gebhart/patrepeval huggingface dataset:
Rational Design and Synthesis of a Novel Anti-leukemic Agent Targeting Bruton′s Tyrosine Kinase (BTK), LFM-A13 [α-Cyano-β-Hydroxy-β-Methyl-N-(2,5-Dibromophenyl)Propenamide] (1999)

In a systematic effort to design potent inhibitors of the anti-apoptotic tyrosine kinase BTK (Bruton's tyrosine kinase) as anti-leukemic agents with apoptosis-promoting and chemosensitizing properties, we have constructed a three-dimensional homology model of the BTK kinase domain. Our modeling studies revealed a distinct rectangular binding pocket near the hinge region of the BTK kinase domain with Leu460, Tyr476, Arg525, and Asp539 residues occupying the corners of the rectangle. The dimensions of this rectangle are approximately 18 x 8 x 9 x 17 A, and the thickness of the pocket is approximately 7 A. Advanced docking procedures were employed for the rational design of leflunomide metabolite (LFM) analogs with a high likelihood to bind favorably to the catalytic site within the kinase domain of BTK. The lead compound LFM-A13, for which we calculated a Ki value of 1.4 microM, inhibited human BTK in vitro with an IC50 value of 17.2 +/- 0.8 microM. Similarly, LFM-A13 inhibited recombinant BTK expressed in a baculovirus expression vector system with an IC50 value of 2.5 microM. The energetically favorable position of LFM-A13 in the binding pocket is such that its aromatic ring is close to Tyr476, and its substituent group is sandwiched between residues Arg525 and Asp539. In addition, LFM-A13 is capable of favorable hydrogen bonding interactions with BTK via Asp539 and Arg525 residues. Besides its remarkable potency in BTK kinase assays, LFM-A13 was also discovered to be a highly specific inhibitor of BTK. Even at concentrations as high as 100 micrograms/ml (approximately 278 microM), this novel inhibitor did not affect the enzymatic activity of other protein tyrosine kinases, including JAK1, JAK3, HCK, epidermal growth factor receptor kinase, and insulin receptor kinase. In accordance with the anti-apoptotic function of BTK, treatment of BTK+ B-lineage leukemic cells with LFM-A13 enhanced their sensitivity to ceramide- or vincristine-induced apoptosis. To our knowledge, LFM-A13 is the first BTK-specific tyrosine kinase inhibitor and the first anti-leukemic agent targeting BTK.
Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines (2008)

Toll-like receptors (TLRs) may need to cooperate with each other to be effective in detecting imminent infection and trigger immune responses. Understanding is still limited about the intracellular mechanism of this cooperation. We found that when certain TLRs are involved, dendritic cells (DCs) establish unidirectional intracellular cross-talk, in which the MyD88-independent TRIF-dependent pathway amplifies the MyD88-dependent DC function through a JNK-dependent mechanism. The amplified MyD88-dependent DC function determines the induction of the T cell response to a given vaccine in vivo. Therefore, our study revealed an underlying TLR mechanism governing the functional, nonrandom interplay among TLRs for recognition of combinatorial ligands that may be dangerous to the host, providing important guidance for design of novel synergistic molecular vaccine adjuvants.
Mitigating fluorescence spectral overlap in wide-field endoscopic imaging (2013)

The number of molecular species suitable for multispectral fluorescence imaging is limited due to the overlap of the emission spectra of indicator fluorophores, e.g., dyes and nanoparticles. To remove fluorophore emission cross-talk in wide-field multispectral fluorescence molecular imaging, we evaluate three different solutions: (1) image stitching, (2) concurrent imaging with cross-talk ratio subtraction algorithm, and (3) frame-sequential imaging. A phantom with fluorophore emission cross-talk is fabricated, and a 1.2-mm ultrathin scanning fiber endoscope (SFE) is used to test and compare these approaches. Results show that fluorophore emission cross-talk could be successfully avoided or significantly reduced. Near term, the concurrent imaging method of wide-field multispectral fluorescence SFE is viable for early stage cancer detection and localization in vivo. Furthermore, a means to enhance exogenous fluorescence target-to-background ratio by the reduction of tissue autofluorescence background is demonstrated.
Effects of d-α-Tocopherol Supplementation on Experimentally Induced Primate Atherosclerosis (1992)

Prevention and regression of induced atherosclerosis by d-α-tocopherol was investigated in 24 male M. fascicularis. One group received a basal diet, while three others consumed an atherogenic diet. Two of the latter groups also received tocopherol, one at the onset of the study (prevention) and the other after atherosclerosis was established by ultrasound evaluation (regression). Atherosclerosis was monitored over a 36-month period by duplex ultrasound imaging of the common carotid arteries. At termination, 24 arterial sites were examined for histopathology. In those animals receiving an atherogenic diet, mean percent ultrasound stenosis at 36 months posttreatment was lower in the tocopherol-supplemented groups (61 and 18%) than in the unsupplemented group (87%). Plasma tocopherol concentration was negatively correlated with percent ultrasound stenosis (p < 0.002). Percent stenosis in the regression group decreased from 33 to 8% (p < 0.05) 8 months after tocopherol supplementation. Although not consistently significant, histopathological changes were greater in untreated compared to treated animals. These results, if confirmed, indicate that d-α-tocopherol may be prophylactically and therapeutically effective in atherosclerosis.
Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein(a) retention and macrophage foam cell formation. (1993)

Prominent features of atheromata include smooth muscle cells, cholesteryl ester-loaded macrophage foam cells, extracellular matrix, extracellularly trapped and aggregated lipoproteins, and various enzymes including lipoprotein lipase (LpL) and sphingomyelinase (SMase). The interplay of these factors was investigated in cell culture. Incubation of bovine aortic smooth muscle cells for 18 h at 37 degrees C with low density lipoprotein (LDL) in the presence of LpL and SMase led to massive aggregation of LDL on the surface of the cells as viewed by phase, fluorescence (using 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate-LDL), and electron microscopy. This aggregation required both enzymes. Studies with 125I-LDL confirmed these observations: 125I-LDL cell association in the presence of LpL plus SMase was 50-100-fold greater than in the absence of the two enzymes and was 10-fold greater than in the presence of either enzyme alone. A similar effect (68-fold enhancement) was seen with 125I-labeled lipoprotein(a) (Lp(a)), another atherogenic lipoprotein. In all cases, 125I-lipoprotein degradation was relatively low (< 5% of cell-associated material). LpL/SMase-mediated association of 125I-LDL with smooth muscle cells was still observed when enzymatically inactive LpL was used. The effect was markedly diminished when the smooth muscle cells were treated with a combination of chondroitin ABC lyase and heparitinase or when mutant Chinese hamster ovary cells that lack cell-surface proteoglycans were used, indicating a specific role for cellular proteoglycans. When smooth muscle cells with 125I-LDL or 125I-Lp(a) aggregates were rinsed and then coincubated with mouse peritoneal macrophages for a further 24 h, visible aggregates disappeared, and there was marked 125I-lipoprotein degradation. Electron micrographs after 24 h of co-culture showed lipid-laden, foamy macrophages situated on top of smooth muscle cells, suggesting that the macrophages phagocytosed and metabolized the smooth muscle cell-associated LDL aggregates. Last, 125I-LDL association with smooth muscle cell extracellular matrix was also synergistically enhanced by LpL and SMase, to a level that was 19-fold greater than in the absence of the two enzymes. Thus, the interaction of LDL and Lp(a) with four atheroma components, namely, smooth muscle cells, extracellular matrix, LpL, and SMase, represents a physiologically plausible mechanism for massive, focal retention and aggregation of atherogenic lipoproteins in the arterial wall with subsequent macrophage foam cell formation.
The Enoyl‐[Acyl‐Carrier‐Protein] Reductase (FabI) of Escherichia coli, which Catalyzes a Key Regulatory Step in Fatty Acid Biosynthesis, Accepts NADH and NADPH as Cofactors and is Inhibited by Palmitoyl‐CoA (1996)

Reduction of enoyl-acyl-carrier-protein (ACP) substrates by enoyl-ACP reductase is a key regulatory step in fatty acid elongation of Escherichia coli. Two enoyl-ACP reductase activities have been described in E. coli, one specific for NADH, the other for NADPH as cofactor. Because of their distinct enzymatic properties, these activities were ascribed to two different proteins. The NADH-dependent enoyl-ACP reductase of E. coli has previously been identified as the FabI protein, which is the target of a group of antibacterial compounds, the diazaborines. We now demonstrate that both enoyl-ACP reductase activities reside in FabI. In crude cell extracts of FabI-overproducing strains, both NADH-dependent and NADPH-dependent enoyl-ACP reductase activities are increased. Mutations in the fabI gene that lead either to temperature-sensitive growth or diazaborine resistance result in the reduction of both activities. When FabI is purified in pH 6.5 buffers, the protein exhibits NADH-dependent and NADPH-dependent reductase activities. Both enzymatic activities are inhibited by diazaborine. The NADPH-dependent enoyl-ACP reductase activity, however, turned out to be approximately eight times more resistant to diazaborine. The difference in sensitivity indicates that binding of either NADPH or NADH to FabI results in distinct changes in the configuration of the protein or, alternatively, it is different due to the different charge of the cofactors. These effects might be responsible for the differences in the enzymatic properties. Both reductase activities of the FabI protein are inhibited by physiologically relevant concentrations of palmitoyl-CoA, which might be important in regulating endogenous fatty acid biosynthesis in E. coli in the presence of exogenous fatty acids.
Unified stochastic engine (USE) for speech recognition (1993)

A unified stochastic engine (USE) that jointly optimizes both acoustic and language models is presented. In the USE, not only can one iteratively adjust language probabilities to fit the given acoustic representations, but one can also adjust acoustic models (including feature representation) guided by language constraints. From the language modeling point of view, the USE makes it possible to encode acoustically confusable words in the language probabilities. From the acoustic modeling point of view, the language-constraint approach makes it possible to focus on acoustic words for which language models lack enough discrimination capacity. The authors report preliminary experimental results for Wall Street Journal continuous 5000-word speaker-independent dictation. The error rate is reduced from 7.3% to 6.9% with the proposed method.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
ChemInform Abstract: An Approach to Bufadienolides from Deoxycholic Acid. Part 1. Strategy and Synthesis of a Model Bufadienolide. (1987)

Abstract The title acid (I) is transformed to the aldehyde (II) by a known procedure.
Web Document Clustering Using Threshold Selection Partitioning. (2004)

Clustering techniques have been applied to categorize documents on World Wide Web. In previous research, PDDP (Principal Direction Divisive Partitioning) is a well-known clustering algorithm. PDDP algorithm employs top-down and unsupervised clustering based on the principal component analysis and splits documents into two sets using a plane perpendicular to the maximum principal direction passing through the centroid of the documents. However, in case that the distribution of documents is biased, this algorithm difficu lt to split into two subsets accurately. In this paper, we propose a new clustering algorithm that improved the separation of the two sets considerably. We give experimentalresults using our clustering algorithm on the NTCIR-4 Web task.
Assessing sequence comparison methods with reliable structurally identified distant evolutionary relationships (1998)

Pairwise sequence comparison methods have been assessed using proteins whose relationships are known reliably from their structures and functions, as described in the SCOP database [Murzin, A. G., Brenner, S. E., Hubbard, T. & Chothia C. (1995) J. Mol. Biol. 247, 536-540]. The evaluation tested the programs BLAST [Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. (1990). J. Mol. Biol. 215, 403-410], WU-BLAST2 [Altschul, S. F. & Gish, W. (1996) Methods Enzymol. 266, 460-480], FASTA [Pearson, W. R. & Lipman, D. J. (1988) Proc. Natl. Acad. Sci. USA 85, 2444-2448], and SSEARCH [Smith, T. F. & Waterman, M. S. (1981) J. Mol. Biol. 147, 195-197] and their scoring schemes. The error rate of all algorithms is greatly reduced by using statistical scores to evaluate matches rather than percentage identity or raw scores. The E-value statistical scores of SSEARCH and FASTA are reliable: the number of false positives found in our tests agrees well with the scores reported. However, the P-values reported by BLAST and WU-BLAST2 exaggerate significance by orders of magnitude. SSEARCH, FASTA ktup = 1, and WU-BLAST2 perform best, and they are capable of detecting almost all relationships between proteins whose sequence identities are >30%. For more distantly related proteins, they do much less well; only one-half of the relationships between proteins with 20-30% identity are found. Because many homologs have low sequence similarity, most distant relationships cannot be detected by any pairwise comparison method; however, those which are identified may be used with confidence.
INHIBITORS OF NADPH OXIDASE REDUCE THE ORGAN INJURY IN HEMORRHAGIC SHOCK (2005)

Reactive oxygen species contribute to the multiple organ dysfunction syndrome in hemorrhagic shock. Here, we investigate the effects of two chemically distinct inhibitors of NADPH oxidase on the circulatory failure and the organ dysfunction and injury associated with hemorrhagic shock in the anesthetized rat. Hemorrhage (sufficient to lower mean arterial blood pressure of 45 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure and in renal dysfunction and liver injury. Treatment of rats upon resuscitation with the NADPH oxidase inhibitors diphenylene iodonium (DPI, 1 mg/kg i.v.) reduced renal dysfunction and liver injury, whereas apocynin (3 mg/kg i.p.) did reduce the liver injury, but not the renal dysfunction caused by hemorrhagic shock. DPI and apocynin also attenuated the lung and intestinal injury (determined by histology) caused by hemorrhage and resuscitation. In the liver, DPI and apocynin abolished the increase in the formation of superoxide anions associated with hemorrhagic shock. However, neither DPI nor apocynin had a significant effect on the delayed circulatory failure caused by hemorrhage and resuscitation. In addition, DPI and apocynin did not reduce the increase in nitric oxide synthesis caused by hemorrhagic shock. Moreover, DPI reduced the activation of the transcription factor activator protein-1 caused by severe hemorrhage and resuscitation in the liver. Thus, we propose that an enhanced formation of superoxide anions by NADPH oxidase contributes to the liver injury caused by hemorrhagic shock, and that inhibitors of NADPH oxidase may represent a novel therapeutic approach for the therapy of hemorrhagic shock.
Timeline Follow-Back (1992)

Although the measurement of drinking is necessary for assessing and evaluating the treatment of alcohol problems, this key dependent variable has not always been reported in outcome studies.1–3 Today, the issue is not whether to measure drinking, but how to measure drinking. Concerns about how best to measure drinking patterns and problems date back to at least 1926, when Pearl stressed the importance of separating steady daily drinkers from occasional heavy drinkers.4
Searching for Novel Biomarkers Using High Resolution Diffusion Tensor Imaging (2011)

Diffusion tensor imaging is capable of resolving large fiber bundles (e.g. the corpus callosum) and has been quite informative in understanding the overall structural connectivity of the brain. Recent data has shown that traditional resolution limitations can be exceeded in humans in vivo to submillimeter resolution. This chapter discusses these new techniques, and specific applications to small pathways such as the perforant path in the medial temporal lobe. High-resolution diffusion tensor imaging is a promising new tool that can be used to discover novel biomarkers for Alzheimer's disease and other disorders. It allows for a much more detailed investigation of brain white matter than previously possible, perhaps offering clues into the first signs of synaptic deterioration that may precede frank neuron loss. Although these methods are still in their infancy and many challenges have to be overcome before they can be used in a clinical fashion, results so far have been promising. Challenges and future directions are discussed in detail.
Occupancy and mechanism in antibody-mediated neutralization of animal viruses (2002)

Neutralization of virus infectivity by antibodies is an important component of immunity to several virus infections. Here, the immunochemical basis for the action of neutralizing antibodies, and what role their induction of conformational changes in the antigen might play, is reviewed. Theories of the mechanisms by which antibodies neutralize virus infectivity in vitro are also presented. The theoretical and empirical foundation of the hypothesis that viruses are neutralized by a single antibody per virion is critically reviewed. The relationship between antibody occupancy on virions and the mechanism of neutralization is explored. Examples of neutralization mediated through antibody interference with virus attachment and entry are discussed and test implications of refined theories of neutralization by antibody coating of virions are formulated.
Mesenchymal Stem Cells Differentiate into an Endothelial Phenotype, Enhance Vascular Density, and Improve Heart Function in a Canine Chronic Ischemia Model (2005)

In a canine chronic ischemia model, MSCs differentiated into smooth muscle cells and endothelial cells, resulting in increased vascularity and improved cardiac function.
Growth of vertically aligned Si wire arrays over large areas (&gt;1cm2) with Au and Cu catalysts (2007)

Arrays of vertically oriented Si wires with diameters of 1.5μm and lengths of up to 75μm were grown over areas &amp;gt;1cm2 by photolithographically patterning an oxide buffer layer, followed by vapor-liquid-solid growth with either Au or Cu as the growth catalyst. The pattern fidelity depended critically on the presence of the oxide layer, which prevented migration of the catalyst on the surface during annealing and in the early stages of wire growth. These arrays can be used as the absorber material in novel photovoltaic architectures and potentially in photonic crystals in which large areas are needed.
Anti-CD3/Anti-CD28 Bead Stimulation Overcomes CD3 Unresponsiveness in Patients With Head and Neck Squamous Cell Carcinoma (2000)

A subpopulation of patients with HNSCC who are nonresponders to alphaCD3 stimulation has been identified, showing reduced proliferation and IL-12 and IFN-gamma secretion. Nonresponders stimulated with alphaCD3/alphaCD28 beads reversed immune unresponsiveness and induced a type 1 cytokine response. Bead-generated ATCs from patient 11 in the responder group lysed autologous and allogeneic HNSCC in vitro, suggesting a possible effective immunotherapeutic modality in the treatment of HNSCC.
CX3CR1+ Cell–Mediated Salmonella Exclusion Protects the Intestinal Mucosa during the Initial Stage of Infection (2016)

During Salmonella Typhimurium infection, intestinal CX<sub>3</sub>CR1<sup>+</sup> cells can either extend transepithelial cellular processes to sample luminal bacteria or, very early after infection, migrate into the intestinal lumen to capture bacteria. However, until now, the biological relevance of the intraluminal migration of CX<sub>3</sub>CR1<sup>+</sup> cells remained to be determined. We addressed this by using a combination of mouse strains differing in their ability to carry out CX<sub>3</sub>CR1-mediated sampling and intraluminal migration. We observed that the number of S. Typhimurium traversing the epithelium did not differ between sampling-competent/migration-competent C57BL/6 and sampling-deficient/migration-competent BALB/c mice. In contrast, in sampling-deficient/migration-deficient CX<sub>3</sub>CR1<sup>-/-</sup> mice the numbers of S. Typhimurium penetrating the epithelium were significantly higher. However, in these mice the number of invading S. Typhimurium was significantly reduced after the adoptive transfer of CX<sub>3</sub>CR1<sup>+</sup> cells directly into the intestinal lumen, consistent with intraluminal CX<sub>3</sub>CR1<sup>+</sup> cells preventing S. Typhimurium from infecting the host. This interpretation was also supported by a higher bacterial fecal load in CX<sub>3</sub>CR1<sup>+/gfp</sup> compared with CX<sub>3</sub>CR1<sup>gfp/gfp</sup> mice following oral infection. Furthermore, by using real-time in vivo imaging we observed that CX<sub>3</sub>CR1<sup>+</sup> cells migrated into the lumen moving through paracellular channels within the epithelium. Also, we reported that the absence of CX<sub>3</sub>CR1-mediated sampling did not affect Ab responses to a noninvasive S. Typhimurium strain that specifically targeted the CX<sub>3</sub>CR1-mediated entry route. These data showed that the rapidly deployed CX<sub>3</sub>CR1<sup>+</sup> cell-based mechanism of immune exclusion is a defense mechanism against pathogens that complements the mucous and secretory IgA Ab-mediated system in the protection of intestinal mucosal surface.
Monoclonal antibodies reactive with the mouse interleukin 5 receptor. (1989)

The rat mAbs R52.120 and R52.625 inhibit the action of IL-5 on both IL-5-sensitive cell lines and freshly isolated splenic B lymphocytes. Neither antibody inhibits the proliferative cell responses promoted by IL-2, IL-3, or IL-4. Purified R52.120+ lymphoid spleen cells contain 15-20-fold higher numbers of B lymphocytes responding to IL-5 in the form of maturation into antibody-producing cells. By immunofluorescence staining and flow fluorocytometry, the R52.120 and R52.625 antibodies bound to all 12 IL-5-sensitive cell lines tested. Both antibodies react with 2-4% cells in the spleen, 5% lymphoid cells, and 10-15% myeloid cells in the bone marrow, and 10-14% in the peritoneum of C57BL/6, DBA/2, and BALB/c adult mice. No positive cells for either antibody were detected in the thymus and lymph nodes of these mice. Both R52.120 and R52.625 antibodies specifically inhibit the binding of radiolabeled IL-5 to its receptor. Finally, R52.120 and R52.625 antibodies precipitate from 35S-methionine-labeled IL-5-R+ cell lysates three proteins with Mr 46,000, 130,000, and 140,000. Taken together from these results, we conclude that the R52.120 and R52.625 mAbs recognize epitopes on the IL-5-R complex very close or identical to the IL-5 binding sites.