gebhart/patrepeval huggingface dataset:
Structure‐activity relationships for a series of phenylglycine derivatives acting at metabotropic glutamate receptors (mGluRs) (1995)

1. The actions of a series of twelve phenylglycine derivatives at metabotropic glutamate receptors (mGluRs) linked to both phosphoinositide hydrolysis (PI) and cyclic AMP were investigated. 2. PI hydrolysis was determined by the accumulation of [3H]-inositol-monophosphate ([3H]-IP1) in neonatal ral cortical slices prelabelled with [3H]-myo-inositol. The non-selective mGluR agonist (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid ((1S,3R)-ACPD) produced a concentration-dependent increase in [3H]-IP1 (EC50 approximately 20 microM). This agonist was subsequently used to investigate potential antagonist activity of the phenylglycine derivatives. Of the compounds tested (+)-alpha-methyl-4-carboxyphenylglycine (M4CPG) and (RS)-alpha-ethyl-4-carboxyphenylglycine (E4CPG) were the most active with KP values of 0.184 +/- 0.04 mM and 0.367 +/- 0.2 mM respectively. 3. Activity at adenylyl cylase-coupled mGluRs was investigated by determining the accumulation of [3H]-cyclic AMP in adult rat cortical slices. [3H]-cyclic AMP accumulation, elicited by 30 microM forskolin, was inhibited by (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-1) and L-2-amino-4-phosphonobutanoate (L-AP4) with respective EC50 values of 0.3 microM and 10 microM. Neither agonist was able to inhibit completely forskolin stimulated cyclic AMP accumulation; this is evidence that not all adenylyl cyclase is susceptible to modulation by mGluRs. Phenylglycine derivatives were examined for their ability to antagonize the inhibition of [3H]-cyclic AMP accumulation by L-CCG-1 or L-AP4 at their EC50 concentrations. 4. A rank order of potency of the phenylglycine derivatives as antagonists of L-AP4 and L-CCG-1 was obtained. The most effective compound. (RS)-alpha-methyl-3-carboxymethylphenylglycine (M3CMPG) had IC50 values in the order of 1 microM against L-AP4 and 0.4 microM against L-CCG-1. 5. The results from this study indicate that phenylglycine-derived compounds can discriminate between groups of metabotropic glutamate receptors and may also display some selective activity between subtypes within groups. Future work based on these findings may lead to the development of more selective and potent compounds as important pharmacological tools.
Role of carbohydrate in multimeric structure of factor VIII/von Willebrand factor protein. (1983)

The carbohydrate moiety of the factor VIII/von Willebrand (vW) factor protein is important in the expression of vW factor activity and the intravascular survival of the protein. Studies of normal human factor VIII/vW factor protein indicate that there is a requirement of a full complement of penultimate galactose for the maintenance of a normal multimeric structure. Release of penultimate galactose by beta-galactosidase or modification by galactose oxidase results in loss of the largest molecular weight multimers and increased numbers of intermediate and smaller multimers. In contrast, terminal galactose on the factor VIII/vW factor protein does not appear to play a significant role in the maintenance of the multimer organization. The abnormalities in multimeric structure and molecular size were demonstrated by NaDodSO4/polyacrylamide/agarose gel electrophoresis, NaDodSO4/glyoxyl-agarose electrophoresis, and sucrose density ultracentrifugation. These studies indicate that the penultimate galactose plays a role in the maintenance of the largest multimers of the factor VIII/vW factor protein. This may explain why, in some patients with variant forms of vW disease, a carbohydrate abnormality also may affect the multimeric structure of the plasma factor VIII/vW factor protein.
PRECLINICAL EFFICACY EVALUATION OF PROPOSED MEDICATIONS FOR DRUG ABUSE TREATMENT (1992)

1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298–0613 USA and 2National Institute on Drug Abuse, Bethesda, MD 21224 USA
Ligand Control in Enantioselective Desymmetrization of Bicyclic Hydrazines: Rhodium(I)‐Catalyzed Ring‐Opening versus Hydroarylation (2008)

Abstract The efficient desymmetrization of 2,3‐bicyclic hydrazines with boronic acids through rhodium‐catalyzed ring‐opening or reductive arylation is described. Excellent levels of enantioselectivity are achieved in ring‐opening with ortho ‐substituted boronic acids, using Josiphos‐type ligands. Alternatively, reductive arylation occurs selectively with electron‐poor Josiphos and Walphos ligands. A CH activation/1,4‐migration mechanism was established through deuterium transfer experiments.
Applications of swept-frequency acoustic interferometry technique in chemical diagnostics (1996)

Swept-Frequency Acoustic Interferometry (SFAI) is a noninvasive fluid characterization technique currently being developed for chemical weapons treaty verification. The SFAI technique determines sound speed and sound attenuation in a fluid over a wide frequency range completely noninvasively from outside a container (e.g., pipe, tank, reactor vessel, etc.,). These acoustic parameters, along with their frequency-dependence, can be used to identify various chemicals. This technique can be adapted for a range of chemical diagnostic applications, particularly, in process control where monitoring of acoustic properties of chemicals may provide appropriate feedback information. Both experimental data and theoretical modeling are presented. Examples of several novel applications of the SFAI technique are discussed.
Computerized Quantitation of Synergism and Antagonism of Taxol, Topotecan, and Cisplatin Against Human Teratocarcinoma Cell Growth: a Rational Approach to Clinical Protocol Design (1994)

Our findings suggest that, as a result of synergy, the doses of these agents needed to achieve an antitumor effect may be reduced by twofold to eightfold when these agents are given in combination. The present quantitative data analyses for synergism or antagonism provide a basis for a rational design of clinical protocols for combination chemotherapy in patients with advanced germ cell tumors.
TRAIL/Apo-2L: Mechanisms and Clinical Applications in Cancer (2001)

TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) is a member of the TNF family that promotes apoptosis by binding to the transmembrane receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. Its cytotoxic activity is relatively selective to the human tumor cell lines without much effect on the normal cells. Hence, it exerts an antitumor activity without causing toxicity, as apparent by studies with several xenograft models. This review discusses the intracellular mechanisms by which TRAIL induces apoptosis. The major pathway of its action proceeds through the formation of DISC and activation of caspase-8. The apoptotic processes, therefore, follow two signaling pathways, namely the mitochondrial-independent activation of caspase-3, and mitochondrial-dependent apoptosis due to cleavage of BID by caspase-8, the formation of apoptosomes, and activation of caspase-9 and the downstream caspases. Bcl-2 and Bcl-X(L) have no effect on TRAIL-induced apoptosis in lymphoid cells, whereas these genes block or delay apoptosis in nonlymphoid cancer cells. TRAIL participates in cytotoxicity mediated by activated NK cells, monocytes, and some cytotoxic T cells. Hence, TRAIL may prove to be an effective antitumor agent. In addition, it may enhance the effectiveness of treatment with chemotherapeutic drugs and irradiation. Nontagged Apo-2L/TRAIL does not cause hepatotoxicity in monkeys and chimpanzees and in normal human hepatocytes. Thus, nontagged Apo-2L/TRAIL appears to be a promising new candidate for use in the treatment of cancer.
Intravitreal Antimicrobials (2006)

Intravitreal injection of antimicrobials has become the mainstay of treatment of intraocular infections. Once injected into the eye, antibiotics diffuse through the vitreous cavity and are eliminated by either a posterior or an anterior route. Betalactam antibiotics resemble penicillin with the exception of replacement of a five-member thiazolidine ring. Amphotericin B is the most frequently chosen antimicrobial for treatment of intra-ocular fungal infections. Aminoglycosides are semisynthetic analogs of Actinomycetes fungi p roducts. Aminoglycosides have been the most widely studied class of antibiotics for their intraocular toxic potential. Toxicity may be totally unrelated to the therapeutic effect or may be an extension of the drug's pharmacologic properties. Electroretinographic toxicity criteria have also been employed but concurrent controls in which a placebo is injected in the fellow eye simultaneously are important since surgical invasion of the eye alone can reduce the electroretinographic response.
Interleukin 4 Reduces Expression of Inhibitory Receptors on B Cells and Abolishes CD22 and FcγRII-mediated B Cell Suppression (2002)

Inhibitory receptors CD22, Fc gamma RII (CD32), CD72, and paired immunoglobulin-like receptor (PIR)-B are critically involved in negatively regulating the B cell immune response and in preventing autoimmunity. Here we show that interleukin 4 (IL-4) reduces expression of all four on activated B cells at the level of messenger RNA and protein. This reduced expression is dependent on continuous exposure to IL-4 and is mediated through Stat6. Coligation of Fc gamma RII to the B cell receptor (BCR) via intact IgG increases the B cell activation threshold and suppresses antigen presentation. IL-4 completely abolishes these negative regulatory effects of Fc gamma RII. CD22 coligation with the BCR also suppresses activation -- this suppression too is abolished by IL-4. Thus, IL-4 is likely to enhance the B cell immune response by releasing B cells from inhibitory receptor suppression. By this coordinate reduction in expression of inhibitory receptors, and release from CD22 and Fc gamma RII-mediated inhibition, IL-4 is likely to play a role in T cell help of B cells and the development of T helper cell type 2 responses. Conversely, B cell activation in the absence of IL-4 would be more difficult to achieve, contributing to the maintenance of B cell tolerance in the absence of T cell help.
Genetic Evidence for a Normal-Weight “Metabolically Obese” Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes (2014)

The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (β = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (β = 0.021; P = 3 × 10(-4)), higher alanine transaminase (β = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (β = -0.010; P = 9 × 10(-13)), and lower adiponectin (β = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele β = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (β = -0.015; P = 6 × 10(-7)). Individuals carrying ≥17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.
Neuroscience and “real world” practice: music as a therapeutic resource for children in zones of conflict (2012)

Recent developments in music neuroscience are considered a source for reflection on, and evaluation and development of, musical therapeutic practice in the field, in particular, in relation to traumatized children and postconflict societies. Music neuroscience research is related to practice within a broad biopsychosocial framework. Here, examples are detailed of work from North Uganda, Palestine, and South Thailand.
Deep learning can predict microsatellite instability directly from histology in gastrointestinal cancer (2019)

Microsatellite instability determines whether patients with gastrointestinal cancer respond exceptionally well to immunotherapy. However, in clinical practice, not every patient is tested for MSI, because this requires additional genetic or immunohistochemical tests. Here we show that deep residual learning can predict MSI directly from H&E histology, which is ubiquitously available. This approach has the potential to provide immunotherapy to a much broader subset of patients with gastrointestinal cancer.
Non-Peptide RGD Surrogates Which Mimic a Gly-Asp β-Turn:  Potent Antagonists of Platelet Glycoprotein IIb−IIIa (1997)

Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb-IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II' Gly-Asp beta-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb-IIIa.
Cognitive Outcome in Adult Women Affected by Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency (2006)

This study differs from others in the older age of its participants, grouping by SL/SV diagnosis and assessment of medical treatment and compliance as determined through hormone assays. Our findings provide additional support for the conclusion that, in adult women with CAH, previous prenatal androgen exposure does not enhance spatial abilities, impair verbal abilities nor alter hand preferences in a long-lasting way.
Ozonation of Single-Walled Carbon Nanotubes and Their Assemblies on Rigid Self-Assembled Monolayers (2002)

Ozonation of single-walled carbon nanotubes (O3-SWNTs) produces oxygenated functional groups, e.g., carboxylic acid, ester, and quinone moieties, which can be removed from the SWNT surface by heating at 600−800 °C. The annealed SWNTs appear to be pristine. The electrical resistance of the O3-SWNTs depends on the degree of oxidation and is about 20−2000 times higher than that of pristine SWNTs, owing to the deformation of the π-conjugation structure along the tube. The O3-SWNTs are easily dispersed in dimethylformamide (DMF) and show enhanced solubility in other polar solvents such as water and ethanol. The O3-SWNT suspensions consist of individual and shortened tubes due to the separation of nanotube bundles and the shortening that results from oxidation. Toward fabrication of SWNT-based molecular electronic devices, two methods have been used to assemble the O3-SWNTs on functionalized self-assembled monolayers (SAMs) of conjugated oligo(phenylene ethynylene)s. The first, termed “chemical assembly”, is based on a condensation reaction between the carboxylic acid functionalities of O3-SWNTs and the amine functionalities of SAMs to form amides. The results show that O3-SWNTs coat the amino-terminated SAM with a high degree of surface coverage. The second method is based on physical adsorption via layer-by-layer (LBL) deposition with bridging of metal cations, i.e., Fe3+ on carboxylate-terminated SAMs or Cu2+ on thiol-terminated SAMs. The oxidatively shortened O3-SWNTs are shown to be perpendicular to the surface with random adsorption of longer tubes. The patterned nanotube assemblies may be useful in hybridized electronic devices, where device functions can be modified by the orientation and stacking of SWNTs and the properties of the SAM.
Growth of Mycobacteria on Carbon Monoxide and Methanol (2002)

Several mycobacterial strains, such as Mycobacterium flavescens, Mycobacterium gastri, Mycobacterium neoaurum, Mycobacterium parafortuitum, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium smegmatis, Mycobacterium tuberculosis, and Mycobacterium vaccae, were found to grow on carbon monoxide (CO) as the sole source of carbon and energy. These bacteria, except for M. tuberculosis, also utilized methanol as the sole carbon and energy source. A CO dehydrogenase (CO-DH) assay, staining by activity of CO-DH, and Western blot analysis using an antibody raised against CO-DH of Mycobacterium sp. strain JC1 (formerly Acinetobacter sp. strain JC1 [J. W. Cho, H. S. Yim, and Y. M. Kim, Kor. J. Microbiol. 23:1-8, 1985]) revealed that CO-DH is present in extracts of the bacteria prepared from cells grown on CO. Ribulose bisphosphate carboxylase/oxygenase (RubisCO) activity was also detected in extracts prepared from all cells, except M. tuberculosis, grown on CO. The mycobacteria grown on methanol, except for M. gastri, which showed hexulose phosphate synthase activity, did not exhibit activities of classic methanol dehydrogenase, hydroxypyruvate reductase, or hexulose phosphate synthase but exhibited N,N-dimethyl-4-nitrosoaniline-dependent methanol dehydrogenase and RuBisCO activities. Cells grown on methanol were also found to have dihydroxyacetone synthase. Double immunodiffusion revealed that the antigenic sites of CO-DHs, RuBisCOs, and dihydroxyacetone synthases in all mycobacteria tested are identical with those of the Mycobacterium sp. strain JC1 enzymes.
Natural Killer T Cell Activation Inhibits Hepatitis B Virus Replication in Vivo (2000)

We have previously reported that hepatitis B virus (HBV)-specific CD8(+) cytotoxic T lymphocytes and CD4(+) helper T lymphocytes can inhibit HBV replication in the liver of HBV transgenic mice by secreting interferon (IFN)-gamma when they recognize viral antigen. To determine whether an activated innate immune system can also inhibit HBV replication, in this study we activated natural killer T (NKT) cells in the liver of HBV transgenic mice by a single injection of alpha-galactosylceramide (alpha-GalCer), a glycolipid antigen presented to Valpha14(+)NK1.1(+) T cells by the nonclassical major histocompatibility complex class I-like molecule CD1d. Within 24 h of alpha-GalCer injection, IFN-gamma and IFN-alpha/beta were detected in the liver of HBV transgenic mice and HBV replication was abolished. Both of these events were temporally associated with the rapid disappearance of NKT cells from the liver, presumably reflecting activation-induced cell death, and by the recruitment of activated NK cells into the organ. In addition, prior antibody-mediated depletion of CD4(+) and CD8(+) T cells from the mice did not diminish the ability of alpha-GalCer to trigger the disappearance of HBV from the liver, indicating that conventional T cells were not downstream mediators of this effect. Finally, the antiviral effect of alpha-GalCer was inhibited in mice that are genetically deficient for either IFN-gamma or the IFN-alpha/beta receptor, indicating that most of the antiviral activity of alpha-GalCer is mediated by these cytokines. Based on these results, we conclude that alpha-GalCer inhibits HBV replication by directly activating NKT cells and by secondarily activating NK cells to secrete antiviral cytokines in the liver. In view of these findings, we suggest that, if activated, the innate immune response, like the adaptive immune response, has the potential to control viral replication during natural HBV infection. In addition, the data suggest that therapeutic activation of NKT cells may represent a new strategy for the treatment of chronic HBV infection.
Effect of hypoxia on serum concentration of transferrin and other serum proteins in human subjects. (1970)

Abstract The effect of hypoxia on serum transferrin concentration in human subjects was investigated by measuring serum total iron-binding capacity (TIBC) and transferrin concentration in patients with cardiac and respiratory disease in whom arterial blood oxygen saturation was also determined and in healthy subjects exposed to reduced atmospheric pressure equivalent to an altitude of 15,000 feet. No relationship was found between the TIBC or transferrin concentration values of the patients and their blood oxygen saturations. Exposure to reduced pressure for periods from 6 hr. to 4 days had no effect on serum TIBC or transferrin concentration or on the concentrations of the electrophoretic serum protein fractions. It is concluded that hypoxia has little or no effect on serum transferrin concentration in human subjects.
Dietary Genistein Inhibits Metastasis of Human Prostate Cancer in Mice (2008)

Dietary genistein has been linked to lower prostate cancer (PCa) mortality. Metastasis is the ultimate cause of death from PCa. Cell detachment and invasion represent early steps in the metastatic cascade. We had shown that genistein inhibits PCa cell detachment and cell invasion in vitro. Genistein-mediated inhibition of activation of focal adhesion kinase (FAK) and of the p38 mitogen-activated protein kinase (MAPK)-heat shock protein 27 (HSP27) pathway has been shown by us to regulate PCa cell detachment and invasion effects, respectively. To evaluate the antimetastatic potential of genistein, we developed an animal model suited to evaluating antimetastatic drug efficacy. Orthotopically implanted human PC3-M PCa cells formed lung micrometastasis by 4 weeks in >80% of inbred athymic mice. Feeding mice dietary genistein before implantation led to blood concentrations similar to those measured in genistein-consuming men. Genistein decreased metastases by 96%, induced nuclear morphometric changes in PC3-M cells indicative of increased adhesion (i.e., decreased detachment) but did not alter tumor growth. Genistein increased tumor levels of FAK, p38 MAPK, and HSP27 "promotility" proteins. However, the ratio of phosphorylated to total protein trended downward, indicating a failure to increase relative amounts of activated protein. This study describes a murine model of human PCa metastasis well suited for testing antimetastatic drugs. It shows for the first time that dietary concentrations of genistein can inhibit PCa cell metastasis. Increases in promotility proteins support the notion of cellular compensatory responses to antimotility effects induced by therapy. Studies of antimetastatic efficacy in man are warranted and are under way.