gebhart/patrepeval huggingface dataset:
Effects of a Novel Glycogen Synthase Kinase-3 Inhibitor on Insulin-Stimulated Glucose Metabolism in Zucker Diabetic Fatty (fa/fa) Rats (2002)

Defects in liver and muscle glycogen synthesis are major factors contributing to postprandrial hyperglycemia in patients with type 2 diabetes. Therefore, activation of glycogen synthase through inhibition of glycogen synthase kinase (GSK)-3 represents a potential new therapeutic target. To examine this possibility, we performed oral glucose tolerance tests (OGTTs) and euglycemic-insulinemic clamp studies in Zucker diabetic fatty (fa/fa) rats before and after treatment with novel GSK-3 inhibitors. GSK-3 inhibition caused a 41 +/- 2% (P < 0.001) and 26 +/- 4% (P < 0.05) reduction in the area under the glucose and insulin concentration curves, respectively, during the OGTT. This improvement in glucose disposal could mostly be attributed to an approximate twofold increase in liver glycogen synthesis. In contrast, there was no significant increase in muscle glycogen synthesis despite an approximate threefold activation of muscle glycogen synthase activity. GSK-3 inhibitor treatment increased liver glycogen synthesis about threefold independent of insulin concentration during the clamp studies. In contrast, muscle glucose uptake and muscle glycogen synthesis were independent of drug treatment. GSK-3 inhibitor treatment lowered fasting hyperglycemia in diabetic rats by 6.0 +/- 1.3 mmol/l but had no significant effect on glucose disposal during the clamp. In conclusion, GSK-3 inhibition significantly improved oral glucose disposal, mostly by increasing liver glycogen synthesis. These studies suggest that GSK-3 inhibition may represent an important new therapeutic target for treatment of patients with type 2 diabetes.
Changes in the Fine Specificity of gp100(209–217)-Reactive T Cells in Patients Following Vaccination with a Peptide Modified at an HLA-A2.1 Anchor Residue (1999)

In a recent clinical trial, HLA-A2+ melanoma patients were vaccinated with a peptide derived from the melanoma Ag gp100, which had been modified at the second position (g9-209 2M) to enhance MHC binding affinity. Vaccination led to a significant increase in lymphocyte precursors in 10 of 11 patients but did not result in objective cancer responses. We observed that some postvaccination PBMC cultures were less reactive with tumor cells than they were with g9-209 peptide-pulsed T2 cells. In contrast, g9-209-reactive tumor-infiltrating lymphocyte cultures generally reacted equally with tumor cells and g9-209 peptide-pulsed T2 cells. To investigate this difference in T cell reactivity, T cell cloids derived from the PBMC of three patients vaccinated with g9-209 2M were compared with T cell cloids isolated from g9-209-reactive TIL cultures. All of the T cell cloids obtained from TIL reacted with HLA-A2+, gp100+ melanoma cell lines as well as with g9-209 and g9-209 2M peptide-pulsed targets. In contrast, only 3 of 20 PBMC-derived T cell cloids reacted with melanoma cell lines in addition to g9-209 and to g9-209 2M peptide-pulsed targets. Twelve of twenty PBMC-derived cloids reacted with g9-209 and g9-209 2M peptide-pulsed targets but not with melanoma cell lines. And 5 of 20 PBMC-derived cloids recognized only the g9-209 2M-modified peptide-pulsed targets. These results suggest that immunizing patients with the modified peptide affected the T cell repertoire by expanding an array of T cells with different fine specificities, only some of which recognized melanoma cells.
Mouse C-reactive protein. Generation of cDNA clones, structural analysis, and induction of mRNA during inflammation (1990)

A full-length C-reactive protein (CRP) cDNA clone has been isolated from a CBA/J-strain-mouse acute-phase liver library. The 1614-nucleotide cDNA specifies mRNA 5' and 3' untranslated regions of 81 and 858 bases respectively that flank 675 bases encoding mouse pre-CRP. The derived amino acid sequence predicts a 19-residue leader peptide followed by a 206-residue mature mouse CRP that shows considerable sequence identity with both human and rabbit CRP. Northern-blot analysis of mouse liver CRP mRNA concentrations after inflammatory stimuli and comparison with hepatic induction of mRNA for the major mouse acute-phase protein serum amyloid P component established that CRP, a major acute-phase reactant in human and rabbit, is a minor acute-phase reactant in mouse. The size and organization of the mouse CRP mRNA 5' and 3' untranslated regions are significantly different from those of human and rabbit CRP mRNA and may have implications for its anomalous minimal induction during acute inflammation.
Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis # † (2009)

A growing body of literature suggests that a deterioration in fatty acid oxidation and VLDL secretion from the liver, caused by the impediment of VLDL synthesis, might induce serious lipid oxidation and DNA oxidative damage, impacting the degree of liver injury and thereby contributing to the progression of NASH. Therefore, dysfunctional VLDL synthesis and release may be a key factor in progression to NASH.
A Comparative Study of the Initial Stability of Cementless Hip Prostheses (1989)

In the process of prosthetic loosening, the initial motion of the implant relative to the bone is a key element. In order to provide quantitative information, three straight and one curved cementless hip stems were submitted to in vitro tests in autopsy specimens of the femur under dynamic axial and torsional loads with the displacements measured in several directions. The results were compared to those of an additional group of cemented straight stem prostheses providing reference values. Subsidence of cementless implants on the average was significantly higher than the cemented reference, but single implants were comparable to the reference. Rotational motion was distinctly higher than the reference values, with considerable differences between designs. When comparing displacements perpendicular to the main load direction, the sagittal plane motion was found to be at least double the motion in the frontal plane. Micromotions at the prosthesis/bone interfaces under the load case selected were smallest for the curved and highest for one of the straight prostheses.
Design and applications of optical microsphere resonators (2003)

Microscopic spherical silica particles, as small as 0.1 mm in diameter, can function as optical whispering-gallery-mode resonators supporting Q-values of 108 and beyond. Such enormously high quality factors represent unique performance characteristics: an extremely narrow resonant linewidth, long decay time and a high energy density. Envisioned uses for these miniature high-Q resonators include, for example, cavity-QED experimentation, detection and sensing, frequency stabilization, and optical filtering functions.\n\nUntil recently, the primary obstacle discouraging applications-oriented development of microsphere resonators has been the fundamental novelty of the various fabrication and handling processes involved – especially in the construction of the advanced optical couplers necessary for efficient sphere mode excitation. In this thesis, novel coupler designs and fabrication methods are presented. New microsphere resonator applications are demonstrated as well, including a narrow-band wavelength-drop device and an acceleration sensor. The most important invention is the antiresonant waveguide coupler, SPARROW, which allows inexpensive and consistent wafer-based fabrication of very efficient microsphere coupling tools.
Identifying and Characterizing Binding Sites and Assessing Druggability (2009)

Identification and characterization of binding sites is key in the process of structure-based drug design. In some cases there may not be any information about the binding site for a target of interest. In other cases, a putative binding site has been identified by computational or experimental means, but the druggability of the target is not known. Even when a site for a given target is known, it may be desirable to find additional sites whose targeting could produce a desired biological response. A new program, called SiteMap, is presented for identifying and analyzing binding sites and for predicting target druggability. In a large-scale validation, SiteMap correctly identifies the known binding site as the top-ranked site in 86% of the cases, with best results (>98%) coming for sites that bind ligands with subnanomolar affinity. In addition, a modified version of the score employed for binding-site identification allows SiteMap to accurately classify the druggability of proteins as measured by their ability to bind passively absorbed small molecules tightly. In characterizing binding sites, SiteMap provides quantitative and graphical information that can help guide efforts to critically assess virtual hits in a lead-discovery application or to modify ligand structure to enhance potency or improve physical properties in a lead-optimization context.
Concentrations of Blood Vitamin A, C, E, Coenzyme Q10 and Urine Cotinine Related to Cigarette Smoking Exposure (2009)

This study shows that smokers had significantly lower vitamin C levels among nonenzymatic antioxidants, namely, vitamin A, C, E and coenzyme Q10. High detection rate of urine cotinine in nonsmokers show the seriousness of passive smoking exposure, therefore more social efforts should be directed to reduce passive smoking exposure.
Animal Models of Type 2 Diabetes: Clinical Presentation and Pathophysiological Relevance to the Human Condition (2006)

The prevalence of diabetes throughout the world has increased dramatically over the recent past, and the trend will continue for the foreseeable future. One of the major concerns associated with diabetes relates to the development of micro- and macrovascular complications, which contribute greatly to the morbidity and mortality associated with the disease. Progression of the disease from prediabetic state to overt diabetes and the development of complications occur over many years. Assessment of interventions designed to delay or prevent disease progression or complications in humans also takes years and requires tremendous resources. To better study both the pathogenesis and potential therapeutic agents, appropriate animal models of type 2 diabetes (T2D) mellitus are needed. However, for an animal model to have relevance to the study of diabetes, either the characteristics of the animal model should mirror the pathophysiology and natural history of diabetes or the model should develop complications of diabetes with an etiology similar to that of the human condition. There appears to be no single animal model that encompasses all of these characteristics, but there are many that provide very similar characteristics in one or more aspects of T2D in humans. Use of the appropriate animal model based on these similarities can provide much needed data on pathophysiological mechanisms operative in human T2D.
Pharmacophore Development and Application Toward the Identification of Novel, Small-Molecule Autotaxin Inhibitors (2010)

Autotaxin (ATX) is a secreted glycoprotein with lysophospholipase D (LPLD) activity that generates the bioactive lipid lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been linked to the promotion and progression of cancer as well as cardiovascular disease and obesity. Despite the fact that ATX inhibitors have the potential to be useful chemotherapeutics for multiple indications, few examples of potent ATX inhibitors are described in the current literature. Here we describe the development of pharmacophore models for the inhibition of ATX by nonlipids and apply these tools to the discovery of additional ATX inhibitors using the NCI open chemical repository database. From this database of > 250,000 compounds, 168 candidate inhibitors were identified. Of these candidates, 106 were available for testing and 33 were identified as active (those that inhibited ATX activity by > or =50% at a single 10 microM concentration), a 31% hit rate. Five of these compounds had IC(50) < 1.5 microM and the most potent compound possessed a K(i) of 271 nM.
Tetrakis(trimethysilyl)hypophosphate P2O2(OTMS)4: Synthesis, reactivity and application as flame retardant (2007)

Abstract The preparation of tetrakis(trimethy‐ silyl)hypophosphate, P 2 O 2 (OTMS) 4 (TMS = SiMe 3 ), which is easily obtained from cheap starting materials, is reported. Reaction with protic substrates (H 2 O, alcohols) proceeds under stepwise cleavage of silylethers, ROTMS, and formation of hypophosphoric acid, P 2 O 2 (OH) 4 . Amines in the presence of molecular sieves lead to desilylation and formation of ammonium salts of the [P 2 O 2 (OTMS) 2 (O − ) 2 ] dianion. On cotton fabrics, P 2 O 2 (OTMS) 4 hydrolyzes to give P 2 O 2 (OH) 4 within about 1 h when exposed to air, and this compound acts as an efficient flame retardant (limiting oxygen index &gt;26%) even at low loadings (P content &lt;3%). © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:721–731, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20373
Influence of molecular size on tissue distribution of antibody fragments (2015)

Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be ~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues.
Genes and Transposons Are Differentially Methylated in Plants, but Not in Mammals (2003)

DNA methylation is found in many eukaryotes, but its function is still controversial. We have studied the methylation of plant and animal genomes using a PCR-based technique amenable for high throughput. Repetitive elements are methylated in both organisms, but whereas most mammalian exons are methylated, plant exons are not. Thus, targeting of methylation specifically to transposons appears to be restricted to plants. We propose that the mechanistic basis of this difference may involve RNA interference. Sequencing strategies that depend on differential methylation are predicted to have different outcomes in plant and mammalian genomes.
Study of Highly Constitutively Active Mutants Suggests How cAMP Activates cAMP Receptor Protein (2005)

The cAMP receptor protein (CRP) of Escherichia coli undergoes a conformational change in response to cAMP binding that allows it to bind specific DNA sequences. Using an in vivo screening method following the simultaneous randomization of the codons at positions 127 and 128 (two C-helix residues of the protein interacting with cAMP), we have isolated a series of novel constitutively active CRP variants. Sequence analysis showed that this group of variants commonly possesses leucine or methionine at position 127 with a beta-branched amino acid at position 128. One specific variant, T127L/S128I CRP, showed extremely high cAMP-independent DNA binding affinity comparable with that of cAMP-bound wild-type CRP. Further biochemical analysis of this variant and others revealed that Leu(127) and Ile(128) have different roles in stabilizing the active conformation of CRP in the absence of cAMP. Leu(127) contributes to an improved leucine zipper at the dimer interface, leading to an altered intersubunit interaction in the C-helix region. In contrast, Ile(128) stabilizes the proper position of the beta4/beta5 loop by functionally communicating with Leu(61). By analogy, the results suggest two direct local effects of cAMP binding in the course of activating wild-type CRP: (i) C-helix repositioning through direct interaction with Thr(127) and Ser(128) and (ii) the concomitant reorientation of the beta4/beta5 loop. Finally, we also report that elevated expression of T127L/S128I CRP markedly perturbed E. coli growth even in the absence of cAMP, which suggests why comparably active variants have not been described previously.
Endothelial cell–Matrix interactions (2002)

Dynamic interactions between endothelial cells and components of their surrounding extracellular matrix are necessary for the invasion, migration, and survival of endothelial cells during angiogenesis. These interactions are mediated by matrix receptors that initiate intracellular signaling cascades in response to binding to specific extracellular matrix molecules. The interactions between endothelial cells and their environment are also modulated by enzymes that degrade different matrix components and thus enable endothelial invasion. Recent reports on gene targeting in mice have confirmed the role of two classes of matrix receptors, integrins and cell surface heparan sulfate proteoglycans, and a group of matrix degrading proteolytic enzymes, matrix metalloproteinases, in angiogenesis. The significance of endothelial cell-matrix interactions is further supported by several ongoing clinical trials that analyze the effects of drugs blocking this interaction on angiogenesis-dependent growth of human tumors.
Thromboxane A2 and Prostacyclin Generation in the Microvasculature of Patients with Atherosclerosis – Effect of Low-Dose Aspirin (1989)

Generation of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a greater than 90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PGF1 alpha levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples. We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.
Multidimensional Access Methods (1996)

Search operations in databases require special support at the physical level. This is true for conventional databases as well as spatial databases, where typical search operations include the point query (find all objects that contain a given search point) and the region query (find all objects that overlap a given search region). More than
Practical Aspects of Hyaluronan Based Medical Products (2005)

The ballooning body of research devoted to hyaluronan (HA) reflects its enormous potential for various medical applications. There have been many successes of varying degrees in the development of medical products based on HA, but also some setbacks. While there is obviously ample information available on the chemistry and various properties of thi
Overview of battery power regulation and storage (1991)

Battery energy systems are an electric utility technology whose applications are not yet fully demonstrated. The applications and benefits achieved by existing and planned facilities, and those that are possible, are discussed. The performance of existing facilities and the benefits predicted by models show that battery energy systems can be an economically attractive addition to the equipment now used to generate and transmit electric power.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
GlycoProtein biosynthesis in yeast. protein conformation affects processing of high mannose oligosaccharides on carboxypeptidase Y and invertase. (1983)

Carboxypeptidase Y and invertase from baker's yeast, Saccharomyces cerevisiae, have two classes of Nlinked high mannose oligosaccharides which may be distinguished on the basis of their susceptibility to hydrolysis by endo-8-N-acetylglucosaminidase H (Endo H).Thus, three of the four oligosaccharides on carboxypeptidase Y and seven of nine of those on invertase are readily released by Endo H when these proteins are in their native state (accessible), while the fourth chain on carboxypeptidase Y and the remaining two on invertase are hydrolyzed by Endo H only when these proteins are denatured (inaccessible).Analysis of the three accessible oligosaccharides from carboxypeptidase Y revealed these to be mostly Manll_lnGlcNAc in size and to account for 80% of the mannose and essentially all of the phosphate associated with this enzyme.By contrast, the fourth chain from carboxypeptidase Y ranged in size from Man8-lzGlcNAc and contained no phosphate.Comparison of peptide maps with the primary sequence of carboxypeptidase Y (Svendsen, I., Martin, B. M., Viswanatha, T., and Johansen, J. T. (1982) Carlsberg Res.Cornnun 47, 15-27) allowed assignment of the resistant fourth oligosaccharide to the N-glycosylation sequon located at Asn8.l.A similar analysis of the accessible oligosaccharide pool from invertase showed that all of the phosphate and over 85% of the mannose was in species larger than ManzoGlcNAc, but the oligosaccharides released after denaturation ranged in size from Man8-12GlcNAc and were devoid of phosphate.The smaller size and lack of peripheral modification found on the oligosaccharides that are initially resistant to Endo H is most easily explained by the hypothesis that as carboxypeptidase Y and invertase fold into their mature configuration, certain glycosylated domains become inaccessible to the mannosyl transferases which catalyze chain extension and phosphomannose addition.The acquisition of carbohydrate by all eucaryotic organisms, including yeast, starts with transfer of the oligosaccharide from the common biosynthetic intermediate, Glcs-MansGlcNAcz-P-P-Doll, and culminates in mature N-linked glycans via a multistep processing pathway with the most