gebhart/patrepeval huggingface dataset:
The Physicochemical Challenges of Designing Multiple Ligands (2006)

Compounds designed to bind more than one target can provide a therapeutic benefit relative to highly target-selective ligands. The physicochemical properties of designed multiple ligands were found to be less druglike than those for preclinical compounds in general. These properties are controlled by the superfamily to which the targets belong and the lead discovery strategy that was followed. The properties for peptide G-protein-coupled receptor (GPCR) ligands were the least favorable for oral delivery, whereas transporter, monoamine GPCR, and oxidase ligands were the most druglike. The lead discovery strategy, framework combination or screening, exerts a profound influence on the property values. Combining the frameworks from two selective ligands often results in large, complex dual ligands, but druglike ligands can be achieved if the degree of framework overlap is maximized and the size of the selective ligands minimized. For some target combinations, a screening approach may provide a route to smaller, less complex leads.
Differential expression and cell cycle regulation of the cyclin-dependent kinase 4 inhibitor p16Ink4. (1994)

p16Ink4 (inhibitor of cyclin-dependent kinase 4) is a cell cycle regulator that specifically binds to and inhibits Cdk4. Recently, the human mts1 (multiple tumor suppressor 1) gene, deleted or mutated in various primary tumors and in a large number of transformed cell lines, was found to be identical to ink4. In this study we have surveyed by immunoblotting the protein levels of p16Ink4 in normal and transformed human cells. We determined that p16Ink4 was differentially expressed in diploid cells derived from different tissues, in contrast to another cell cycle inhibitor, p21Waf1, which is ubiquitously expressed. In some tumor cell lines p16Ink4 protein was not detected, presumably because of a homozygous deletion of its gene. By contrast, it was found to be overexpressed in other cell lines when compared to levels in their normal counterparts. Interestingly, high levels of p16Ink4 protein correlated with functional inactivation of the retinoblastoma gene product. We also found that p16Ink4 protein expression varies during the cell cycle peaking during S phase. These results show a functional relationship between p16Ink4 and the retinoblastoma gene product and indicate that p16Ink4 is required for Cdk4 inhibition only at the G1-S transition at the time when Cdk4 kinase activity is no longer necessary.
Discussion of Keynote Address by I.W. Johnston (1986)

I wish to comment on one aspect of the Keynote Paper on Soft Rock. Since I do not have a copy of the written version of the Paper to refer to in preparing this discussion, I have to trust to my memory of what was stated in the oral presentation at the Symposium. I refer to a particular Figure which was presented which showed the effect of varying degrees of drainage on a pressuremeter test in soft rock. This Figure indicated that a completely undrained test produced a 'softer' pressure-expansion response than a drained test in the same material. Varying degrees of drainage were shown to produce ranges of responses varying gradually from the 'soft' undrained response to the 'stiff' drained response, depending on the degree of drainage permitted. These results were presented as having been generated from a finite element modelling of the pressuremeter test. Presumably (though I do not recall if this was explicitly stated) this same model was used to produce many of the rest of the numerical model results presented.
113 NITRIC OXIDE AND MULTIPLE ORGAN FAILURE (1995)

The William Harvey Research Institute, St. Bartholomew's Hospital Medical College, Charterhouse Square, London, ECIM 6BQ, U.K.
Genome-wide gene-expression profiles of breast-cancer cells purified with laser microbeam microdissection: identification of genes associated with progression and metastasis. (2004)

Breast carcinoma is a complex disease characterized by accumulation of multiple genetic alterations, and the understanding of the molecular basis of mammary tumorigenesis is still incomplete. In this study we analyzed gene-expression profiles of 81 surgical specimens of 12 ductal carcinoma in situ (DCIS) and 69 invasive ductal carcinoma (IDC). After applying laser-microbeam micro-dissection to all samples we achieved 98-99% pure populations of breast cancer cells, and of normal breast epithelial cells used as controls. A cDNA-microarray analysis of 23,040 genes in these samples and a subsequent unsupervised hierarchical clustering distinguished two tumor groups, mainly in terms of estrogen-receptor (ER) status. We then undertook a supervised analysis and identified 325 genes that were commonly either up- or down-regulated in both pathologically discrete stages (DCIS and IDC), indicating that these genes might play important roles in malignant transformation of breast ductal cells. In addition, we searched invasion-associated gene candidates whose expression was altered in IDC, but not in DCIS, and identified 24 up-regulated genes and 41 down-regulated genes. Furthermore, we identified 34 genes that were expressed differently in tumors from patients with lymph node metastasis as opposed to no metastasis. On that basis we developed a scoring system that correlated well with the metastatic status. Tumors from all of the 37 test patients with lymph-node metastasis yielded positive scores by our definition, whereas 38 of the 40 tumors (95%) without lymph node metastasis had negative scores. Our data should provide useful information for identifying predictive markers for invasion or metastasis, and suggest potential target molecules for treatment of breast cancers.
Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for theα5β1 integrin (2003)

Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor for several growth factors of the VEGF family. Endothelial cells express a membrane-spanning form of VEGFR-1 and secrete a soluble variant of the receptor comprising only the extracellular region. The role of this variant has not yet been completely defined. In this study, we report that the secreted VEGFR-1 is present within the extracellular matrix deposited by endothelial cells in culture, suggesting a possible involvement in endothelial cell adhesion and migration. In adhesion assays, VEGFR-1 extracellular region specifically promoted endothelial cell attachment. VEGFR-1-mediated cell adhesion was divalent cation-dependent, and inhibited by antibodies directed against the alpha 5 beta 1 integrin. Moreover, VEGFR-1 promoted endothelial cell migration, and this effect was inhibited by anti-alpha 5 beta 1 antibodies. Direct binding of VEGFR-1 to the alpha 5 beta 1 integrin was also detected. Finally, binding to VEGFR-1 initiated endothelial cell spreading. Altogether these results indicate that the soluble VEGFR-1 secreted by endothelial cells becomes a matrix-associated protein that is able to interact with the alpha 5 beta 1 integrin, suggesting a new role of VEGFR-1 in angiogenesis, in addition to growth factor binding.
Mechanical Properties of Reversibly Cross-Linked Ultrathin Polyelectrolyte Complexes (2006)

Tensile properties of microcoupons of polyelectrolyte complex, formed by the multilayering method, were determined using a micromechanical analysis system. The degree of internal ion-pair ("electrostatic") cross-linking was reversibly controlled by exposure to salt solution of varying concentration, which "doped" counterions into the films, breaking polymer/polymer ion pairs in the process. Linear stress-strain behavior was observed for a poly(styrene sulfonate)/poly(diallyldimethylammonium) multilayer up to 2% deformation. The dependence of modulus on cross-link density could be rationalized well by classical theories of rubber elasticity, including some insight on the topology of polyelectrolyte complexes.
Reversal of experimental neuropathic pain by T-type calcium channel blockers (2003)

Experimental nerve injury results in exaggerated responses to tactile and thermal stimuli that resemble some aspects of human neuropathic pain. Neuronal hyperexcitability and neurotransmitter release have been suggested to promote such increased responses to sensory stimuli. Enhanced activity of Ca(2+) current is associated with increased neuronal activity and blockade of N- and P-types, but not L-type, calcium channels have been found to block experimental neuropathic pain. While T-type currents are believed to promote neuronal excitability and transmitter release, it is unclear whether these channels may also contribute to the neuropathic state. Rats were prepared with L(5)/L(6) spinal nerve ligation, and tactile and thermal hypersensitivities were established. Mibefradil or ethosuximide was administered either intraperitoneally, intrathecally (i.th.), or locally into the plantar aspect of the injured hindpaw. Systemic mibefradil or ethosuximide produced a dose-dependent blockade of both tactile and thermal hypersensitivities in nerve-injured rats; responses of sham-operated rats were unchanged. Local injection of mibefradil also blocked both end points. Ethosuximide, however, was inactive after local administration, perhaps reflecting its low potency when compared with mibefradil. Neither mibefradil nor ethosuximide given i.th. produced any blockade of neuropathic behaviors. The results presented here suggest that T-type calcium channels may play a role in the expression of the neuropathic state. The data support the view that selective T-type calcium channel blockers may have significant potential in the treatment of neuropathic pain states.
Characteristic properties of cutting fluid additives derived from the reaction products of hydroxyl fatty acids with some acid anhydrides (1998)

Abstract Several adducts were prepared from the thermal reaction of hydroxyl fatty acids (ricinoleic acid oligomers, 12‐hydroxystearic acid oligomers, oleyl alcohol, dehydrated castor oil fatty acids, and dimer acid) with maleic anhydride and screened as water‐soluble cutting fluids. For example, aqueous solutions of triethanolamine salts with the products of ricinoleic acid oligomers, 12‐hydroxystearic acid dimer, and 12‐hydroxysteric acid hexamer showed good antirust properties for waterbased cutting fluids. Various half esters of hydroxyl fatty compounds with acid anhydrides were prepared. Aqueous solutions of triethanolamine salts of half esters of maleic anhydride and succinic anhydride and phthalic anhydride with hydroxyl fatty acids gave good antirust and antiwear properties for waterbased cutting fluids.
Are Escherichia coli dam- as compared to dam+ hypermutable by base analogs? (1987)

It was shown that some base analogs, like n2Pur and n2oh6Ade (but not n2om6Ade or oh4Cyd) which strongly inhibit growth of dam- cells, mutagenize and preselect dam- populations. As a result dam- mut(-)--devoid of mismatch repair, dam+ revertants, or dam(-)--insensitive to a base analog are exclusively obtained after mutagenesis. The composition of these mutants depends on the base analog applied. By using reconstruction experiments, the frequency of these mutations induced by n2Pur was calculated.
Effect of rapamycin on immunity induced by vector-mediated dystrophin expression in mdx skeletal muscle (2012)

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Therapeutic gene replacement of a dystrophin cDNA into dystrophic muscle can provide functional dystrophin protein to the tissue. However, vector-mediated gene transfer is limited by anti-vector and anti-transgene host immunity that causes rejection of the therapeutic protein. We hypothesized that rapamycin (RAPA) would diminish immunity due to vector-delivered recombinant dystrophin in the adult mdx mouse model for DMD. To test this hypothesis, we injected limb muscle of mdx mice with RAPA-containing, poly-lactic-co-glycolic acid (PLGA) microparticles prior to dystrophin gene transfer and analyzed treated tissue after 6 weeks. RAPA decreased host immunity against vector-mediated dystrophin protein, as demonstrated by decreased cellular infiltrates and decreased anti-dystrophin antibody production. The interpretation of the effect of RAPA on recombinant dystrophin expression was complex because of an effect of PLGA microparticles.
Low-power small-area ±7.28 ps jitter 1 GHz DLL-based clock generator (2003)

A 1 GHz DLL-based clock generator in 0.35 /spl mu/m CMOS occupies 0.08 mm/sup 2/. It has fast locking time and no jitter-accumulation problem. A phase detector with reset circuitry and a frequency multiplier overcome the limited locking range and frequency multiplication problem of conventional DLL-based systems. Measured peak-to-peak jitter is /spl plusmn/7.28 ps.
The role of seaweed extracts, Ascophyllum nodosum, in type reduction in fecundity of Meloidogyne javanica (1994)

Les effets d'extraits commerciaux de l'algue marine Ascophyllum nodosum sur la fecondite du nematode Meloidogyne javanica, eleve sur tomate (Lycopersicon esculentum cv. Ailsa Craig) sont evalues. Apres une generation, le nombre d'œufs du nematode recuperes sur les plantes traitees diminue considerablement en comparaison avec les plantes temoins, traitees avec de l'eau pure. Un plus faible nombre d'œufs sont recuperes sur les plantes infestees par des juveniles ayant incube dans des extraits d'algue en comparaison avec les plantes infestees par des juveniles ayant incube dans de l'eau pure
Production of calcium phosphate coatings on Ti6Al4V obtained by Nd : yttrium-aluminum-garnet laser cladding (2001)

Among the various techniques that have been investigated to produce Hydroxyapatite (HA) coatings in order to promote fixation and osteointegration of cementless prosthesis, the plasma spray (PS) technique is the most popular method commercially in use. PS presents some disadvantages such as the poor coating-to-substrate adhesion, low mechanical strength, and brittleness of the coating. In order to overcome the drawbacks of plasma spraying, an approach on how to bind HA to the Ti alloy will be introduced in this work, using a well-known technique in the metallurgical field: laser surface cladding. Different techniques were applied to characterize the coated samples, including x-ray diffraction, scanning electron microscopy, and energy dispersive x-ray analysis.
Predicting Protein Structures Accurately (2004)

In their Research Article “Design of a novel globular protein fold with atomic-level accuracy,” B. Kuhlman et al. describe an extremely successful attempt to design a new protein (Top7) that folds to a predefined structure (21 Nov, p. [1364][1]). This is the first time an artificial protein of
A Compressive Sensing Approach to NBI Cancellation in Mobile OFDM Systems (2010)

We propose a novel algorithm based on compressive sensing (CS) theory to estimate narrow band interference (NBI) signals experiencing time-varying frequency-selective fading channels in orthogonal frequency division multiplexing (OFDM) systems. In addition, we investigate the case of asynchronous jamming where there is a frequency offset between the NBI and desired signals. Furthermore, we propose a reduced-complexity implementation for our proposed algorithm with negligible performance loss. Finally, we show that our proposed approach can be applied to both cyclic-prefix and zero-padding OFDM systems. Simulation results show the effectiveness of our proposed algorithm in mitigating NBI.
Synthesis of human [9-leucine-B]insulin (1976)

The synthesis and isolation in purified form of [Leu9-B]insulin, a biologically active analogue of human insulin, is described. This analogue differs from the parent molecule in that the polar residue, serine, occupying position 9 in the B chain and located on the outside of the insulin molecule, has been replaced with the hydrophobic leucine residue. For the synthesis of this analogue the [Leu9]B chain of human insulin was chemically synthesized by the fragment condensation approach and isolated in the S-sulfonated form. Combination of this compound with the sulfhydryl form of human A chain afforded [Leu9-B]insulin. Separation of this analogue from the combination mixture and isolation as the hydrochloride in purified form were accomplished by chromatography on a carboxymethylcellulose column with an acetate buffer (pH 3.3) and an exponential sodium chloride gradient. [Leu9-B]Insulin possesses a potency of 13-14 IU/mg when assayed by the mouse convulsion method and 11-12 IU/mg by the radioimmunoassay method as compared to 23-25 IU/mg possessed by the natural hormone.
Successful islet transplantation in spontaneous diabetes. (1979)

Optimism for islet transplantation is based on reversal of diabetes artificially induced in animals by pancreatectomy or beta cell toxins. In naturally occurring diabetes, implanted islets might be destroyed by the etiologic agent of the original disease; e.g., virus infection, genetic factors, or autoimmunity. Genetically determined diabetes in obese mice, in fact, is resistant to islet transplantation. Since these mice are hyperinsulinemic and not similar to human juvenile onset diabetes (JOD), more appropriate models were sought, "BB" rats spontaneously develop a syndrome remarkably similar to human JOD. We have studied 279 BB rats. In 31 rats the sudden onset of severe hyperglycemia was observed. Sinc BB rats proved to be AgB2 on serological typing, WF (AgB2) donors were selected. Six hundred Wistar-Furth isolated islets were transplanted intraportally in 10 BB diabetic rats immunosuppressed with antilymphocyte serum. All 10 recipients became normoglycemic, remaining so for 1 to 6 monts. An additional animal model studied was virus-induced diabetes in mice, since viral etiology of human diabetes seems likely. DBA mice receiving encephalomyocarditis virus became severely and persistently diabetic. Eight received syngeneic fetal pancreas to the renal subcapsule and became normoglycemic. Removal of the graft 30 days later demonstrated viable islets histologically and resulted in recurrent diabetes. That virally induced murine diabetes and one spontaneous syndrome in rats which is similar to human JOD responded to beta cell implantation argues that this treatment will be effective in man.
Projective structure from uncalibrated images: structure from motion and recognition (1994)

Address the problem of reconstructing 3-D space in a projective framework from two or more views, and the problem of artificially generating novel views of the scene from two given views (reprojection). The author describes an invariance relation that provides a new description of structure, which the author calls projective depth, that is captured by a single equation relating image point correspondences across two or more views and the homographics of two arbitrary virtual planes. The framework is based on knowledge of correspondence of features across views, is linear and extremely simple, and the computations of structure readily extend to overdetermination using multiple views. Experimental results demonstrate a high degree of accuracy in both tasks: reconstruction and reprojection.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
An interactive web database of factor H-associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations (2005)

Factor H (FH) is a central complement regulator comprised of 20 short complement repeat (SCR) domains. Nucleotide changes within this gene (CFH) have been observed in patients with hemolytic uremic syndrome (HUS), and also membranoproliferative glomerulonephritis and age-related macular degeneration. All parts of FH are affected, but many mutations are clustered in the C-terminal part of FH. Up to now, structural analyses of HUS have been based on SCR-20, a domain that is involved in FH interactions with C3b, heparin, and endothelial cells. In order to identify the structural and functional consequence of HUS mutations, further disease-associated mutations were analyzed in terms of homology and nuclear magnetic resonance (NMR) models for factor H SCR domains. An interactive web database of 54 human HUS-associated mutations and others was created from the literature (www.FH-HUS.org). This has comprehensive search and analysis tools, integrating phenotypic and genetic data with structural analysis. Each mutation can be highlighted on the SCR structure together with the patient FH and C3 levels where available. Two new insights were obtained from our collection of data. First, phenotypic data on FH clarify our previously-proposed classification of Type I and Type II disorders that both lead to HUS, where Type I affects FH secretion and folding, and Type II leads to expressed protein in plasma that is functionally defective. Second, the new mutations show more clearly that SCR domains from SCR-16 to SCR-19 are important for the ligand binding activities of FH as well as SCR-20. This FH web database will facilitate the interpretation of new mutations and polymorphisms when these are identified in patients, and it will clarify the functional role of FH.
The cytokeratin filament-aggregating protein filaggrin is the target of the so-called "antikeratin antibodies," autoantibodies specific for rheumatoid arthritis. (1993)

In rheumatoid arthritis (RA), the high diagnostic value of serum antibodies to the stratum corneum of rat esophagus epithelium has been widely reported. These so-called "antikeratin antibodies," detected by indirect immunofluorescence, were found to be autoantibodies since they also labeled human epidermis. Despite their name, the actual target of these autoantibodies was not known. In this study, a 40-kD protein (designated as 40K), extracted from human epidermis and specifically immunodetected by 75% of RA sera, was purified and identified as a neutral/acidic isoform of basic filaggrin, a cytokeratin filament-aggregating protein, by peptide mapping studies and by the following evidences: (a) mAbs specific for filaggrin reacted with the 40K protein; (b) the autoantibodies, affinity-purified from RA sera on the 40K protein, immunodetected purified filaggrin; (c) the reactivity of RA sera to the 40K protein was abolished after immunoadsorption with purified filaggrin; (d) the 40K protein and filaggrin had similar amino acid compositions. Furthermore, autoantibodies against the 40K protein and the so-called "antikeratin antibodies" were shown, by immunoadsorption experiments, to be largely the same. The identification of filaggrin as a RA-specific autoantigen could contribute to the understanding of the pathogenesis of this disease and, ultimately, to the development of methods for preventing the autoimmune response.