gebhart/patrepeval huggingface dataset:
Design and synthesis of glucagon partial agonists and antagonists (1986)

The hyperglycemia and ketosis of diabetes mellitus are generally associated with elevated levels of glucagon in the blood. This suggests that glucagon is a contributing factor in the metabolic abnormalities of diabetes mellitus. A glucagon-receptor antagonist might provide important evidence for glucagons's role in this disease. In this work we describe how we combined structural modifications that led to glucagon analogues with partial agonist activity to give glucagon analogues that can act as competitive antagonists of glucagon-stimulated adenylate cyclase activity. Using solid-phase synthesis methodology and preparative reverse-phase high-performance liquid chromatography, we synthesized the following seven glucagon analogues and obtained them in high purity: [D-Phe4,Tyr5,Arg12]glucagon (2); [D-Phe4,Tyr5,Lys17,18]glucagon (3); [Phe1,Glu3,Lys17,18]glucagon (4); [Glu3,Val5,Lys17,18]glucagon (5); [Asp3,D-Phe4,Ser5,Lys17,18]glucagon (6); I4-[Asp3,D-Phe4,Ser5,Lys17,18]glucagon (7); [Pro3]glucagon (8). Purity was assessed by enzymatic total hydrolysis, by chymotryptic peptide mapping, and by reverse-phase high-performance liquid chromatography. The new analogues were tested for specific binding, for their effect on the adenylate cyclase activity in rat liver membranes, and for their effect on the blood glucose levels in normal rats relative to glucagon. Analogues showing no adenylate cyclase activity were examined for their ability to act as antagonists by displacing glucagon-stimulated adenylate cyclase dose-response curves to the right (higher concentrations). The binding potencies of the new analogues relative to glucagon (= 100) were respectively 1.0 (2), 1.3 (3), 3.8 (4), 0.4 (5), 1.3 (6), 5.3 (7), and 3 (8). Glucagon analogues 3-5 and 8 were all weak partial agonists with EC50 values of 500 (3), 250 (4), 1600 (5), and 395 nM (8), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Molecular Requirements of High-Fidelity Replication-Competent DNA Backbones for Orthogonal Chemical Ligation (2017)

The molecular properties of the phosphodiester backbone that made it the evolutionary choice for the enzymatic replication of genetic information are not well understood. To address this, and to develop new chemical ligation strategies for assembly of biocompatible modified DNA, we have synthesized oligonucleotides containing several structurally and electronically varied artificial linkages. This has yielded a new highly promising ligation method based on amide backbone formation that is chemically orthogonal to CuAAC "click" ligation. A study of kinetics and fidelity of replication through these artificial linkages by primer extension, PCR, and deep sequencing reveals that a subtle interplay between backbone flexibility, steric factors, and ability to hydrogen bond to the polymerase modulates rapid and accurate information decoding. Even minor phosphorothioate modifications can impair the copying process, yet some radical triazole and amide DNA backbones perform surprisingly well, indicating that the phosphate group is not essential. These findings have implications in the field of synthetic biology.
Structure-Based Design of (5-Arylamino-2H-pyrazol-3-yl)-biphenyl-2‘,4‘-diols as Novel and Potent Human CHK1 Inhibitors (2007)

The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.
Calcium-sensing receptor as a potential modulator of vascular calcification in chronic kidney disease (2009)

Secondary hyperparathyroidism plays an important role in the mineral and bone disorders that are associated with cardiovascular events in chronic kidney disease patients. Secondary hyperparathyroidism is partially due to decreased calcium-sensing receptor expression in parathyroid glands in these patients. Calcimimetics have been demonstrated to be particularly useful to control parathyroid hormone (PTH) oversecretion and concomitantly reduce serum Ca2+ and phosphorus levels in dialysis patients. However, recent findings highlight the role of calcium-sensing receptor allosteric coactivators as inhibitors of the development of vascular calcification. Calcimimetics could prevent the vascular calcification process by controlling not only PTH overfunction, hypercalcemia and hyperphosphatemia, but also by directly modulating vascular calcium-sensing receptors. In this review, the authors describe the recently demonstrated role played by calcium-sensing receptor and its modulation by calcimimetics on uremia-induced vascular calcification.
Differential Privacy: An Economic Method for Choosing Epsilon (2014)

Differential privacy is becoming a gold standard notion of privacy; it offers a guaranteed bound on loss of privacy due to release of query results, even under worst-case assumptions. The theory of differential privacy is an active research area, and there are now differentially private algorithms for a wide range of problems. However, the question of when differential privacy works in practice has received relatively little attention. In particular, there is still no rigorous method for choosing the key parameter ε, which controls the crucial tradeoff between the strength of the privacy guarantee and the accuracy of the published results. In this paper, we examine the role of these parameters in concrete applications, identifying the key considerations that must be addressed when choosing specific values. This choice requires balancing the interests of two parties with conflicting objectives: the data analyst, who wishes to learn something abou the data, and the prospective participant, who must decide whether to allow their data to be included in the analysis. We propose a simple model that expresses this balance as formulas over a handful of parameters, and we use our model to choose ε on a series of simple statistical studies. We also explore a surprising insight: in some circumstances, a differentially private study can be more accurate than a non-private study for the same cost, under our model. Finally, we discuss the simplifying assumptions in our model and outline a research agenda for possible refinements.
Cough hypersensitivity as a neuro‐immune interaction (2015)

Cough is an intrinsic protective reflex. However, chronic cough affects a considerable proportion of general population and has a major impact on quality of life. A recent paradigm shift to 'cough hypersensitivity syndrome' suggests that chronic cough arises from hypersensitivity of the airway sensory nerves. As cough reflex is determined by interaction of the nervous system with immune system, persistent dysregulation of one or both of these systems may lead to chronic cough hypersensitivity. Here we review the current evidence for the neuro-immune interactions that underlie cough hypersensitivity and discuss future therapeutic strategies.
Arginine de novo and nitric oxide production in disease states (2012)

Arginine is derived from dietary protein intake, body protein breakdown, or endogenous de novo arginine production. The latter may be linked to the availability of citrulline, which is the immediate precursor of arginine and limiting factor for de novo arginine production. Arginine metabolism is highly compartmentalized due to the expression of the enzymes involved in arginine metabolism in various organs. A small fraction of arginine enters the NO synthase (NOS) pathway. Tetrahydrobiopterin (BH4) is an essential and rate-limiting cofactor for the production of NO. Depletion of BH4 in oxidative-stressed endothelial cells can result in so-called NOS3 "uncoupling," resulting in production of superoxide instead of NO. Moreover, distribution of arginine between intracellular transporters and arginine-converting enzymes, as well as between the arginine-converting and arginine-synthesizing enzymes, determines the metabolic fate of arginine. Alternatively, NO can be derived from conversion of nitrite. Reduced arginine availability stemming from reduced de novo production and elevated arginase activity have been reported in various conditions of acute and chronic stress, which are often characterized by increased NOS2 and reduced NOS3 activity. Cardiovascular and pulmonary disorders such as atherosclerosis, diabetes, hypercholesterolemia, ischemic heart disease, and hypertension are characterized by NOS3 uncoupling. Therapeutic applications to influence (de novo) arginine and NO metabolism aim at increasing substrate availability or at influencing the metabolic fate of specific pathways related to NO bioavailability and prevention of NOS3 uncoupling. These include supplementation of arginine or citrulline, provision of NO donors including inhaled NO and nitrite (sources), NOS3 modulating agents, or the targeting of endogenous NOS inhibitors like asymmetric dimethylarginine.
Invasion of primary nasopharyngeal epithelial cells by Neisseria meningitidis is controlled by phase variation of multiple surface antigens (1996)

We have investigated bacterial factors required for the entry of Neisseria meningitidis serogroup B into mucosal cells using a novel in vitro infection model of primary cultures of human nasopharyngeal epithelium. An invasive meningococcal phenotype was obtained after several cycles of selection for intracellular bacteria with gentamicin. Invasive bacteria differed from those in the initial inoculum in that they lacked a capsule and pili, exhibited a nonsialylated low-molecular-weight type of lipopolysaccharide (LPS), and produced a new 28-kDa opacity outer membrane protein. LPS revertants of the selected meningococci expressed a nonsialylated L3,(7,9) type of LPS and were also invasive, while after LPS sialylation bacterial entry was inhibited. Variants lacking the 28-kDa opacity protein were poorly invasive. Coexpression of the outer membrane protein Opc and the 28-kDa opacity protein strongly inhibited microbial invasion into the primary cultured nasopharyngeal cells. Conversely, meningococcal internalization by cells of various epithelia] cell lines was correlated with the expression of Opc rather than the 28-kDa opacity protein. Our data indicate that a concurrent phase switching of multiple phase-variable bacterial surface components may be a prerequisite for meningococcal invasion into nasopharyngeal epithelium and that meningococcal class 5 proteins (Opa and Opc) may promote tissue tropism.
Synthesis of ninhydrin analogues (1996)

Ninhydrin is an important reagent which has applications not only in biochemistry and chemistry but also in forensic science as a latent fingerprint reagent. Ninhydrin reacts with minute amounts of amino acids present in fingerprint deposits to form the highly colored condensation product called Ruhemann's purple. Post-ninhydrin treatment with metal salts followed by illumination with an appropriate light source causes latent prints to luminesce. To further enhance the utility of this procedure, several ninhydrin analogues have been synthesized and evaluated. The goal of these structural modifications has been optimization of the chromophoric and luminescent properties of the Ruhemann's purple adduct. The "ideal" reagent must be highly sensitive and provide excellent background contrast. It should react to give a colored fingerprint which is also fluorescent without secondary treatment. Previous research has demonstrated that it is difficult to a priori predict which modifications will result in improved performance. The goal of this project was to purposefully design novel ninhydrin analogues with enhanced properties and to develop efficient methodologies for their synthesis. We proposed and carried out syntheses of three types of ninhydrin analogues. The first type consisted of compounds formed by linking two ninhydrin moieties together. These "bisninhydrin" analogues have the potential to form polymeric Ruhemann's purple species. A different class of compounds have the presence of a sulfur atom as the common element and are patterned after similar sulfur-containing analogues which were shown to be highly effective. The third type of analogue relies on the extension of the conjugated system to enhance its properties. A variety of aryl ninhydrins were prepared by a versatile and highly convergent method employing a palladium-catalyzed cross-coupling reaction as the key step. All analogues were evaluated for efficacy by the United States Secret Service. The synthesis of the most promising reagent, 5-(2-thienyl)ninhydrin was optimized. Background information on ninhydrin, fingerprinting, and the synthesis of ninhydrin analogues is presented.
Glucocorticoids Affect Human Dendritic Cell Differentiation and Maturation (1999)

Because dendritic cells (DC) play a major role in the initiation of T cell-mediated immunity, we studied the effects of glucocorticoids, well-known inhibitors of the immune and inflammatory response, on the differentiation and maturation of human DC. DC were differentiated from human monocytes by culture with GM-CSF and IL-4 for 7 days with and without dexamethasone (Dex). Cells treated with Dex (10-8 M) (Dex-DC) developed a characteristic dendritic morphology; however, membrane phenotype analysis demonstrated that they were not fully differentiated. Dex-DC expressed low levels of CD1a and, unlike untreated cells, high levels of CD14 and CD16. Molecules involved in Ag presentation (CD40, CD86, CD54) were also impaired. In contrast, molecules involved in Ag uptake (mannose receptor, CD32) and cell adhesion (CD11/CD18, CD54) were up-regulated. After exposure to TNF-alpha or CD40 ligand, Dex-DC expressed lower levels of CD83 and CD86 than untreated cells. Dex-DC showed a higher endocytic activity, a lower APC function, and a lower capacity to secrete cytokines than untreated cells. Overall, these results indicate that DC differentiated in the presence of Dex are at a more immature stage. Moreover, Dex also partially blocked terminal maturation of already differentiated DC. In conclusion, our data suggest that glucocorticoids may act at the very first step of the immune response by modulating DC differentiation, maturation, and function.
Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson–Gilford progeria syndrome mutation (2005)

Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi2 statistic). These studies suggest a possible treatment strategy for HGPS.
Antiproliferative activity of Chinese medicinal herbs on breast cancer cells in vitro. (2003)

Chinese medicinal herbs are traditionally used to prevent and treat a variety of diseases, including cancer. These herbal preparations are purported to have many biological effects including direct antiproliferative effects on cancer cells, anti-mutagenic activity, and stimulatory or suppressive effects on immune responses. The present study investigates the effects of aqueous extracts from seventy-one Chinese medicinal herbs on the growth of five breast cancer cell lines (SK-BR-3, MCF7, MDA-MB-231, BT-474 and MCNeuA). Twenty-one percent (15 out of 71) of the extracts demonstrated greater than 50% growth inhibition on at least 4 of the 5 cell lines. Dose-response curves were obtained for several of the most potent crude extracts and demonstrated IC50 values ranging from < 10 micrograms/ml to > 1 mg/ml. Six of seven herbs tested induced high molecular weight DNA fragmentation, an early marker of apoptosis, while one of these also induced low molecular weight DNA fragmentation. Flow cytometric analysis of breast cancer cells exposed to one of these herbs (Rheum palmatum) suggested that it arrests cells in the G2/M phase of the cell cycle. These results indicate that many of the herbs used in traditional Chinese medicine for the treatment of cancer have significant growth inhibitory effects on breast cancer cells in vitro.
Formation of type IA fibre Bragg gratings in germanosilicate optical fibre (2004)

A report is made that the rate at which type IA fibre Bragg gratings may be inscribed is related to the intensity of the UV inscription laser and that these gratings may be written in only a few minutes. Also presented is the model of the refractive index of type IA gratings.
Preparation of protease-free and ribonuclease-free pancreatic deoxyribonuclease. (1978)

When pancreatic DNase I is used as a specific biochemical reagent in the preparation of nuclear ribonucleic acids or nuclear proteins, freedom from contaminating ribonucleases or proteases is an important property of the enzyme preparation. A simple one-step procedure has been developed to effect complete removal of trypsin, chymotrypsin, and chymotrypsinogen by a combination of affinity chromatography and salting-out adsorption on lima bean protease inhibitor coupled to Sepharose (a column (0.9 X 60 cm) operated in series with a regeneratable 1-ml bed). Commercial preparations of DNase (about 10 mg) give a quantitative yield of the enzyme that is protease-free as evidenced by full stability for more than 10 days at pH 8 and 37 degrees C even in the absence of the protecting action of Ca2+. Removal of the last traces of RNase has been accomplished by affinity chromatography on a column (0.4 X 72 cm) of 5'-(4-aminophenyl-phosphoryl)-uridine 2'(3')-phosphate-Sepharose; the product is a highly active DNase that gives no detectable hydrolysis of RNA by assay on radioactive substrates.
In Vitro Evaluation of Experimental Agents for Anti‐HIV Activity (1993)

This unit presents an assay that has proven useful as an initial screening test is an HIV cytopathic effect (CPE) inhibition assay in which immortalized T cell lines (e.g., ATH8 or MT2) that are profoundly sensitive to the cytopathic effect of certain strains of HIV are utilized as target cells. Additional protocols assess the anti-HIV activity of certain candidate agents by measuring inhibition of syncytium formation or p24 gag protein production by ELISA. Calculation of the 50% inhibitory concentration (IC(50)) is also presented.
Validation of highly discriminating multiplex short tandem repeat amplification systems for individual identification (1996)

Short tandem repeat (STR) loci are routinely employed for individual identification. WE have examined the performance and reproducibility of a highly informative co-amplification system containing the tetranucleotide STR loci: HUMVWFA31/A, HUMTH01, D20S85, D8S1179, HUMFIBRA, D21S11, and D18S51, in conjunction with the amelogenin sex test, in addition to a modified system omitting the locus D20S85. Polymerase chain reaction (PCR) products were fluorescently detected on an automated sequencer and automatically sized against an internal size standard by Genescan software. Both systems were routinely able to type 500 pg of undegraded DNA. At DNA concentrations between 50-500 pg, partial profiles were produced, but no allelic drop-out was observed. Balanced amplification of all loci occurred over a wide range of DNA concentrations from 50 pg to 10 ng. Alteration of reagent concentrations and cycling parameters from optimal resulted in variation in the efficiency of individual locus amplification relative to the other loci within the system. This was also observed at high ionic strength or extreme pH. However, at all reagent concentrations and conditions, allelic drop-out was not observed. These multiplex systems have potential in both routine forensic and intelligence database applications.
Cytogenetic Analysis by In Situ Hybridization with Fluorescently Labeled Nucleic Acid Probes (1986)

The ability to detect cytogenetic abnormalities has increased as improved methods for chromosome identification have been developed. Banding techniques (Casperson et al. 1968; Yunis 1981) now allow identification of all human chromosomes as well as detection of a broad spectrum of structural and numerical chromosome aberrations. However, banding analysis has important limitations. It requires preparation of high-quality metaphase spreads and the attendant cell culture; it is not easily automated; and it requires time-consuming work by skilled observers. These limitations affect the application of banding analysis in a variety of clinical and experimental settings. Prenatal detection of aberrations is slow and laborious because of the cell culture and scoring process. Quantitative analysis of the frequency of translocated chromosomes for biological dosimetry is also hampered by the lengthy scoring process. Tumor cytogenetic analysis is limited by the difficulty of preparing high-quality metaphase spreads that are representative of the tumorigenic cells in the...
Recovering specular surfaces using curved line images (2009)

We present a new shape-from-distortion framework for recovering specular (reflective/refractive) surfaces. While most existing approaches rely on accurate correspondences between 2D pixels and 3D points, we focus on analyzing the curved images of 3D lines which we call curved line images or CLIs. Our approach models CLIs of local reflections or refractions using the recently proposed general linear cameras (GLCs). We first characterize all possible CLIs in a GLC. We show that a 3D line will appear as a conic in any GLC. For a fixed GLC, the conic type is invariant to the position and orientation of the line and is determined by the GLC parameters. Furthermore, CLIs under single reflection/refraction can only be lines or hyperbolas. Based on our new theory, we develop efficient algorithms to use multiple CLIs to recover the GLC camera parameters. We then apply the curvature-GLC theory to derive the Gaussian and mean curvatures from the GLC intrinsics. This leads to a complete distortion-based reconstruction framework. Unlike conventional correspondence-based approaches that are sensitive to image distortions, our approach benefits from the CLI distortions. Finally, we demonstrate applying our framework for recovering curvature fields on both synthetic and real specular surfaces.