto. Interconnected termite galleries were found to extend up to 79 m and to cover areas of 266 and 1091 m 2 . Colony foraging populations at the two sites were estimated at 2.1 and 3.2 million termites. These foraging distances and population estimates exceed those reported for R . flavipes in other regions.
Endogenous Anti-HER2 Antibodies Block HER2 Phosphorylation and Signaling through Extracellular Signal-Regulated Kinase (2005)

Immunologic targeting of the oncoprotein HER2/neu with monoclonal antibodies is an important component of current therapeutic strategies for patients with locally and systemically advanced breast cancer. Engineered antibodies targeting HER2 may have agonist or antagonist effects on HER2, but little is known about whether endogenous antibodies modulate HER2 activity. Vaccination of patients with HER2 peptides successfully induced antibodies in a minority of patients with HER2-expressing malignancy. A subset of antibodies specifically suppressed phosphorylation of HER2 on tyrosine Y1248, a residue critical for HER2 signaling through extracellular signal-regulated kinase. These antibodies also suppressed extracellular signal-regulated kinase phosphorylation and inhibited colony formation in soft agar. The majority of the antibodies that suppressed HER2 phosphorylation displayed specificity for amino acids 328 to 345 and 369 to 384. The isotype of anti-HER2 antibodies was predominantly IgG3 of low avidity, suggesting a Th1 response to peptide vaccine. Endogenous anti-HER2 antibodies can effectively suppress HER2 kinase activity and downstream signaling to inhibit the transformed phenotype of HER2-expressing tumor cells.
El trabajo forzado en infraestructuras ferroviarias bajo el franquismo (1938 - 1957): una estimación cuantitativa (2012)

espanolEn este articulo se aborda el trabajo de presos y prisioneros de guerra en la ampliacion y reconstruccion de vias ferreas durante la guerra civil espanola y la dictadura franquista. En una primera parte se presentan los problemas metodologicos que se deben sortear para avanzar en este tipo de investigacion, haciendo mencion especial a lo disperso e incompleto de la documentacion historica accesible a los investigadores. Posteriormente se presenta una estimacion del volumen global de presos y prisioneros en estas infraestructuras, avanzando en un analisis diferenciado por tipo de trabajo realizado: reparaciones de los danos de la guerra, trabajos en la doble via y apertura de nuevas lineas ferreas. En cada uno de estas modalidades se analiza la evolucion cronologica de la presencia de la mano de obra forzada, asi como las principales obras en las que esta participo. EnglishIn this paper we analyse the deployment of prisoners and prisoners of war (POW) repairing and improving railway infrastructures during Spanish Civil War and Franco´s dictatorship. In the first part we take account of methodological problems that this kind of research has to face, mainly due to the scattered and incomplete historical documentation available for historians. After that we present a quantitative estimate of the global volume of prisoners and POWs working in these infrastructures, according to the different kind of tasks carried out: repairing of war damages double way works, or the opening of new railway lines. For each on these modalities, we analyse the chronological evolution, as well as the main places were these captive men worked.
The future of microprocessors (2011)

Energy efficiency is the new fundamental limiter of processor performance, way beyond numbers of processors.
BACTERIOPHAGE DISPLAY AND DISCOVERY OF PEPTIDE LEADS FOR DRUG DEVELOPMENT (1997)

Phage display makes large-peptide diversity libraries readily attainable for identifying novel peptide ligands for receptors and other protein or non-protein targets. This technology kindles enthusiasm for the idea that large and protein-protein interaction surfaces (epitopes) can be distilled down to small pharmacophores. These may be accessible to organic scaffolding, yielding new orally active drugs that might otherwise have taken greater time and effort to be discovered through chemical-library screening. This review, though not comprehensive with respect to the explosive volume of phage display work over the last few years, focuses on recent developments in phage-displayed peptide technology.