gebhart/patrepeval huggingface dataset:
Synthesis and Pharmacological Profiling of Analogues of Benzyl Quinolone Carboxylic Acid (BQCA) as Allosteric Modulators of the M1 Muscarinic Receptor (2013)

Established therapy in Alzheimer's disease involves potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortex and hippocampus. Adverse effects, due to indiscriminate activation of other muscarinic receptor subtypes, are common. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution, being exquisitely M1-selective over other muscarinic subtypes. A common difficulty with allosteric ligands is interpreting SAR, based on composite potency values derived in the presence of fixed concentration of agonist. In reality these values encompass multiple pharmacological parameters, each potentially and differentially sensitive to structural modification of the ligand. We report novel BQCA analogues which appear to augment ligand affinity for the receptor (pK(B)), intrinsic efficacy (τB), and both binding (α) and functional (β) cooperativity with acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators will provide insight into their mode of action.
Dna Hypomethylation In Cancer Cells (2009)

DNA hypomethylation was the initial epigenetic abnormality recognized in human tumors. However, for several decades after its independent discovery by two laboratories in 1983, it was often ignored as an unwelcome complication, with almost all of the attention on the hypermethylation of promoters of genes that are silenced in cancers (e.g., tumor-suppressor genes). Because it was subsequently shown that global hypomethylation of DNA in cancer was most closely associated with repeated DNA elements, cancer linked-DNA hypomethylation continued to receive rather little attention. DNA hypomethylation in cancer can no longer be considered an oddity, because recent high-resolution genome-wide studies confirm that DNA hypomethylation is the almost constant companion to hypermethylation of the genome in cancer, just usually (but not always) in different sequences. Methylation changes at individual CpG dyads in cancer can have a high degree of dependence not only on the regional context, but also on neighboring sites. DNA demethylation during carcinogenesis may involve hemimethylated dyads as intermediates, followed by spreading of the loss of methylation on both strands. In this review, active demethylation of DNA and the relationship of cancer-associated DNA hypomethylation to cancer stem cells are discussed. Evidence is accumulating for the biological significance and clinical relevance of DNA hypomethylation in cancer, and for cancer-linked demethylation and de novo methylation being highly dynamic processes.
The structure of endothelial cell thrombospondin (1987)

The glycoprotein thrombospondin is distributed between the extracellular matrix and the platelet-sequestered pool in the resting state and it undergoes redistribution upon platelet stimulation. It is believed to play a role in matrix structure and in coagulation. We have studied the structural domains of endothelial cell (EC) thrombospondin by use of the serine proteases thrombin, trypsin and chymotrypsin and have characterized the heparin-binding domains of this molecule. For this purpose we used purified thrombospondin synthesized and secreted by bovine aortic endothelial cells grown in the presence of radiolabeled methionine. We find that the susceptibility of EC thrombospondin to proteolysis is five-fold smaller than that of platelet thrombospondin. In the presence of 2 mM Ca ions the molecule is cleaved by 20 U/ml thrombin at a single locus, to yield fragments of 160 kDa and 35 kDa. Trypsin digestion for 5 min at room temperature at an enzyme-to-substrate ratio of 1:20 produces a stable fragment of 140 kDa but not the 30-kDa fragment observed in platelet thrombospondin. Chymotrypsin, under identical conditions to those used for trypsin, cleaves EC thrombospondin into four stable fragments of 160 kDa, 140 kDa, 27 kDa and 18 kDa. Chelation of Ca by EDTA increases susceptibility of the molecule to proteolysis. Under the conditions used a cryptic thrombin-cleavage site, not hitherto observed in platelet thrombospondin, was observed in EC thrombospondin. The location of this site is near a chymotrypsin-susceptible site, which has been observed in the long connecting arm, which is particularly Ca-stabilized. Heparin-binding capacity of EC thrombospondin was observed in at least two separate loci. Both thrombin and chymotrypsin produced small fragments (35 kDa and 27 kDa respectively) which bound to heparin with high affinity, and large fragments (160 kDa for thrombin and 140 kDa for chymotrypsin) which had low affinity. Chelation of Ca substantially decreased the low-affinity binding of the large fragments but not the high-affinity binding of the small fragments. Two-dimensional gel electrophoresis of the chymotryptic heparin-binding fragments shows that each molecule gave rise to a heterogeneous array of fragments of high molecular mass bound by disulfide bonds, indicating that there is a difference in the rate of cleavage between the three subunits of EC thrombospondin. Trypsin, despite its limited degradation, completely eliminated the heparin-binding capacity of both high and low-affinity loci, in contrast to platelet thrombospondin where the high affinity remains intact.(ABSTRACT TRUNCATED AT 400 WORDS)
An essential Saccharomyces cerevisiae gene homologous to SNF2 encodes a helicase-related protein in a new family. (1992)

The Saccharomyces cerevisiae SNF2 gene affects the expression of many diversely regulated genes and has been implicated in transcriptional activation. We report here the cloning and characterization of STH1, a gene that is homologous to SNF2. STH1 is essential for mitotic growth and is functionally distinct from SNF2. A bifunctional STH1-beta-galactosidase protein is located in the nucleus. The predicted 155,914-Da STH1 protein is 72% identical to SNF2 over 661 amino acids and 46% identical over another stretch of 66 amino acids. Both STH1 and SNF2 contain a putative nucleoside triphosphate-binding site and sequences resembling the consensus helicase motifs. The large region of homology shared by STH1 and SNF2 is conserved among other eukaryotic proteins, and STH1 and SNF2 appear to define a novel family of proteins related to helicases.
Random association between the peptide repertoire of A2.1 class I and several different DR class II molecules (1991)

The interaction between synthetic peptides and A2.1 class I MHC molecules has been investigated using an inhibition of Ag presentation assay and unbiased peptide sets derived of either viral or eucaryotic origin. For the various sets, strong binding (defined as significant inhibition at the 30 micrograms/ml level) was detected in 7 to 46% of the peptides tested, with an overall frequency of 26%. A set of self-peptides derived from human beta 2 microglobulin was also included in the study. In this case, strong binding was detected in 3 of 15 peptides (20%), thus formally demonstrating a lack of self-/non-self-discrimination at the level of class I molecules. When the whole A2.1-binding database of 105 peptides thus generated was examined by sequence analysis, a significant correlation was found with a recently proposed A2.1-binding motif, whereas no particular positive or negative association was detected between the capacity to bind A2.1 and three different class II alleles (DR1, DR5, and DR7). Finally, using this approach, several peptides capable of binding both A2.1 and multiple DR alleles have been identified, suggesting possible candidates for development of peptide vaccines eliciting both class I and class II restricted responses.
Operator placement for in-network stream query processing (2005)

In sensor networks, data acquisition frequently takes place at low-capability devices. The acquired data is then transmitted through a hierarchy of nodes having progressively increasing network band-width and computational power. We consider the problem of executing queries over these data streams, posed at the root of the hierarchy. To minimize data transmission, it is desirable to perform "in-network" query processing: do some part of the work at intermediate nodes as the data travels to the root. Most previous work on in-network query processing has focused on aggregation and inexpensive filters. In this paper, we address in-network processing for queries involving possibly expensive conjunctive filters, and joins. We consider the problem of placing operators along the nodes of the hierarchy so that the overall cost of computation and data transmission is minimized. We show that the problem is tractable, give an optimal algorithm, and demonstrate that a simpler greedy operator placement algorithm can fail to find the optimal solution. Finally we define a number of interesting variations of the basic operator placement problem and demonstrate their hardness.
IICAB: A Little Known International Resource at ISU (1999)

It may not surprise you to hear that Ames, Iowa, is well known across the United States as a center of veterinary knowledge. It may surprise you, however, to learn that Ames, Iowa, is even better known outside the United States for its animal health expertise. This is due, in part, to the work of the Institute for International Cooperation in Animal Biologics (IICAB). What,you may ask, is IICAB?
Advanced computer architecture: parallelism, scalability, programmability (1993)

From the Publisher:
This book deals with advanced computer architecture and parallel programming techniques. The material is suitable for use as a textbook in a one-semester graduate or senior course,offered by Computer Science,Computer Engineering,Electrical Engineering,or Industrial Engineering programs.
Translating Human Embryonic Stem Cells from 2-Dimensional to 3-Dimensional Cultures in a Defined Medium on Laminin- and Vitronectin-Coated Surfaces (2011)

While defining the environment for human embryonic stem cell (hESC) culture on 2-dimensional (2D) surfaces has made rapid progress, the industrial-scale implementation of this technology will benefit from translating this knowledge into a 3-dimensional (3D) system, thus enabling better control, automation, and volumetric scale-up in bioreactors. The current study describes a system with defined conditions that are capable of supporting the long-term 2D culture of hESCs and the transposing of these conditions to 3D microcarrier (MC) cultures. Vitronectin (VN) and laminin (LN) were chosen as matrices for the long-term propagation of hESCs in a defined culture medium (STEMPRO(®)) for conventional 2D culture. Adsorption of these proteins onto 2D tissue culture polystyrene (TCPS) indicated that surface density saturation of 510 and 850 ng/cm(2) for VN and LN, respectively, was attained above 20 μg/mL deposition solution concentration. Adsorption of these proteins onto spherical (97±10 μm), polystyrene MC followed a similar trend and coating surface densities of 450 and 650 ng/cm(2) for VN and LN, respectively, were used to support hESC propagation. The long-term expansion of hESCs was equally successful on TCPS and MC, with consistently high expression (>90%) of pluripotent markers (OCT-4, MAB-84, and TRA-1-60) over 20 passages and maintenance of karyotypic normality. The average fold increase in cell numbers on VN-coated MC per serial passage was 8.5±1.0, which was similar to LN-coated MC (8.5±0.9). Embryoid body differentiation assays and teratoma formation confirmed that hESCs retained the ability to differentiate into lineages of all 3 germ layers, thus demonstrating the first translation to a fully defined MC-based environment for the expansion of hESCs.
Concomitant External-beam Irradiation and Chemotherapy Followed by High-dose Rate Brachytherapy Boost in the Treatment of Squamous Cell Carcinoma of the Vagina: A Single-Center Retrospective Study. (2016)

Concomitant EBRT and chemotherapy followed by BT is the best treatment for vaginal carcinoma.
A Method for Obtaining and Analyzing Sensitivity Data (1948)

Abstract The standard method of dealing with sensitivity of dosage-mortality data is the probit technique developed by Bliss and Fisher. This paper provides an alternative technique based on a special system for obtaining such data. It has some advantages when observations must be taken on individuals rather than groups of individuals, and it may be preferred in certain other situations.
Role of Metal Ions in the T- To R-Allosteric Transition in the Insulin Hexamer (1999)

The role of metal ions in the T- to R-allosteric transition is ascertained from the investigation of the T- to R-allosteric transition of transition metal ions substituted-insulin hexamers, as well as from the kinetics of their dissociation. These studies establish that ligand field stabilization energy (LFSE), coordination geometry preference, and the Lewis acidity of the metal ion in the zinc sites modulate the T- to R-state transition. (1)H NMR, (113)Cd NMR, and UV-vis measurements demonstrate that, under suitable conditions, Fe2+/3+, Ni2+, and Cd2+ bind insulin to form stable hexamers, which are allosteric species. (1)H NMR R-state signatures are elicited by addition of phenol alone in the case of Ni(II)- and Cd(II)-substituted insulin hexamers. The Fe(II)-substituted insulin hexamer is converted to the ferric analogue upon addition of phenol. For the Fe(III)-substituted insulin hexamer, appearance of (1)H NMR R-state signatures requires, additionally to phenol, ligands containing a nitrogen that can donate a lone pair of electrons. This is consistent with stabilization of the R-state by heterotropic interactions between the phenol-binding pocket and ligand binding to Fe(III) in the zinc site. UV-vis measurements indicate that the (1)H NMR detected changes in the conformation of the Fe(III)-insulin hexamer are accompanied by a change in the electronic structure of the iron site. Kinetic measurements of the dissociation of the hexamers provide evidence for the modulation of the stability of the hexamer by ligand field stabilization effects. These kinetic studies also demonstrate that the T- to R-state transition in the insulin hexamer is governed by coordination geometry preference of the metal ion in the zinc site and the compatibility between Lewis acidity of the metal ion in the zinc site and the Lewis basicity of the exogenous ligands. Evidence for the alteration of the calcium site has been obtained from (113)Cd NMR measurements. This finding adds to the number of known conformational changes that occur during the T- to R-transition and is an important consideration in the formulation of allosteric mechanisms of the insulin hexamer.
Pantropic retroviral vectors integrate and express in cells of the malaria mosquito, Anopheles gambiae. (1996)

The lack of efficient mechanisms for stable genetic transformation of medically important insects, such as anopheline mosquitoes, is the single most important impediment to progress in identifying novel control strategies. Currently available techniques for foreign gene expression in insect cells in culture lack the benefit of stable inheritance conferred by integration. To overcome this problem, a new class of pantropic retroviral vectors has been developed in which the amphotropic envelope is completely replaced by the G glycoprotein of vesicular stomatitis virus. The broadened host cell range of these particles allowed successful entry, integration, and expression of heterologous genes in cultured cells of Anopheles gambiae, the principle mosquito vector responsible for the transmission of over 100 million cases of malaria each year. Mosquito cells in culture infected with a pantropic vector expressing hygromycin phosphotransferase from the Drosophila hsp70 promoter were resistant to the antibiotic hygromycin B. Integrated provirus was detected in infected mosquito cell clones grown in selective media. Thus, pantropic retroviral vectors hold promise as a transformation system for mosquitoes in vivo.
Modeling of 5′ Nuclease Real-Time Responses for Optimization of a High-Throughput Enrichment PCR Procedure for Salmonella enterica (2002)

The performance of a 5' nuclease real-time PCR assay was studied to optimize an automated method of detection of preenriched Salmonella enterica cells in buffered peptone water (BPW). The concentrations and interactions of the PCR reagents were evaluated on the basis of two detection responses, the threshold cycle (C(T)) and the fluorescence intensity by a normalized reporter value (DeltaR(n)). The C(T) response was identified as the most suitable for detection modeling to describe the PCR performances of different samples. DNA extracted from S. enterica serovar Enteritidis was studied in double-distilled H2O (ddH2O) and in two different enrichment media (brain heart infusion and BPW) with two PCR mixtures based on AmpliTaq Gold or rTTH: A descriptive model was proposed and fitted to the available experimental data. Equivalent PCR performances for the two PCR mixtures were obtained when DNA was diluted in ddH2O. However, the level of detection of DNA was affected when BPW was present during amplification. Use of the rTth mixture generated a 1-log-unit wider linear range of amplification, and the DNA detection levels were 2 x 10(-13) g/microwell for the rTth mixture and 2 x 10(-12) g/microwell for the AmpliTaq Gold mixture. To verify the improved amplification capacity of the rTth mixture, BPW was inoculated with 1 CFU of S. enterica serovar Enteritidis per ml and the mixture was incubated at 30 degrees C. Samples for PCR were withdrawn every 4 h during a 36-h enrichment. Use of the rTth mixture resulted in an earlier PCR detection during enrichment than use of the AmpliTaq Gold mixture. For accurate detection (C(T) < or = 30) of S. enterica serovar Enteritidis inoculated in BPW, the rTth mixture required 8.4 h of enrichment, while the AmpliTaq Gold mixture needed 11.6 h. In conclusion, the principle applied can improve the methodology of 5' nuclease real-time PCR for numerical optimization of sample pretreatment strategies to provide automated diagnostic PCR procedures.
INHIBITORS OF HIV-1 PROTEASE: A Major Success of Structure-Assisted Drug Design (1998)

Retroviral protease (PR) from the human immunodeficiency virus type 1 (HIV-1) was identified over a decade ago as a potential target for structure-based drug design. This effort was very successful. Four drugs are already approved, and others are undergoing clinical trials. The techniques utilized in this remarkable example of structure-assisted drug design included crystallography, NMR, computational studies, and advanced chemical synthesis. The development of these drugs is discussed in detail. Other approaches to designing HIV-1 PR inhibitors, based on the concepts of symmetry and on the replacement of a water molecule that had been found tetrahedrally coordinated between the enzyme and the inhibitors, are also discussed. The emergence of drug-induced mutations of HIV-1 PR leads to rapid loss of potency of the existing drugs and to the need to continue the development process. The structural basis of drug resistance and the ways of overcoming this phenomenon are mentioned.
Methodologies for Cross-Domain Data Fusion: An Overview (2015)

Traditional data mining usually deals with data from a single domain. In the big data era, we face a diversity of datasets from different sources in different domains. These datasets consist of multiple modalities, each of which has a different representation, distribution, scale, and density. How to unlock the power of knowledge from multiple disparate (but potentially connected) datasets is paramount in big data research, essentially distinguishing big data from traditional data mining tasks. This calls for advanced techniques that can fuse knowledge from various datasets organically in a machine learning and data mining task. This paper summarizes the data fusion methodologies, classifying them into three categories: stage-based, feature level-based, and semantic meaning-based data fusion methods. The last category of data fusion methods is further divided into four groups: multi-view learning-based, similarity-based, probabilistic dependency-based, and transfer learning-based methods. These methods focus on knowledge fusion rather than schema mapping and data merging, significantly distinguishing between cross-domain data fusion and traditional data fusion studied in the database community. This paper does not only introduce high-level principles of each category of methods, but also give examples in which these techniques are used to handle real big data problems. In addition, this paper positions existing works in a framework, exploring the relationship and difference between different data fusion methods. This paper will help a wide range of communities find a solution for data fusion in big data projects.
Exploring the Prospects for a Nanometer-scale Gene Chip (2006)

We are exploring the feasibility of sequencing a single molecule of DNA using a revolutionary type of silicon integrated circuit that incorporates an on-chip nanopore mechanism with a molecular trap. The essential component is a single, nanometer-diameter pore in a robust, nanometer-thick membrane formed from a metal oxide semiconductor (MOS) capacitor. To sequence the molecule, the voltage induced by the dipole moment associated with each base is measured using the electrodes on the capacitor as the DNA translocates through the pore
Elevated serum-circulating RNA in patients with conventional renal cell cancer. (2008)

The data suggest that elevated circulating RNA may be a valuable diagnostic tool for discriminating conventional RCC patients from normal individuals or from these with renal oncocytoma. Elevated serum circulating RNA provides a new research area as biomarker for the diagnosis of conventional RCC.
Growth and recession of aquatic macrophytes on a shaded section of the River Lambourn, England, from 1971 to 1980 (1982)

SUMMARY. The growth and recession of macrophytes on a shaded section of the R. Lambourn were documented by a mapping procedure. With the exception of Ranunculus spp., the changes in total cover did not indicate directly the pattern of growth and recession of the macrophyles. Analysis of gross changes, expressed as gains and losses on cover, indicated that colonization of gravel and silt by the dominant macrophyte, Berula erecta , did not vary seasonally. Colonization was at a constant rate of about 8% of the site each month throughout the year and this accounted for 50% of the total number of gains by Berula. Gains of Berula from Ranunculus showed an annual cycle with a maximum during the summer when Ranunculus was in recession. Gains of Berula from Callitriche spp. also varied annually but the maximum was during the autumn. Total losses of Berula were at a constant rate throughout the year but were to gravel and silt during the winter, to Ranunculus in spring and early summer and to Callitriche in late summer and autumn. Analysis of loss of Berula with time indicated that the position of the Berula carpet was constantly changing. The growth and recession of Berula could not be linked in a meaningful way to environmental variables. Callitriche and Ranunculus both showed an annual pattern of growth and recession. There was temporal separation of the two macrophytes with Ranunculus growing mainly in spring and early summer and Callitriche showing maximum growth in late summer and autumn, and some evidence of spatial separation. The observed differences between years in the growth of Callitriche could not be attributed to any of the environmental variables measured. Discharge was thought to be an important variable controlling the growth of Ranunculus since increase of Ranunculus in the spring was positively correlated with the mean discharge at that time. In years when discharge was low, the growth of Rununculus appeared to be restricted by shading from epiphytic algae which accumulated on the plant surfaces under these conditions.