gebhart/patrepeval huggingface dataset:
Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition ofde NovoPurine Nucleotide Biosynthesis (2018)

Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo[2,3- d]pyrimidine analogues 7-12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α and β or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11, and 12 showed increased in vitro antiproliferative activities (∼11-fold) over the nonfluorinated analogues 2, 3, 5, and 6 toward engineered Chinese hamster ovary and HeLa cells expressing FRs or PCFT. Compounds 8, 9, 11, and 12 also inhibited proliferation of IGROV1 and A2780 epithelial ovarian cancer cells; in IGROV1 cells with knockdown of FRα, 9, 11, and 12 showed sustained inhibition associated with uptake by PCFT. All compounds inhibited glycinamide ribonucleotide formyltransferase, a key enzyme in the de novo purine biosynthesis pathway. Molecular modeling studies validated in vitro cell-based results. NMR evidence supports the presence of an intramolecular fluorine-hydrogen bond. Potent in vivo efficacy of 11 was established with IGROV1 xenografts in severe compromised immunodeficient mice.
Retinal thickness measurements from optical coherence tomography using a Markov boundary model (2001)

We present a system for detecting retinal boundaries in optical coherence tomography (OCT) B-scans. OCT is a relatively new imaging modality giving cross-sectional images that are qualitatively similar to ultrasound. However, the axial resolution with OCT is much higher, on the order of 10 microm. Objective, quantitative measures of retinal thickness may be made from OCT images. Knowledge of retinal thickness is important in the evaluation and treatment of many ocular diseases. The boundary-detection system presented here uses a one-dimensional edge-detection kernel to yield edge primitives. These edge primitives are rated, selected, and organized to form a coherent boundary structure by use of a Markov model of retinal boundaries as detected by OCT. Qualitatively, the boundaries detected by the automated system generally agreed extremely well with the true retinal structure for the vast majority of OCT images. Only one of the 1450 evaluation images caused the algorithm to fail. A quantitative evaluation of the retinal boundaries was performed as well, using the clinical application of automatic retinal thickness determination. Retinal thickness measurements derived from the algorithm's results were compared with thickness measurements from manually corrected boundaries for 1450 test images. The algorithm's thickness measurements over a 1-mm region near the fovea differed from the corrected thickness measurements by less than 10 microm for 74% of the images and by less than 25 microm (10% of normal retinal thickness) for 98.4% of the images. These errors are near the machine's resolution limit and still well below clinical significance. Current, standard clinical practice involves a qualitative, visual assessment of retinal thickness. A robust, quantitatively accurate system such as ours can be expected to improve patient care.
Exploring the Energy Landscape of Antibody−Antigen Complexes: Protein Dynamics, Flexibility, and Molecular Recognition (2008)

The production of antibodies that selectively bind virtually any foreign compound is the hallmark of the immune system. While much is understood about how sequence diversity contributes to this remarkable feat of molecular recognition, little is known about how sequence diversity impacts antibody dynamics, which is also expected to contribute to molecular recognition. Toward this goal, we examined a panel of antibodies elicited to the chromophoric antigen fluorescein. On the basis of isothermal titration calorimetry, we selected six antibodies that bind fluorescein with diverse binding entropies, suggestive of varying contributions of dynamics to molecular recognition. Sequencing revealed that two pairs of antibodies employ homologous heavy chains that were derived from common germline genes, while the other two heavy chains and all six of the light chains were derived from different germline genes and are not homologous. Interestingly, more than half of all the somatic mutations acquired during affinity maturation among the six antibodies are located in positions unlikely to contact fluorescein directly. To quantify and compare the dynamics of the antibody-fluorescein complexes, three-pulse photon echo peak shift and transient grating spectroscopy were employed. All of the antibodies exhibited motions on three distinct time scales, ultrafast motions on the <100 fs time scale, diffusive motions on the picosecond time scale, and motions that occur on time scales longer than nanoseconds and thus appear static. However, the exact frequency of the picosecond time scale motion and the relative contribution of the different motions vary significantly among the antibody-chromophore complexes, revealing a high level of dynamic diversity. Using a hierarchical model, we relate the data to features of the antibodies' energy landscapes as well as their flexibility in terms of elasticity and plasticity. In all, the data provide a consistent picture of antibody flexibility, which interestingly appears to be correlated with binding entropy as well as with germline gene use and the mutations introduced during affinity maturation. The data also provide a gauge of the dynamic diversity of the antibody repertoire and suggest that this diversity might contribute to molecular recognition by facilitating the recognition of the broadest range of foreign molecules.
Role of beta 1 and beta 2 integrins in the adhesion of human CD34hi stem cells to bone marrow stroma. (1992)

Hematopoietic stem cell interaction with elements of the underlying stroma is essential for sustained normal hematopoiesis. Here we have determined that adhesion receptors in the integrin family play a role in promoting adhesion of human hematopoietic stem cells to cultured human marrow stromal cells. Enriched CD34hi progenitor cells expressed VLA-4, VLA-5, and at least one or more beta 2 integrins. Homogeneous marrow stromal cell monolayers capable of supporting proliferation of cocultivated CD34hi cells expressed VCAM-1 and fibronectin (ligands for VLA-4 and VLA-5) as well as ICAM-1 (ligand for LFA-1 and Mac-1). Adhesion-blocking experiments indicated that VLA-4/VCAM-1, VLA-5/fibronectin, and beta 2-integrin/ICAM-1 pathways all are important for CD34hi cell attachment to stromal cells. Consistent with this suggestion, IL-1 stimulation of stromal cells caused both increased VCAM-1 and ICAM-1 expression and increased attachment by CD34hi bone marrow cells. In addition, CD34hi cells utilized VLA-4 to adhere to purified VCAM-1 and employed VLA-5 (and to a lesser extent VLA-4) to adhere to purified fibronectin. Together these results suggest that CD34hi stem cells may utilize multiple integrin-mediated adhesion pathways to localize within specialized microenvironmental niches created by marrow stromal cells.
Organic/Inorganic Imide Nanocomposites from Aminophenylsilsesquioxanes (2003)

We present here part of an ongoing study on structure−processing−property relationships in cubic silsesquioxane (cube) nanocomposites. Here, we focus on imide nanocomposites prepared from octaaminophenylsilsesquioxane (OAPS) as a model nanobuilding block for rigid, high-temperature hybrid nanocomposite materials. OAPS units are linked NH2 vertex to NH2 vertex by reaction with various dianhydrides to form three-dimensional nanocomposites. The architecture of the organic tethers between vertices can be manipulated to optimize processability, rigidity, and thermomechanical properties. Studies were initiated using an extreme tether structure with zero flexibility prepared by solvent casting and then curing mixtures of OAPS with pyromellitic dianhydride (PMDA) at 330 °C. The resulting materials are extremely brittle, making thermomechanical property measurements quite difficult. Tether rigidity, length, and cross-link densities were then modified using reactions of OAPS with oxydiphthalic anhydride (ODPA) and diluting with oxydianiline (ODA) to adjust nanocomposite stiffness. FTIR and DMA of the OAPS/ODPA/ODA nanocomposites suggest that cure temperatures of >500 °C are necessary for optimal imidization. However, increasing the cross-link density alone by increasing OAPS loading without curing at high temperatures also significantly improves thermomechanical stabilities. DMA, TGA, and nanoindentation measurements show that macroscopic relaxation is eliminated completely at OAPS loadings of >60 mol % providing 5% mass loss at temperatures >570 °C and compressive moduli of ≈3.8 GPa.
Screening System for the Maillard Reaction Inhibitor from Natural Product Extracts. (2002)

An assay for the Maillard reaction has been developed to screen efficiently inhibitors from natural resources such as extracts of plants. The fluorometric analysis of fluorescent material based on advanced glycation endproducts (AGEs) was applied to measurement of an inhibitory index of the Maillard reaction to detect all of the inhibitors at each step of the complicated reaction. To solve the two major problems, slowness of the reaction rate and the existence of interfering substances such as quencher and fluorescent material in the screening sources, we devised the following procedures. Slowness of the reaction rate was solved by raising the reaction temperature to 60°C at which the conformation of bovine serum albumin (BSA) did not change greatly. To remove the interfering substances, AGEs-BSA was precipitated from the reaction mixture. Thus, an efficient assay system by measuring the fluorescent intensity based on AGEs was established to isolate the glycation inhibitors from natural product extracts.
Antisense repression in Cryptococcus neoformans as a laboratory tool and potential antifungal strategy (2002)

Antisense repression was used as a method to alter gene function in the human-pathogenic fungus Cryptococcus neoformans. The calcineurin A gene (CNA1) and the laccase gene (LAC1) were targeted since disruption of these loci results in phenotypes that are easy to screen (temperature sensitivity and lack of melanin, respectively). Serotype D yeasts were transformed with a plasmid containing the CNA1 cDNA in an antisense orientation under the control of the inducible GAL7 promoter, and serotype A yeasts were transformed with a plasmid containing the LAC1 cDNA in an antisense orientation under the control of the constitutive actin promoter. The calcineurin transformants demonstrated a temperature-sensitive phenotype only when grown on galactose, and the laccase transformants had decreased melanin production. Northern blot analysis of the calcineurin antisense transformants confirmed that the inducible phenotype was associated with a decrease in the native CNA1 transcript levels. Furthermore, it was possible to modestly impair growth of C. neoformans at 37 degrees C by using a 30 bp antisense oligonucleotide targeting CNA1. Antisense repression is now available as a tool for molecular studies in this organism, and may be applicable to other human-pathogenic fungi that have less amenable genetic systems.
Factor VIIIa A2 subunit residues 558-565 represent a factor IXa interactive site. (1994)

Factor VIIIa is a non-covalent heterotrimer of A1, A2, and A3-C1-C2 subunits. Previously, we speculated that the central portion of the A2 subunit, in and around the activated protein C-sensitive bond at Arg562-Gly (Fay, P. J., Smudzin, T.M., and Walker, F.J. (1991) J. Biol. Chem. 266, 20139-20145), is important for macromolecular interactions within the factor Xase enzyme complex. A peptide corresponding to factor VIII residues 558-565, SVDQRGNQ and designated FVIII558-565, was chemically synthesized and inhibited factor Xa generation in a purified system with an apparent KI of 105 microM. Tryptic cleavage of FVIII558-565 eliminated its inhibitory activity, whereas a scrambled sequence version of the peptide possessed < 30% the inhibitory activity of the native version. Overlapping peptides FVIII556-564 and FVIII561-569 were also inhibitory and confirmed the importance of residues in and around the scissile bond for functional factor Xase. Kinetic analysis revealed that peptide-mediated inhibition was non-competitive with respect to factor X. However, increasing factor IXa concentration overcame the observed inhibition. Furthermore, the peptide inhibited the factor IXa-dependent enhancement of factor VIIIa reconstituted from isolated A1/A3-C1-C2 dimer plus A2 subunit. Isolated factor VIII heavy chain (contiguous A1-A2 domains) was cleaved at Arg336 by an equimolar concentration of factor IXa in a reaction that was phospholipid-independent. No proteolysis of the isolated A1 subunit was observed in a similar reaction. These results indicate that the A2 subunit sequence delineated by residues 558-565 contributes to the interaction of cofactor with protease and that this interaction is essential for intrinsic factor Xase activity. Furthermore, that this peptide blocks both factor Xase activity and the capacity of factor IXa to stabilize the labile factor VIIIa heterotrimer suggest that this latter property is of physiologic significance.
Human free secretory component is composed of the first 585 amino acid residues of the polymeric immunoglobulin receptor (1997)

The main objective of this work was to unequivocally determine the C-terminal sequence of human milk free secretory component (SC). It was found to end at arginine-585, i.e. 33 amino acids downstream from the major heterogeneous C-terminal residue previously identified for colostrum SC. In contrast, our data showed that the C-terminal end of SC was found to be homogeneous. Conflicting assignments, Asp/Gln, a missing Asn-211, Asp/Asn, Glu/Gln were corrected and found to agree with the cDNA sequence. An Ala/Val substitution at position 562 (domain VI) was identified. Its genetic significance is uncertain at present.
The molecular basis of thrombolysis and its clinical application in stroke (2009)

The rationale for thrombolysis, the most promising pharmacological approach in acute ischaemic stroke, is centred on the principal cause of most ischaemic strokes: the thrombus that occludes the cerebral artery, and renders part of the brain ischaemic. The occluding thrombus is bound together within fibrin. Fibrinolysis acts by activation of plasminogen to plasmin; plasmin splits fibrinogen and fibrin and lyses the clot, which then allows reperfusion of the ischaemic brain. Thrombolytic agents include streptokinase (SK) and recombinant tissue-type plasminogen activator (rt-PA) amongst others under test or development. SK is nonfibrin-specific, has a longer half-life than tissue-type plasminogen activator (t-PA), prevents re-occlusion and is degraded enzymatically in the circulation. rt-PA is more fibrin-specific and clot-dissolving, and is metabolized during the first passage in the liver. In animal models of ischaemic stroke, the effects of rt-PA are remarkably consistent with the effects seen in human clinical trials. For clinical application, some outcome data from the Cochrane Database of Systematic Reviews which includes all randomized evidence available on thrombolysis in man were used. Trials included tested urokinase, SK, rt-PA, pro-urokinase, or desmoteplase. The chief immediate hazard of thrombolytic therapy is fatal intracranial bleeding. However, despite the risk, the human trial data suggest the immediate hazards and the apparent substantial scope for net benefit of thrombolytic therapy given up to 6 h of acute ischaemic stroke. So far the fibrin-specific rt-PA is the only agent to be approved for use in stroke. This may be due to its short half-life and its absence of any specific amount of circulating fibrinogen degradation products, thereby leaving platelet function intact. The short half-life does not leave rt-PA without danger for haemorrhage after the infusion. Due to its fibrin-specificity, it can persist within a fibrin-rich clot for one or more days. The molecular mechanisms with regards to fibrin-specificity in thrombolytic agents should, if further studied, be addressed in within-trial comparisons. rt-PA has antigenic properties and although their long-term clinical relevance is unclear there should be surveillance for allergic reactions in relation to treatment. Although rt-PA is approved for use in selected patients, there is scope for benefit in a much wider variety of patients. A number of trials are underway to assess which additional patients - beyond the age and time limits of the current approval - might benefit, and how best to identify them.
Delivery of rapamycin by PLGA nanoparticles enhances its suppressive activity on dendritic cells (2007)

The purpose of this study was to evaluate the effect of rapamycin delivery by poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles on the maturation of dendritic cells (DCs). DCs were generated from mouse bone marrow and exposed to particulate and soluble rapamycin without any additional treatment, or with pre- or posttreatment with lipopolysaccharide (LPS). Annexin V-FITC/PI staining was performed on DC cultures to assess the viability of DCs during study. Surface phenotype of DCs was characterized for the expression of maturation markers, that is, MHC class II, CD86, and CD40 by flow cytometry. Cell culture supernatants were analyzed for the production of TGF-beta, IL-12, and IL-10 cytokines using sandwich ELISA method. DCs from Balb/C mice were cocultured with T cells from C57BL/6 mice and allogenic mixed lymphocyte reaction was assessed by [3H]-Thymidine incorporation. Unlike free rapamycin that has shown little if any effect on the expression of maturation markers in immature DCs, PLGA encapsulated rapamycin decreased the expression of all maturation markers under the study, that is, MHC class II, CD86, and CD40, significantly. LPS pre- or posttreated DCs demonstrated decreased expression of MHC class II, CD86, and CD40 in the presence of soluble or encapsulated rapamycin. The cytokine secretion profiles revealed high levels of TGF-beta and very low levels of IL-10 and IL-12 production. Rapamycin in soluble or encapsulated form significantly inhibited mixed lymphocyte reaction in DCs. The inhibitory effect of rapamycin on the maturation of DCs with respect to DC phenotype, cytokine production, and functional effects on the proliferation of T cells was significantly increased by PLGA delivery.
Hardware property checker for run-time Hardware Trojan detection (2015)

Nowadays, Hardware Trojans (HTs) become a real threat because of IC design and fabrication outsourcing trend. In the state of the art, many efforts were devoted to counter this threat, especially at netlist level. However, some clever HTs are actually a combination between a hardware and a software vulnerability, which, together, allow an exploitation. In this paper, we intend to detect such advanced HT, by resorting to a run-time detection. This method consists in identifying some high-level and critical behavioral invariants, and by checking them during the circuit operation. The assertion and Property Specification Language (PSL) is used to describe the properties to be checked. Then, a Hardware Property Checker (HPC) is created and integrated in the IC in order to verify these properties in runtime. We discuss how to define the critical properties for HPC. We also explain how this method is complementary with others, especially how the Hardware Checker can itself be protected against a tampering attempt. A case of study on LEON processor was performed to demonstrate the feasibility of this detection technique.
Cutting Edge: Suppression of T Cell Chemotaxis by Sphingosine 1-Phosphate (2002)

Murine CD4 and CD8 T cells express predominantly types 1 and 4 sphingosine 1-phosphate (S1P) G protein-coupled receptors (designated S1P1 and S1P4 or previously endothelial differentiation gene-encoded 1 and 6) for S1P, which has a normal plasma concentration of 0.1-1 microM. S1P now is shown to enhance chemotaxis of CD4 T cells to CCL-21 and CCL-5 by up to 2.5-fold at 10 nM to 0.1 microM, whereas 0.3-3 microM S1P inhibits this chemotaxis by up to 70%. Chemotaxis of S1P(1), but not S1P(4), transfectants to CXCL1 and CXCL4 was similarly affected by S1P. Activation of CD4 T cells, which decreases S1P receptor expression, suppressed effects of S1P on chemotaxis. Pretreatment of labeled CD4 T cells with S1P before reintroduction into mice inhibited by a maximum of 75% their migration into chemokine-challenged s.c. air pouches. The S1P-S1P(1) receptor axis thus controls recruitment of naive T cells by maintaining their response threshold to diverse lymphotactic factors.
Signal component control (1952)

THE proposed AIEE symbols and definitions for feedback control systems1 will be employed throughout this paper except for one omission and two additions. It will be assumed that the command signal is received with suitable magnitude and in appropriate electrical, mechanical, or other physical form so that the “reference input elements” will be omitted, although the term “reference input” will be retained to signify the input signal to the control system. The term ”signal component control” (sec) will be introduced to designate the control method, and the term “signal component control device” will be employed to specify the particular associated equipment.
Increasing and detecting memory address congruence (2002)

A static memory reference exhibits a unique property when its dynamic memory addresses are congruent with respect to some non-trivial modulus. Extraction of this congruence information at compile-time enables new classes of program optimization. In this paper, we present methods for forcing congruence among the dynamic addresses of a memory reference. We also introduce a compiler algorithm for detecting this property. Our transformations do not require interprocedural analysis and introduce almost no overhead. As a result, they can be incorporated into real compilation systems. On average, our transformations are able to achieve a five-fold increase in the number of congruent memory operations. We are then able to detect 95% of these references. This success is invaluable in providing performance gains in a variety of areas. When congruence information is incorporated into a vectorizing compiler we can increase the performance of a G4 AltiVec processor up to a factor of two. Using the same methods, we are able to reduce energy consumption in a data cache by as much as 35%.
Program plan for the development of advanced synthetic-diamond drill bits for hard-rock drilling (1993)

Eight companys have teamed with Sandia Labs to work on five projects as part of a cooperative effort to advance the state of the ar in synthetic-diamond drill bit design and manufacture. DBS (a Baroid Company), Dennis Tool Company, Hughes Christensen Company, Maurer Engineering, Megadiamond, Security Diamond Products, Slimdril International, and Smith International. Objective of each project is to develop advanced bit technology that results in new commercial products with longer bit life and higher penetration rates in hard formations. Each project explores a different approach to synthetic-diamond cutter and bit design and, consequently, uses different approaches to developing the technology. Each of these approaches builds or the respective companies` capabilities and current product interests. Sandia`s role is to assure integration of the individual projects into a coherent program and tc provide unique testing and analytical capabilities where needed. One additional company, Amoco Production Research, will provide synthetic-diamond drill bit research expertise and field testing services for each project in the program.