gebhart/patrepeval huggingface dataset:
Improving Alzheimer's disease phase II clinical trials (2012)

Over the past 30 years, many drugs have been studied as possible treatments for Alzheimer's disease, but only four have demonstrated sufficient efficacy to be approved as treatments, of which three are in the same class. This lack of success has raised questions both in the pharmaceutical industry and academia about the future of Alzheimer's disease therapy. The high cost and low success rate of drug development across many disease areas can be attributed, in large part, to late-stage clinical failures (Schachter and Ramoni, Nat Rev Drug Discov 2007;6:107-8). Thus, identifying in phase II, or preferably phase I, drugs that are likely to fail would have a dramatic impact on the costs associated with developing new drugs. With this in mind, the Alzheimer's Association convened a Research Roundtable on June 23 and 24, 2011, in Washington, DC, bringing together scientists from academia, industry, and government regulatory agencies to discuss strategies for improving the probability of phase II trial results predicting success when considering the go/no-go decision-making process leading to the initiation of phase III.
Polyacrylamide-Based Redox Polymer for Connecting Redox Centers of Enzymes to Electrodes (1995)

Enzyme electrodes based on complexing a water-soluble copolymer of acrylamide and vinylimidazole with [Os(dmebpy)2C1]+/2+ (dmebpy = 4,4'-dimethyl-2,2'-bipyridine) and cross-linking with oxidases by water-soluble cross-linkers are described. The potential of the polyacrylamide-based redox polymer is +55 mV (SCE), a typical electron diffusion coefficient (De) in the redox hydrogel that results from its cross-linking is (1.3 +/- 0.1) x 10(-9) cm2/s. The properties of the enzyme electrodes formed when this redox hydrogel "wired" horseradish peroxidase (HRP), lactate oxidase (LOx) or glucose oxidase (GOx) depended on the thickness of the hydrogel film, the chemistry of their cross-linking, and their enzyme content. At the wired HRP electrodes, H2O2 was electrocatalytically reduced to water at 0.0 V (SCE). Lactate and glucose were electrocatalytically oxidized at 0.16 V (SCE). The GOx electrodes, when made with 140 micrograms/cm2 thick polymer films, were selective for glucose in the presence of physiological concentrations of urate and ascorbate.
Damping of Tropical Instability Waves caused by the action of surface currents on stress (2009)

Ocean eddies and fronts affect surface stress via two mechanisms: (1) ocean surface currents altering the relative motion between air and sea and, hence, the stress fields and (2) ocean sea surface temperature (SST) gradients forcing changes in stability and near‐surface winds. In this paper, we quantify the first effect and how it impacts Tropical Instability Waves (TIW) in the eastern Pacific. High‐resolution satellite data and a regional coupled model are used to distinguish between stress changes due to the surface currents and those due to the changes in stability and near‐surface winds. It is found that both mechanisms affect the surface stress curl, but they do so at different latitudes, allowing for their effect on Ekman pumping to be distinguished. The Ekman pumping due to the surface current effect alone, leads to significant damping of the TIWs. In terms of the eddy kinetic energy, the inclusion of surface current in the stress leads to decay with an e‐folding time comparable with the period of the TIWs. It is, thus, an important damping mechanism to be included in ocean and coupled ocean‐atmosphere models.
Drosophila Wnt-1 Undergoes a Hydrophobic Modification and Is Targeted to Lipid Rafts, a Process That Requires Porcupine (2004)

Wnt signaling pathways regulate many developmental responses; however, little is known about how Wnt ligands function on a biochemical level. Recent studies have shown that Wnt-3a is palmitoylated before secretion. Here we report that Drosophila Wnt-1 (Wingless) also undergoes a lipid modification. Lipidation occurs in the endoplasmic reticulum and is dependent on Porcupine, a putative O-acyltransferase. After modification, DWnt-1 partitions as a membrane-anchored protein and is sorted into lipid raft detergent-insoluble microdomains. Lipidation, raft targeting, and secretion can be blocked by the addition of 2-bromopalmitate, a competitive inhibitor of O-acyltransferase activity. Based on these results we propose a model whereby lipidation targets Wnt-1 to secretory vesicles that deliver the ligand to specialized microdomains at the cell surface where it can be packaged for secretion.
Direct Analysis of Intact Proteins from Escherichia coli Colonies by Liquid Extraction Surface Analysis Mass Spectrometry (2014)

Top-down identification of proteins by liquid extraction surface analysis (LESA) mass spectrometry has previously been reported for tissue sections and dried blood spot samples. Here, we present a modified "contact" LESA method for top-down analysis of proteins directly from living bacterial colonies grown in Petri dishes, without any sample pretreatment. It was possible to identify a number of proteins by use of collision-induced dissociation tandem mass spectrometry followed by searches of the data against an E. coli protein database. The proteins identified suggest that the method may provide insight into the bacterial response to environmental conditions. Moreover, the results show that the "contact" LESA approach results in a smaller sampling area than typical LESA, which may have implications for spatial profiling.
A Surface Component in Group A, C, and G Streptococci with Non-Immune Reactivity for Immunoglobulin G (1973)

Abstract Fifty-seven strains of streptococci belonging to groups A, C, and G were tested for γ-globulin Fc-reactivity with sensitized sheep red cells. Twenty-six per cent of the strains were positive. Forty-four per cent of the strains produced a soluble factor with similar γ-globulin reactivity. With a radioimmunologic assay to detect streptococcal reactivity, human IgG was found to be positive, whereas human IgA, IgM, IgD, and IgE were negative. The reactivity was detected in heavy chain preparations but not in light chains, F(ab′)2 fragments nor in Fc fragments. Experiments using isolated myeloma globulins representing the four IgG subclasses indicated that streptococci might react not only with IgG1-, IgG2-, and IgG4-like protein A but also with IgG3 molecules. One of the two IgG3 myeloma globulins studied did react with a group A streptococcus and both myeloma globulins did react with a group G streptococcus. Serum samples from 14 selected animal species also indicated differences between the γ-globulin reactivity of protein A and streptococci. Marsupials as well as the Rhea bird were non-reactive with streptococci. The results obtained with eleven other species indicated that the group A and G streptococcal reactivities were similar but differed significantly from staphylococcal protein A reactivity.
Speculative disambiguation: a compilation technique for dynamic memory disambiguation (1994)

Ambiguous memory references have always been one of the main sources of performance bottlenecks. Many papers have addressed this problem using static disambiguation. These methods work extremely well when the memory access pattern is linear and predictable. However they are ineffective when the memory access pattern is nonlinear or when the access pattern cannot be determined statically. For these difficult problems, this paper presents speculative disambiguation, a compilation technique for architectures supporting instruction level parallelism and either speculative execution or conditional execution (or both). This technique produces specialized code at compile time to disambiguate memory references at run time. It is shown that on machines with sufficient resources, the technique will always result in lower execution time. Speculative disambiguation has been implemented for a VLIW architecture with guarded execution. Preliminary results indicate that it can help bridge a significant fraction of the performance gap between a good and a perfect static disambiguator. Occasionally it can outperform the perfect static disambiguator.
The relationship between granulocyte elastase‐like activity of cervical mucus and cervical maturation (1991)

Granulocyte elastase (elastase)-like activity in 119 samples of cervical mucus from pregnant women was measured. Though elastase-like activity in normal pregnant women was low in 2nd and 3rd trimesters (less than 20 units), it increased during labor (1st stage of labor: 70 +/- 50 U/l; 2nd stage: 72 +/- 56). Elastase-like activity in pregnant women with imminent premature delivery (24-30 gestational weeks) was also high (78 +/- 57). Elastase-like activity of cervical mucus correlated with Bishop score in both normal term and preterm labor. Elastase-containing granulocytes were identified by immunohistochemistry in ripened cervix in normal and preterm labor. Some granulocytes degranulate and release elastase into the cervical stroma. Others migrate through the basement membrane of the endocervix to reach the cervical canal. Elastase could not be demonstrated in immature cervix as assessed by Bishop score. The staining intensity of elastase in the cervix correlated closely with elastase-like activity in cervical mucus. Thus elastase-like activity in cervical mucus reflects the degree of cervical maturation. These results lead one to speculate that elastase is one of the neutral proteases which depolymerize and degrade collagen in the ripening cervix.
Textile Actuator Fibres : Investigation in materials and methods for coiled polymer fibre muscles (2015)

This thesis contains an investigation in materials and methods for coiled polymer muscles where the end application in mind is to be integrated in a textile structure such as an exo-skeleton glove. Previous artificial muscle fibres have proved little success due to performance, cost and scalability. For example, thermally controlled muscles of carbon nanotube material are expensive and muscles from shape memory metal shows difficulty in control. By instead using simple polymer fibres as thermally driven artificial muscles previous problems can be solved. In the present work, different materials such as a semi crystalline poly(vinylidiene fluoride) (PVDF), with two different molecular weights (MW), and a Shape Memory Polymer (SMP) of thermoplastic polyurethane (TPU) have been melt spun into monofilaments, cold drawn and twisted into coils. By changing parame-ters of the melt spinning equipment, fibres of varying thicknesses and with differ-ent molecular orientation were produced. Also a fishing line of fluorocarbons with a known functioning actuation has been used as a comparison. The fibres have been investigated using Differential Scanning Calorimetry (DSC), Dynamic Me-chanical Thermal Analysis (DMTA) and Scanning Electron Microscopy (SEM). The results from this study indicate that fibres used as coiled artificial muscles need to contain a high degree of crystallinity (not amorphous), be cold drawn at high temperature, contain a high degree of orientation and encompass a uniform fibre diameter. In this study the material of a higher MW showed slightly better properties then the material of a lower MW. In PVDF, an interesting relaxation around 50-60°C was identified as relevant for the actuation properties.
Endohexosaminidase M: Exploring and Exploiting Enzyme Substrate Specificity (2006)

Oxazoline saccharides have been synthesised and tested as glycosyl donors for endohexosaminidase M (Endo M)-catalysed glycosylation of a GlcNAcAsn glycosyl amino acid. Endo M-catalysed glycosylation is not limited to donors containing the Manβ(1-4)GlcNAc linkage, and replacement of the core mannose unit by glucose promotes irreversible glycosylation. In this case, use of a modified oxazoline donor as a transition-state mimic allows enzyme-catalysed synthesis, but precludes product hydrolysis.
Ziconotide: Neuronal Calcium Channel Blocker for Treating Severe Chronic Pain (2004)

Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.
Epithelial Cell Adhesion Molecule (Ep-CAM) Modulates Cell–Cell Interactions Mediated by Classic Cadherins (1997)

The contribution of noncadherin-type, Ca2+-independent cell-cell adhesion molecules to the organization of epithelial tissues is, as yet, unclear. A homophilic, epithelial Ca2+-independent adhesion molecule (Ep-CAM) is expressed in most epithelia, benign or malignant proliferative lesions, or during embryogenesis. Here we demonstrate that ectopic Ep-CAM, when expressed in cells interconnected by classic cadherins (E- or N-cadherin), induces segregation of the transfectants from the parental cell type in coaggregation assays and in cultured mixed aggregates, respectively. In the latter assay, Ep-CAM-positive transfectants behave like cells with a decreased strength of cell-cell adhesion as compared to the parental cells. Using transfectants with an inducible Ep-CAM-cDNA construct, we demonstrate that increasing expression of Ep-CAM in cadherin-positive cells leads to the gradual abrogation of adherens junctions. Overexpression of Ep-CAM has no influence on the total amount of cellular cadherin, but affects the interaction of cadherins with the cytoskeleton since a substantial decrease in the detergent-insoluble fraction of cadherin molecules was observed. Similarly, the detergent-insoluble fractions of alpha- and beta-catenins decreased in cells overexpressing Ep-CAM. While the total beta-catenin content remains unchanged, a reduction in total cellular alpha-catenin is observed as Ep-CAM expression increases. As the cadherin-mediated cell-cell adhesions diminish, Ep-CAM-mediated intercellular connections become predominant. An adhesion-defective mutant of Ep-CAM lacking the cytoplasmic domain has no effect on the cadherin-mediated cell-cell adhesions. The ability of Ep-CAM to modulate the cadherin-mediated cell-cell interactions, as demonstrated in the present study, suggests a role for this molecule in development of the proliferative, and probably malignant, phenotype of epithelial cells, since an increase of Ep-CAM expression was observed in vivo in association with hyperplastic and malignant proliferation of epithelial cells.
Overview: Purinergic Mechanisms (1990)

An overview of the history of studies of the biological actions of extracellular ATP is presented. The basis of the subdivision of receptors for purines into P1-purinoceptors for adenosine and P2-purinoceptors for ATP and ADP are considered, as well as the recent proposal for subdivision of the ATP receptors into P2X-, P2Y-, P2Z-, and P2T- purinoceptor subtypes. These purinoceptor subtypes are discussed with respect to their transduction mechanisms, their distribution, and their physiological roles, including their roles in cotransmission and neuromodulation.
Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptions of six new species combinations and designation of Ehrlichia equi and 'HGE agent' as subjective synonyms of Ehrlichia phagocytophila. (2001)

The genera Anaplasma, Ehrlichia, Cowdria, Neorickettsia and Wolbachia encompass a group of obligate intracellular bacteria that reside in vacuoles of eukaryotic cells and were previously placed in taxa based upon morphological, ecological, epidemiological and clinical characteristics. Recent genetic analyses of 16S rRNA genes, groESL and surface protein genes have indicated that the existing taxa designations are flawed. All 16S rRNA gene and groESL sequences deposited in GenBank prior to 2000 and selected sequences deposited thereafter were aligned and phylogenetic trees and bootstrap values were calculated using the neighbour-joining method and compared with trees generated with maximum-probability, maximum-likelihood, majority-rule consensus and parsimony methods. Supported by bootstrap probabilities of at least 54%, 16S rRNA gene comparisons consistently clustered to yield four distinct clades characterized roughly as Anaplasma (including the Ehrlichia phagocytophila group, Ehrlichia platys and Ehrlichia bovis) with a minimum of 96.1% similarity, Ehrlichia (including Cowdria ruminantium) with a minimum of 97.7% similarity, Wolbachia with a minimum of 95.6% similarity and Neorickettsia (including Ehrlichia sennetsu and Ehrlichia risticii) with a minimum of 94.9% similarity. Maximum similarity between clades ranged from 87.1 to 94.9%. Insufficient differences existed among E. phagocytophila, Ehrlichia equi and the human granulocytic ehrlichiosis (HGE) agent to support separate species designations, and this group was at least 98.2% similar to any Anaplasma species. These 16S rRNA gene analyses are strongly supported by similar groESL clades, as well as biological and antigenic characteristics. It is proposed that all members of the tribes Ehrlichieae and Wolbachieae be transferred to the family Anaplasmataceae and that the tribe structure of the family Rickettsiaceae be eliminated. The genus Anaplasma should be emended to include Anaplasma (Ehrlichia) phagocytophila comb. nov. (which also encompasses the former E. equi and the HGE agent), Anaplasma (Ehrlichia) bovis comb. nov. and Anaplasma (Ehrlichia) platys comb. nov., the genus Ehrlichia should be emended to include Ehrlichia (Cowdria) ruminantium comb. nov. and the genus Neorickettsia should be emended to include Neorickettsia (Ehrlichia) risticii comb. nov. and Neorickettsia (Ehrlichia) sennetsu comb. nov.
Synthesis and assembly of functionally active human vascular endothelial growth factor homodimers in insect cells (1993)

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor with a target-cell specificity highly restricted to vascular endothelial cells. Recombinant baculovirus were constructed for the production of two different forms of the human VEGF protein in insect cells. VEGF165 and VEGF121 proteins produced by Sf158 cells underwent a similar processing compared with mammalian cells, including efficient glycosylation, formation of a disulfide-linked dimer and secretion into the media. Only one of these forms, VEGF165 had a high affinity for heparin and this characteristic was used to purify this form to homogenicity by a two-step heparin-affinity chromatography. The biological activity of the purified 43-kDa homodimer was demonstrated by high-affinity binding to VEGF receptors, and by the induction of DNA synthesis in vascular endothelial cells. A positive angiogenic activity in vivo was demonstrated by the day-13 chorioallantoic-membrane assay. The mitogenic potency of VEGF121 for human umbilical vein endothelial cells was very similar compared to VEGF165. These results demonstrate that an angiogenic growth factor whose normal processing requires glycosylation and disulfide-bridge formation can be efficiently expressed in high concentration (up to 5 micrograms/ml) in insects cells.
The Case for Secondary Hormonal Therapies in the Chemotherapy Age (2006)

The modest activity of these secondary therapies challenges the notion that advancing prostate cancer uniformly becomes hormone refractory. It offers an alternative to the early use of chemotherapy in patients with androgen independent disease.
Mapping Genes in Diabetes: Genetic Epidemiological Perspective (1990)

Research on mapping diabetes-susceptibility genes is dependent on several factors, including the existence of a single major gene for susceptibility, genetic homogeneity, and the existence of appropriate clinical material. The power to detect susceptibility genes is dependent on the risks in relatives and the distance of genetic markers from the susceptibility genes. For insulin-dependent diabetes mellitus (IDDM), the best-fitting risk models are those with a single major locus with residual polygenic factors. The major locus effect is likely represented by genes in the HLA complex, because specific genotypes have been found to affect IDDM risk significantly. Thus, mapping the remaining polygenic IDDM susceptibility factors--each of small effect--is a difficult and long task. For non-insulin-dependent diabetes mellitus (NIDDM), the likely risk models result in few genes with moderate effect. Models of NIDDM have significant residual polygenic variation remaining, reflecting the importance of multiple loci with small effect, environmental effects, or genetic heterogeneity; however, the prospects for mapping genes that provide at least moderate susceptibility for NIDDM now appear promising.
Genomic structure, sequence, and mapping of humanFGF8 with no evidence for its role in craniosynostosis/limb defect syndromes (1997)

Fibroblast growth factor-8 (Fgf8) is a recently identified growth factor that stimulates the androgen-dependent growth of mouse mammary carcinoma cells. Evidence from mouse development also shows that Fgf8 may play an important role in growth and patterning of limbs, face, and the central nervous system. We describe here the human FGF8 genomic sequence and demonstrate conservation between the human and mouse sequences, including alternatively spliced exons in the mouse. Mapping of FGF8 by FISH using an FGF8-containing bacterial artificial chromosome and by genetic linkage using a SSCP variant identified in this study is also reported and refines the FGF8 map location to 10q24. Since FGF8 maps to the same chromosomal region as FGFR2, has indeed been shown to be a ligand for FGFR2, and has an expression pattern consistent with limb and craniofacial anomalies, we have screened two kindreds with Pfeiffer syndrome that were previously linked to markers from 10q24-25 and a large number of individuals with craniosynostosis and limb anomalies for mutations in the coding sequence of FGF8. While no such mutations were identified, a rare polymorphic variant, consisting of an 18-base-pair (six-amino-acid) duplication in exon 1c, is reported that apparently has no clinical effect. Our exclusionary data suggest that mutations in FGF8 would be, at best, an infrequent cause of such disorders.