gebhart/patrepeval huggingface dataset:
GABAB receptors as targets for drug action. (1992)

Data obtained from studies in molecular biology indicate that there may be at least 500 forms of the receptor for the amino acid neurotransmitter gamma-aminobutyric acid (GABA), which are coupled to Cl- channels in mammalian neurones. In addition to this apparent subtyping, the receptors for GABA can be further differentiated on pharmacological grounds into GABAA and GABAB subclasses. GABAA receptors are coupled to Cl- channels, possess allosteric sites for benzodiazepines, barbiturates and neuroactive steroids and mediate fast synaptic inhibition, while GABAB receptors are coupled through G-proteins to neuronal K+ or Ca++ channels. Activation of these receptors increases K+ or decreases Ca++ conductances and mediates slow synaptic inhibition. Inhibition and potentiation of stimulated adenylyl cyclase activity can be attributed to GABAB site activation. The clinically effective muscle relaxant (-)baclofen is a selective agonist for the GABAB site but the therapeutical potential for antagonists of the receptor has yet to be examined. The present article reviews the background to GABAB receptor research and considers the future of drugs targetting the receptor.
Metabolic Effects and Safety Profile of Nebivolol (2001)

Nebivolol, compared with classical beta-blockers, exerts a high selectivity for beta-adrenergic receptors and also reduces peripheral vascular resistance by modulating nitric oxide (NO) release. This dual mechanism of action leads to effective control of blood pressure at a low degree of beta-blockade and explains the lack of any interference with lipid metabolism. For the same reason, the tolerability profile of nebivolol is highly favorable compared with the classical beta-blockers, with less fatigue and dyspnea in hypertensive subjects, and with an improvement of functional capacity and exercise tolerance in patients with left ventricular dysfunction. Furthermore, contrary to atenolol and propranolol, nebivolol does not diminish specific airway conductance. Compared with other first-line antihypertensive agents, nebivolol was shown to be better tolerated than nifedipine and enalapril, and to have a positive effect on general wellbeing. Among the currently available antihypertensive drugs, nebivolol therefore appears to have a most alteractive safety and tolerability profile, which can be attributed to its NO-mediated effects allowing effective control of hypertension at a lower degree of beta-blockade than with first-generation beta-blockers.
In Vitro Targeting of Antibody-Conjugated Echogenic Liposomes for Site-Specific Ultrasonic Image Enhancement (1997)

Tissue-specific ultrasonic enhancement can be used for the detection and characterization of atherosclerosis. We have previously demonstrated the generation of inherently echogenic (acoustically reflective) liposomes solely by varying lipid composition and controlling the method of production. In this study, echogenic liposomes composed of phosphatidylcholine (PC), 4-(p-maleimidophenyl) butyryl phosphatidylethanolamine (MPB-PE), phosphatidylglycerol (PG), and cholesterol were conjugated to human gamma globulin to determine the effect of antibody conjugation on liposomal acoustic reflectivity. The liposomes remained highly echogenic following antibody conjugation. Echogenic liposomes were also conjugated to rabbit antihuman fibrinogen to study their ability to target fibrin. Antibody-conjugated liposomes were targeted to fibrin-coated filter paper and slides, thrombi made in vitro, and segments of atheroma in an animal model of atherosclerosis. Liposomes were detected by scanning electron microscopy, radiolabeling, and imaging with intravascular ultrasound. Electron microscopy revealed attachment of antibody-conjugated liposomes to fibrin on slides and to the fibrous plaques of the arterial segments, whereas unconjugated liposomes did not attach. Similarly, conjugated liposomes did not attach to normal arteries, indicating their binding to the arterial segment is directed towards a component of the fibrous plaque. Ultrasound imaging of the thrombi demonstrated surface attachment of the acoustic conjugated liposomes. 125I-Labeled liposomes conjugated to rabbit anti-human were targeted to fibrin-coated paper. Counting specifically bound radioactivity showed that > 84% of applied liposomes remained attached to the fibrin after washing with saline. These results demonstrate the potential of acoustically reflective liposomes for site-specific targeting and acoustic enhancement.
Species Identification and Strain Differentiation of Dermatophyte Fungi by Analysis of Ribosomal-DNA Intergenic Spacer Regions (1999)

Restriction fragment length polymorphisms (RFLPs) identified in the ribosomal-DNA (rDNA) repeat were used for molecular strain differentiation of the dermatophyte fungus Trichophyton rubrum. The polymorphisms were detected by hybridization of EcoRI-digested T. rubrum genomic DNAs with a probe amplified from the small-subunit (18S) rDNA and adjacent internal transcribed spacer (ITS) regions. The rDNA RFLPs mapped to the nontranscribed spacer (NTS) region of the rDNA repeat and appeared similar to those caused by short repetitive sequences in the intergenic spacers of other fungi. Fourteen individual RFLP patterns (DNA types A to N) were recognized among 50 random clinical isolates of T. rubrum. A majority of strains (19 of 50 [38%]) were characterized by one RFLP pattern (DNA type A), and four types (DNA types A to D) accounted for 78% (39 of 50) of all strains. The remaining types (DNA types E to N) were represented by one or two isolates only. A rapid and simple method was also developed for molecular species identification of dermatophyte fungi. The contiguous ITS and 5.8S rDNA regions were amplified from 17 common dermatophyte species by using the universal primers ITS 1 and ITS 4. Digestion of the amplified ITS products with the restriction endonuclease MvaI produced unique and easily identifiable fragment patterns for a majority of species. However, some closely related taxon pairs, such as T. rubrum-T. soudanense and T. quinkeanum-T. schoenlenii could not be distinguished. We conclude that RFLP analysis of the NTS and ITS intergenic regions of the rDNA repeat is a valuable technique both for molecular strain differentiation of T. rubrum and for species identification of common dermatophyte fungi.
Aqueous humor penetration of topical bimatoprost 0.01% and bimatoprost 0.03% in rabbits: response to authors (2011)

Aqueous humor penetration of topical bimatoprost 0.01% and bimatoprost 0.03% in rabbits: response to authors Joan-En Chang-Lin, Amy L Batoosingh, David A Hollander, Rhett M Schiffman, Diane D-S Tang-LiuAllergan, Inc, Irvine, CA, USAWe read with great interest the recent article by Ogundele and Jasek,1 in which the authors concluded that bimatoprost ophthalmic solution 0.01% (Lumigan®; Allergan, Inc, Irvine, CA) produced lower bimatoprost acid concentration than bimatoprost ophthalmic solution 0.03% (Lumigan; Allergan, Inc) in the aqueous humor of rabbits. This conclusion was made based on two treatment time points (30 and 90 minutes) with a small sample size (n = 4) at each time point and with large variability.
Expression of 25-Hydroxyvitamin D3-1α-Hydroxylase in the Human Kidney (1999)

The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plays a vital role in calcium metabolism, tissue differentiation, and normal bone growth. Biosynthesis of 1,25(OH)2D3 is catalyzed by the mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase). Although activity of this enzyme has been described in several tissues, the kidneys are recognized to be the principal site of 1,25(OH)2D3 production. To date, enzyme activity studies using vitamin D-deficient animals have suggested that 1alpha-hydroxylase is expressed exclusively in proximal convoluted tubules. With the recent cloning of 1alpha-hydroxylase, specific cRNA probes and in-house polyclonal antiserum have been used to determine the distribution of 1alpha-hydroxylase along the human nephron. Immunohistochemistry and in situ hybridization studies indicated strong expression of 1alpha-hydroxylase protein and mRNA in the distal convoluted tubule, the cortical and medullary part of the collecting ducts, and the papillary epithelia. Lower expression was observed along the thick ascending limb of the loop of Henle and Bowman's capsule. Weaker and more variable expression of 1alpha-hydroxylase protein and mRNA was seen in proximal convoluted tubules, and no expression was observed in glomeruli or vascular structures. These data show for the first time the distribution of alpha1-hydroxylase expression in normal human kidney. In contrast to earlier enzyme activity studies conducted in vitamin D-deficient animals, our data indicate that the distal nephron is the predominant site of 1alpha-hydroxylase expression under conditions of vitamin D sufficiency.
Learning Deep Representations of Appearance and Motion for Anomalous Event Detection (2015)

We present a novel unsupervised deep learning framework for anomalous event detection in complex video scenes. While most existing works merely use hand-crafted appearance and motion features, we propose Appearance and Motion DeepNet (AMDN) which utilizes deep neural networks to automatically learn feature representations. To exploit the complementary information of both appearance and motion patterns, we introduce a novel double fusion framework, combining both the benefits of traditional early fusion and late fusion strategies. Specifically, stacked denoising autoencoders are proposed to separately learn both appearance and motion features as well as a joint representation (early fusion). Based on the learned representations, multiple one-class SVM models are used to predict the anomaly scores of each input, which are then integrated with a late fusion strategy for final anomaly detection. We evaluate the proposed method on two publicly available video surveillance datasets, showing competitive performance with respect to state of the art approaches.
Retinoic acid mimics transforming growth factor beta in the regulation of human immunodeficiency virus expression in monocytic cells. (1992)

Retinoic acid (RA) exerts potent suppressive and upregulatory effects on human immunodeficiency virus (HIV) expression in mononuclear phagocytes, strikingly similar to the effects of the cytokine transforming growth factor beta (TGF-beta). RA significantly inhibited phorbol ester-mediated, but not tumor necrosis factor alpha-mediated, induction of HIV transcription in the chronically infected promonocytic U1 cell line. RA and TGF-beta also completely suppressed the induction of virus production in U1 cells by interleukin 6 alone or in combination with glucocorticoids, which predominantly upregulate virus expression at the posttranscriptional level. Despite the close parallel to TGF-beta-induced effects, no evidence was obtained that RA mediated its effect by inducing secretion of active TGF-beta 1, -beta 2, or -beta 3. As with chronically infected U1 cells, similar inhibitory effects were also observed in primary monocyte-derived macrophages previously infected with HIV and then exposed to either RA or TGF-beta. In contrast, stimulation of monocyte-derived macrophages or U937 cells (the parental cell line of U1) with either RA or TGF-beta prior to in vitro infection resulted in the enhancement of virus production. Given the already successful use of retinoids in the treatment of several malignancies and the present demonstration of their capability of blocking the induction of HIV expression in infected mononuclear phagocytes, it would be of interest to pursue the potential role of this class of compounds in the development of strategies aimed at the pharmacologic regulation of HIV expression.
Liquid-Phase Synthesis of Colloids and Redispersible Powders of Strongly Luminescing LaPO4:Ce,Tb Nanocrystals (2001)

Nanoparticles with high photoluminescence quantum yield have been recently considered as possible biolabels and as emitters in optoelectronic devices. Now gram amounts of nontoxic, chemically stable LaPO<sub>4</sub> :Ce,Tb nanocrystals have been obtained in a coordinating solvent. These nanoparticles can be easily redispersed in polar solvents to give scatter-free colloids that exhibit quantum yields of up to 61 %.
Regulation of antibody specificity to Plasmodium falciparum merozoite surface protein-1 by adjuvant and MHC haplotype. (1994)

An effective malaria vaccine must be capable of eliciting a protective immune response in individuals of diverse genetic makeup. In this report, we describe the co-regulation of immune responsiveness to growth-inhibitory Plasmodium falciparum merozoite surface protein-1 (MSP-1) epitopes by MHC-linked immune response genes and by the adjuvant used in MSP-1 vaccine formulations. When congenic mice differing in MHC haplotype were immunized with MSP-1 either in CFA or incorporated into a synthetic monophosphoryl lipid A (LA-15-PH)-liposome formulation, mice of different haplotypes produced anti-MSP-1 Abs capable of inhibiting P. falciparum growth. Mice of H-2b and H-2ja haplotypes produced Abs possessing high levels of inhibitory activity upon immunization with MSP-1 in LA-15-PH/liposomes whereas these haplotypes produced noninhibitory Abs when immunized with MSP-1 in CFA. Conversely, H-2d haplotype mice produced inhibitory Abs when immunized with MSP-1 in CFA but not when immunized with MSP-1 in LA-15-PH/liposomes. The LA-15-PH/liposome adjuvant was more effective than CFA in inducing growth-inhibitory Abs. The level of parasite growth inhibition observed for a particular mouse strain correlated with Ab titers against conserved, C-terminal MSP-1 epitopes, which appear to be important targets for Ab-mediated inhibition in mice immunized with both adjuvant formulations. Our results suggest that adjuvant formulation and MHC genes act in a reciprocal manner to control immune responsiveness to specific epitopes, and raise the possibility of manipulating genetically-controlled responsiveness to vaccine Ags by utilizing alternative adjuvants in vaccine formulations.
Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB/c murine fibroblasts. (1992)

BALB/c 3T3 cells (A31 cells) require the sequential action of growth factors in order to proliferate from a quiescent growth state. Insulin-like growth factor I (IGF-I) is needed late in the G1 phase of the cell cycle, a time at which expression of the c-Ha-ras protooncogene is near maximal. An anti-ras antibody, introduced by microinjection, specifically blocked the ability of IGF-I to stimulate initiation of DNA synthesis. The antibody was specific for IGF-I; it failed to block serum, platelet-derived growth factor, or epidermal growth factor from inducing c-fos mRNA. By contrast, an anti-G alpha-subunit antibody had no effect on IGF-I-stimulated DNA synthesis but inhibited the induction of c-fos mRNA by platelet-derived growth factor or epidermal growth factor. BPA31 cells are tumorigenic A31-derived cells that progress through G1 in the absence of IGF-I. BPA31 cells produced an autocrine IGF-I that was responsible for the loss of late G1 control; the anti-ras antibody arrested the growth of these cells in late G1. The results suggest that ras proteins are essential for an IGF-I-sensitive, G1 control point.
Pituitary Carcinoma of Pars Distalis as a Common Neoplasm in Fischer-344 Rats (1993)

The incidence of invasive spontaneous pituitary carcinomas in Fischer-344 rats were studied. The pituitaries were examined histopathologically together with surrounding tissues including sphenoid bone. The incidence of carcinoma was higher than that previously reported in Fischer-344 rats. All the carcinomas observed in this study showed evidence of local invasion either ventrally into bone and bone marrow or laterally into peripheral nerves and blood vessels. No dorsal infiltration into the brain was recognized. Pituitary carcinoma with local invasion is a relatively common neoplasm when examined histopathologically together with the surrounding tissues.
Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes. (1997)

Standard overexpression transgenic approaches are limited in their ability to model waxing and waning diseases and frequently superimpose development-dependent and -independent phenotypic manifestations. We used the clara cell 10-kD protein (CC10) promoter and the reverse tetracycline transactivator (rtTA) to create a lung-specific, externally regulatable, overexpression transgenic system and used this system to express human interleukin 11 (IL-11) in respiratory structures. Gene induction could be achieved in utero, in neonates and in adult animals. Moreover, gene expression could be turned off by removal of the inducing stimulus. When gene activation was initiated in utero and continued into adulthood, subepithelial airway fibrosis, peribronchiolar mononuclear nodules, and alveolar enlargement (emphysema) were noted. Induction in the mature lung caused airway remodeling and peribronchiolar nodules, but alveolar enlargement was not appreciated. In contrast, induction in utero and during the first 14 d of life caused alveolar enlargement without airway remodeling or peribronchiolar nodules. Thus, IL-11 overexpression causes abnormalities that are dependent (large alveoli) and independent (airway remodeling, peribronchiolar nodules) of lung growth and development, and the CC10-rtTA system can be used to differentiate among these effector functions. The CC10-rtTA transgenic system can be used to model waxing and waning, childhood and growth and development-related biologic processes with enhanced fidelity.
A Bidirectional Neuromodulation Technology for Nerve Recording and Stimulation (2018)

Electrical nerve recording and stimulation technologies are critically needed to monitor and modulate nerve activity to treat a variety of neurological diseases. However, current neuromodulation technologies presented in the literature or commercially available products cannot support simultaneous recording and stimulation on the same nerve. To solve this problem, a new bidirectional neuromodulation system-on-chip (SoC) is proposed in this paper, which includes a frequency-shaping neural recorder and a fully integrated neural stimulator with charge balancing capability. In addition, auxiliary circuits consisting of power management and data transmission circuits are designed to provide the necessary power supply for the SoC and the bidirectional data communication between the SoC and an external computer via a universal serial bus (USB) interface, respectively. To achieve sufficient low input noise for sensing nerve activity at a sub-10 μ V range, several noise reduction techniques are developed in the neural recorder. The designed SoC was fabricated in a 0.18 μ m high-voltage Bipolar CMOS DMOS (BCD) process technology that was described in a previous publication and it has been recently tested in animal experiments that demonstrate the proposed SoC is capable of achieving reliable and simultaneous electrical stimulation and recording on the same nerve.
Five Stages of Evolving Beta-Cell Dysfunction During Progression to Diabetes (2004)

This article proposes five stages in the progression of diabetes, each of which is characterized by different changes in beta-cell mass, phenotype, and function. Stage 1 is compensation: insulin secretion increases to maintain normoglycemia in the face of insulin resistance and/or decreasing beta-cell mass. This stage is characterized by maintenance of differentiated function with intact acute glucose-stimulated insulin secretion (GSIS). Stage 2 occurs when glucose levels start to rise, reaching approximately 5.0-6.5 mmol/l; this is a stable state of beta-cell adaptation with loss of beta-cell mass and disruption of function as evidenced by diminished GSIS and beta-cell dedifferentiation. Stage 3 is a transient unstable period of early decompensation in which glucose levels rise relatively rapidly to the frank diabetes of stage 4, which is characterized as stable decompensation with more severe beta-cell dedifferentiation. Finally, stage 5 is characterized by severe decompensation representing a profound reduction in beta-cell mass with progression to ketosis. Movement across stages 1-4 can be in either direction. For example, individuals with treated type 2 diabetes can move from stage 4 to stage 1 or stage 2. For type 1 diabetes, as remission develops, progression from stage 4 to stage 2 is typically found. Delineation of these stages provides insight into the pathophysiology of both progression and remission of diabetes.
Studies on tryptophen metabolism in patients with bladder cancer. (1973)

Summary Measurement, after 2 g l-tryptophan load p. o., of urinary excretion of some of the metabolites of the tryptophan-niacin pathway was performed on 36 patients with bladder cancer. Assay of hepatic tryptophan pyrrolase activity was done on 21 patients, and assay of kynureninase was done on all patients. Of these patients, increased excretion of kynurenine was found in 12,3-hydroxykynurenine was found in 25, kynurenic acid was found in 9, xanthurenic acid was found in 4, and acetylkynurenine was found in 10. There was no correlation between tryptophan pyrrolase activity and the level of the urinary excretion of tryptophan metabolites, while patients with low kynureninase activity tended to excrete increased quantities of these metabolites. Depressed kynureninase activity and increased excretion of tryptophan metabolites were more marked in the more advanced Stage D 1 and D 2 bladder cancer. Measurements of excretion of the tryptophan metabolites 6 to 12 months after eradication of the disease in 19 patients showed a statistically significant decrease in the excretion of kynurenine, while increased excretion of 3-hydroxykynurenine persisted in 9 of the patients. The excretion of the other metabolites was within normal range in all the patients postoperatively. Similar measurements on two other patients with known evidence of metastases showed an increase in the excretion of the various metabolites in the post-operative compared to the preoperative measurements.
Comparative cellular processing of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp160 by the mammalian subtilisin/kexin-like convertases (1996)

We present here the pulse and pulse-chase analysis of the biosynthesis of the envelope glycoprotein gp160 and its intracellular processing by the subtilisin/kexin-like convertases furin, PACE4, PC1, PC5 and its isoform PC5/6-B. We demonstrate that furin and to a much lesser extent PACE4, PC5/6-B and PC1 are candidate enzymes capable of processing gp160 intracellularly. Furthermore we show that furin can also process gp160/gp120 into gp77/gp53 products by cleavage at the sequence RIQR/GPGR just preceding the conserved GPGR structure found at the tip of the hypervariable V3 loop. The results show that processing into gp120 could occur at or before the trans-Golgi network (TGN) where sulphation of the oligosaccharide moieties of gp160 was detected. In contrast, the formation of gp77/gp53 by furin is a late event occurring after exit from the TGN. Our data also revealed that the alpha glucosidase I inhibitor N-butyldeoxynojirimycin, although affecting the oligosaccharide composition of gp160, does not impair the processing of either gp160 or gp120 by either furin or PACE4. Finally, the co-expression of the [Arg355, Arg358]-alpha-1-antitrypsin Portland variant was shown to potently inhibit the processing of both gp160 and gp120 by these convertases.