gebhart/patrepeval huggingface dataset:
A genetic model for control of hypertriglyceridemia and apolipoprotein B levels in the Johns Hopkins colony of St. Thomas Hospital rabbits. (1992)

The St. Thomas Hospital (STH) rabbit has been previously shown to have a Mendelian form of hypertriglyceridemia, accompanied by accelerated atherosclerosis, and these animals may serve as a useful model for human dyslipoproteinemia syndromes. Here we describe the establishment of a new colony of these STH animals, and present genetic analysis of triglyceride (TG) and apolipoprotein B (apoB) levels. Segregation analysis of TG in 39 STH animals and 24 controls gave evidence of Mendelian segregation for an allele leading to both elevated TG levels and increased variability in these levels. Predicted means from the most parsimonious model for the Johns Hopkins STH colony were quite similar to that seen in the original London colony, and this model accounted for 80% of the variation in TG seen in the sample. This hypertriglyceridemia locus indirectly influenced the mean apoB levels in these rabbits, and segregation analysis of mean apoB levels suggested a second locus controlling apoB levels. Analysis of residual apoB levels (adjusted for predicted effects of the hypertriglyceridemia locus) revealed clearer evidence for a second locus controlling mean apoB levels in this colony. Arguments for two distinct genetic mechanisms operating in these STH animals are presented.
Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats. (1995)

The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurologic developmental defects and dysmorphic features in many organs. Recently, abnormal cholesterol biosynthesis with impaired conversion of 7-dehydrocholesterol to cholesterol has been discovered in homozygotes. To reproduce the biochemical abnormality, BM 15.766, a competitive inhibitor of 7-dehydrocholesterol-delta 7-reductase, the enzyme that catalyzes the conversion of 7-dehydrocholesterol into cholesterol was fed by gavage to rats. After 14 d, plasma cholesterol concentrations declined from 48 mg/dl to 16 mg/dl and 7-dehydro-cholesterol levels rose from trace to 17 mg/dl. Hepatocytes surrounding the central vein developed balloon necrosis. Stimulating cholesterol synthesis with cholestyramine followed by BM 15.766 produced an additional 40% decline (P < 0.05) in plasma cholesterol and 34% increase in 7-dehydrocholesterol levels compared to the inhibitor alone. Adding 2% cholesterol to the diet during the second week of BM 15.766 treatment increased plasma cholesterol threefold and decreased 7-dehydrocholesterol concentrations 55%. Hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity increased 73% with a 3.9-fold rise in mRNA levels but cholesterol 7 alpha-hydroxylase activity decreased slightly though mRNA levels increased 1.4 times with BM 15.766 treatment. These results demonstrate that BM 15.766 is a potent inhibitor of 7-dehydrocholesterol-delta 7-reductase. The model reproduces abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome and is useful to test different treatment strategies. Stimulating early steps of cholesterol synthesis worsens the biochemical abnormalities while feeding cholesterol inhibits abnormal synthesis, improves the biochemical abnormalities and prevents liver damage.
Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase. (1986)

We have isolated two genes from yeast encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase [hydroxymethylglutaryl-coenzyme A reductase (NADPH); HMG-CoA reductase; EC 1.1.1.34], the rate-limiting enzyme of sterol biosynthesis. These genes, HMG1 and HMG2, were identified by hybridization to a cDNA clone encoding hamster HMG-CoA reductase. DNA sequence analysis reveals homology between the amino acid sequence of the proteins encoded by the two yeast genes and the carboxyl-terminal half of the hamster protein. Cells containing mutant alleles of both HMG1 and HMG2 are unable to undergo spore germination and vegetative growth. However, cells containing a mutant allele of either HMG1 or HMG2 are viable but are more sensitive to compactin, a competitive inhibitor of HMG-CoA reductase, than are wild-type cells. Assays of HMG-CoA reductase activity in extracts from hmg1- and hmg2- mutants indicate that HMG1 contributes at least 83% of the activity found in wild-type cells.
Drug Chirality: On the Mechanism of R‐Aryl Propionic Acid Class NSAIDs. Epimerization in Humans and the Clinical Implications for the Use of Racemates (1994)

This review summarizes and comments on the current understanding of both the biochemical and clinical implications of the epimerization of R-aryl propionic (APA) class (1) nonsteroidal anti-inflammatory agents (NSAIDs) to S-enantiomers in humans. This article focuses principally on rac-ibuprofen and its enantiomers. In the United States, five commercialized NSAIDs are APAs. Only two of them, rac-ibuprofen and rac-fenoprofen, are subject to significant epimerization in humans. The remaining three, rac-flurbiprofen, rac-ketoprofen, and S-naproxen, are not of interest in this context.
Nanotube Optoelectronic Memory Devices (2004)

We have combined carbon nanotube field effect transistor devices with a photosensitive polymer to fabricate an optoelectronic memory device. Electric charges are created upon optical illumination by the polymer−nanotube element of the structure, and charge storage occurs in the nanotube transducer. The read and erase functions are performed by a voltage applied across the nanotube channel. Spectral response of the device is adjusted by utilizing different polymers with different absorption characteristics.
Effects of Chronic Sleep Fragmentation on Wake-Active Neurons and the Hypercapnic Arousal Response (2014)

Four weeks of sleep fragmentation (SF4wk) impairs arousal responses to hypercapnia, reduces wake neuron projections and locus coeruleus neuronal excitability, supporting the concepts that some effects of sleep fragmentation may contribute to impaired arousal responses in sleep apnea, which may not reverse immediately with therapy.
DNA-Based Assembly of Gold Nanocrystals (1999)

Specific, designed, nonperiodic arrangements of gold nanocrystals that are 5 and 10 nm in diameter can be prepared with double-stranded DNA serving as a template (see drawing; A' and B' denote oligonucleotide sequences complementary to sequences A and B). The methods described should be applicable to nanocrystals composed of various materials.
Synthetic Access to Atomically Dispersed Metals in Metal–Organic Frameworks via a Combined Atomic-Layer-Deposition-in-MOF and Metal-Exchange Approach (2016)

The combination (AIM-ME) of atomic layer deposition in metal–organic frameworks (MOFs) and metal exchange (ME) is introduced as a technique to install dispersed metal atoms into the mesoporous MOF, NU-1000. Zn-AIM, which contains four Zn atoms per Zr6 node, has been synthesized through AIM and further characterized through density functional calculations to provide insight into the possible structure. Zn-AIM was then subjected to modification via transmetalation to yield uniform porous materials that present nonstructural Cu, Co, or Ni atoms.
Defective lymphocyte glycosidases in the macrophage activation cascade of juvenile osteopetrosis (1996)

Generation of macrophage-activating factor requires a precursor protein, Gc protein (serum vitamin D3-binding protein), as well as participation of beta-galactosidase of inflammation-primed B lymphocytes and sialidase of T lymphocytes. The treatment of human peripheral blood mononuclear cells with an inflammatory lysophospholipid induced beta-galactosidase and sialidase activity of lymphocytes, leading to the generation of macrophage-activating factor and activation of monocytes/macrophages. However, lysophospholipid treatment of peripheral blood mononuclear cells from three infantile patients with osteopetrosis resulted in no significant activation of monocytes/macrophages. The lysophospholipid-inducible beta-galactosidase activity of B lymphocytes as well as that of the sialidase of T lymphocytes was found to be defective in these patients.
Liver X Receptor Stimulates Cholesterol Efflux and Inhibits Expression of Proinflammatory Mediators in Human Airway Smooth Muscle Cells (2007)

Human (h) airway smooth muscle (ASM) cells are important mediators of the inflammatory process observed in asthma and other respiratory diseases. We show here that primary hASM cells express liver X receptor (LXR; alpha and beta subtypes), an oxysterol-activated nuclear receptor that controls expression of genes involved in lipid and cholesterol homeostasis, and inflammation. LXR was functional as determined by transient assays using LXR-responsive reporter genes and by analysis of mRNA and protein expression of endogenous LXR target genes in cells exposed to LXR agonists. LXR activation induced expression of the ATP-binding cassette transporters ABCA1 and ABCG1 and increased efflux of cholesterol to apolipoprotein AI and high-density lipoprotein acceptors, pointing to a role for hASM cells in modulating cholesterol homeostasis in the airway. Under inflammatory conditions, hASM cells release a variety of chemokines and cytokines that contribute to inflammatory airway diseases. Activation of LXR inhibited the expression of multiple cytokines in response to proinflammatory mediators and blocked the release of both granulocyte macrophage colony-stimulating factor and granulocyte colony stimulating factor. LXR activation also inhibited proliferation of hASM cells and migration toward platelet-derived growth factor chemoattractant, two important processes that contribute to airway remodeling. Our findings reveal biological roles for LXR in ASM cells and suggest that modulation of LXR activity offers prospects for new therapeutic approaches in the treatment of asthma and other inflammatory respiratory diseases.
Correlation between Pretreatment Levels of Interferon Response Genes and Clinical Responses to an Immune Response Modifier (Imiquimod) in Genital Warts (2000)

Imiquimod (IQ) has been successfully used in treatment of genital warts. In clinical settings, patients responded well but wart reduction rates varied. Our aim was to find a correlation between clinical responses and pretreatment (constitutive) levels of genes that might be involved in the molecular action of IQ. Since IQ is a cytokine inducer, we analyzed levels of expression of genes of the JAK/STAT signaling pathway and their inhibitors as well as interferon response factors (IRFs) in pretreatment biopsy specimens from complete responders (99 to 100% wart reduction rate) versus incomplete responders (75 to 92% wart reduction rate) by reverse transcription-PCR. We found that mRNA levels of signal transducer and activator of transcription 1 (STAT1) and IRF1 were higher in complete responders than in incomplete responders. Incomplete responders expressed larger amounts of STAT3, IRF2, and protein inhibitor of activated STAT1 (PIAS1) mRNAs compared to complete responders before IQ treatment. We hypothesize that high-level expression of STAT1 and IRF1 is advantageous for a better IQ response. The observed differences in constitutive mRNA levels of these genes may be the consequence of alterations in cellular differentiation and/or variable expression of endogenous interferons. Previous in vitro studies showed that keratinocyte differentiation coordinates the balance between positive and negative signals along the JAK/STAT pathway by regulating the IRF1:IRF2 and STAT1:PIAS1 ratios and thus affecting induction of IQ-inducible genes. Specifically, differentiation supports constitutive expression of STAT1 and IRF1 mRNAs but not expression of IRF2 and PIAS1. Our data are in good agreement with studies that showed the importance of STAT1 in cytokine induction and activation of interferon-responsive genes by IQ.
Immunotoxin Methods and Protocols (2000)

More potent and selective for killing cancer cells than chemotherapy, immunotoxins constitute a new class of human therapeutics that have widespread applications and a potential that has not yet been fully recognized. In Immunotoxin Methods and Protocols, leading experts from laboratories around the world describe in step-by-step detail their cutting-edge methods for developing and applying these powerful proteins. The conjugates created by these researchers contain entire monoclonal antibodies, single chain antibody fragments, and cytokines as their carrier ligands. Their toxic portion can include such conventional chemotherapeutics as doxirubicin, such ribosome-inactivating proteins as the ricin A chain or saporin, or such bacterial toxins as diptheria toxin. Also described are a variety of applications that demonstrate the versatility of these agents, including the treatment of primary malignant brain tumors, the generation of selective brain lesions to localize critical functions, and the targeting of the AIDS virus. Each readily reproducible method is optimized for experimental success with hands-on instructions, invaluable notes on pitfalls to avoid, and informative explanations of why certain steps are necessary. Authoritative and highly practical, Immunotoxin Methods and Protocols provides today's cancer researchers, neuroscientists, and oncologists with state-of-the-art tools for exploring these powerful biological agents and their rapidly increasing applications
2-Arachidonoyl-glycerol suppresses interferon-γ production in phorbol ester/ionomycin-activated mouse splenocytes independent of CB1 or CB2 (2005)

Abstract 2-Arachidonoyl-glycerol (2-AG), an endogenous ligand for cannabinoid receptor types 1 and 2 (CB1 and CB2), has previously been demonstrated to modulate immune functions including suppression of interleukin-2 expression and nuclear factor of activated T cells (NFAT) activity. The objective of the present studies was to investigate the effect of 2-AG on interferon-γ (IFN-γ) expression and associated upstream signaling events. Pretreatment of splenocytes with 2-AG markedly suppressed phorbol 12-myristate 13-acetate plus calcium ionophore (PMA/Io)-induced IFN-γ secretion. In addition, 2-AG suppressed IFN-γ steady-state mRNA expression in a concentration-dependent manner. To unequivocally determine the putative involvement of CB1 and CB2, splenocytes derived from CB1−/−/CB2−/− knockout mice were used. No difference in the magnitude of IFN-γ suppression by 2-AG in wild-type versus CB1/CB2 null mice was observed. Time-of-addition studies revealed that 2-AG treatment up to 12 h post-cellular activation resulted in suppression of IFN-γ, which was consistent with a time course conducted with cyclosporin A, an inhibitor of NFAT activity. Coincidentally, 2-AG perturbed the nuclear translocation of NFAT protein and blocked thapsigargin-induced elevation in intracellular calcium, suggesting that altered calcium regulation might partly explain the suppression of NFAT nuclear translocation and subsequent IFN-γ production. Indeed, Io partially attenuated the 2-AG-induced suppression of PMA/Io-stimulated IFN-γ production. Taken together, these data demonstrate that 2-AG suppresses IFN-γ expression in murine splenocytes in a CB receptor-independent manner and that the mechanism partially involves suppression of intracellular calcium signaling and perturbation of NFAT nuclear translocation.
DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53‐dependent myopathy in vivo (2010)

Our work demonstrates the myopathic potential of DUX4 in animal muscle. Considering previous studies showed DUX4 was elevated in FSHD patient muscles, our data support the hypothesis that DUX4 overexpression contributes to FSHD development. Moreover, we provide a p53-dependent mechanism for DUX4 toxicity that is consistent with previous studies showing p53 pathway activation in FSHD muscles. Our work justifies further investigation of DUX4 and the p53 pathway in FSHD pathogenesis.
Inhibition of Tumor Growth and Angiogenesis by Soluble EphB4 (2004)

EphB receptors and their ephrinB ligands play a key role in the formation of a regular vascular system. Recent studies have also shown the involvement of Eph/ephrin interactions in malignant tumor progression and angiogenesis. We have generated soluble monomeric EphB4 (sEphB4)-expressing A375 melanoma cells to study the effect of dominant negatively acting sEphB4 on tumor growth and angiogenesis. Soluble EphB4-expressing A375 tumors grown subcutaneously in nude mice show dramatically reduced tumor growth compared to control tumors. The proliferative capacity of sEphB4-expressing cells in monolayer culture is not altered. Yet, sEphB4-expressing A375 cells cannot establish proper cell-cell contacts in three-dimensional spheroids. However, sEphB4 transfectants have reduced proliferation and apoptosis rates when grown in three-dimensional culture in vitro or in subcutaneous tumors in vivo. Analysis of the vascular phenotype of the tumors revealed a reduction of intratumoral microvessel density in sEphB4-expressing tumors. Corresponding to these mouse experiments, a matched pair analysis of EphB4 and ephrinB2 expression in human colon carcinomas revealed significantly upregulated levels of EphB4 expression compared to adjacent normal tissue. Taken together, the data identify dual effects of sEphB4 on the tumor and the vascular compartment that collectively inhibit tumor growth.
Large scale isolation of genes as DNA fragment lengths by continuous elution electrophoresis through an agarose matrix (1998)

A simple procedure for the isolation of genes as DNA fragment lengths is described. By using a commercial continuous elution protein electrophoresis apparatus and incorporating an agarose matrix, preparative scale amounts (300 microg) of DNA can be purified by fragment lengths from a mixture of genomic fragment lengths with high recovery yields. Fractions corresponding to unique fragment length ranges are screened for individual genes by dot-blot analysis. Using this technique, we have isolated two genes: PGK1, a single copy housekeeping gene; and p53 (exons 3-11), a tumor suppressor gene, whose DNA fragment lengths elute at 4 and 7.5 kbp, respectively, from a single preparative run. As an example of the utility of the technique, we applied it to improving the sensitivity of the ligation-mediated polymerase chain reaction (LMPCR)--a nucleic acid amplification technique used for the detection and mapping of DNA damage along genes. By eliminating excess nontargeted genomic DNA, the agarose matrix continuous elution electrophoresis (CEE) procedure provided a 24-fold increase in signal strength attributable to base damage caused by exposing DNA to reactive oxygen species. Genomic DNA fragment length purification by agarose matrix CEE should also prove useful in other research areas requiring gene isolation, such as genomics and molecular biology.
HtrA2 Promotes Cell Death through Its Serine Protease Activity and Its Ability to Antagonize Inhibitor of Apoptosis Proteins (2002)

Grim, HID, and Reaper and mammalian DIABLO/Smac. We now demonstrate that HtrA2, a mammalian homologue of the Escherichia coli heat shock-inducible protein HtrA, can bind to MIHA/XIAP, MIHB, and baculoviral OpIAP but not survivin. Although produced as a 50-kDa protein, HtrA2 is processed to yield an active serine protease with an N terminus similar to that of Grim, Reaper, HID, and DIABLO/Smac that mediates its interaction with XIAP. HtrA2 is largely membrane-associated in healthy cells, with a significant proportion observed within the mitochondria, but in response to UV irradiation, HtrA2 shifts into the cytosol, where it can interact with IAPs. HtrA2 can, like DIABLO/Smac, prevent XIAP inhibition of active caspase 3 in vitro and is able to counteract XIAP protection of mammalian NT2 cells against UV-induced cell death. The proapoptotic activity of HtrA2 in vivo involves both IAP binding and serine protease activity. Mutations of either the N-terminal alanine of mature HtrA2 essential for IAP interaction or the catalytic serine residue reduces the ability of HtrA2 to promote cell death, whereas a complete loss in proapoptotic activity is observed when both sites are mutated.
High Efficiency In Vivo Genome Engineering with a Simplified 15-RVD GoldyTALEN Design (2013)

Transcription activator-like effector nucleases (TALENs) enable genome engineering in cell culture and many organisms. Recently, the GoldyTALEN scaffold was shown to readily introduce mutations in zebrafish (Danio rerio) and livestock through non-homologous end joining (NHEJ) and homology-directed repair (HDR). To deploy the GoldyTALEN system for high-throughput mutagenesis in model organisms, a simple design with high efficacy is desirable. We tested the in vivo efficacy of a simplified 15-RVD GoldyTALEN design (spacer between 13-20 bp and T nucleotide preceding each TALEN binding site) in zebrafish. All 14 tested TALEN pairs (100%) introduced small insertions and deletions at somatic efficacy ranging from 24 to 86%, and mutations were inheritable at high frequencies (18-100%). By co-injecting two GoldyTALEN pairs, inheritable deletions of a large genomic fragment up to 18 kb were successfully introduced at two different loci. In conclusion, these high efficiency 15-RVD GoldyTALENs are useful for high-throughput mutagenesis in diverse application including hypothesis testing from basic science to precision medicine.
Structure, Function and Polymorphism of Human Cytosolic Sulfotransferases (2008)

The sulfotransferase (SULTs) catalyzes the sulfonation of a multitude of xenobiotics, hormones and neurotransmitters. This review has summarised the SULT family in detail, the structure of the twelve known enzymes, in their four known groups (SULT1, SULT2, SULT4, and SULT6) and the substrates for each respective SULT. Hepatic sulfonation is a common phase II metabolic mechanism for increasing molecular hydrophilicity in preparation for biliary excretion or efflux across the hepatic basolateral membrane for subsequent renal clearance. To date, a total of 13 human cytosolic SULT genes have been identified which spread across four families; SULT1, SULT2, SULT4, and SULT6. The established structures of SULTs provide evidence for both enzyme/substrate and enzyme/cofactor binary complexes, consistent with a random bi-bi mechanism and ruling out an ordered mechanism in which binding of substrate requires binding of cofactor (or vice versa). Members of the SULT1 family have demonstrated the ability to sulfonate simple (small planar) phenols including estradiol, thyroid hormones, environmental xenobiotics and drugs. The SULT2 family members catalyze sulfonation of hydroxyl groups of steroids, such as androsterone, allopregnanolone, and dehydroepiandrosterone. As yet, no known substrate or function has been identified for the SULT4 family, and the SULT6B1 gene, expressed in the testis of primates, has neither the protein nor its enzymatic activity characterized. The extent of nucleotide variation found in members of the SULT gene family is similar to that observed for other groups of human genes. Substrate inhibition was observed for most substrates with a trend in maximum velocity (V(max)) of *1>*3>*2. There does appear to be an inter-ethnic/inter-racial difference in the incidence of the various SULT1A1 alleles also. There is mounting evidence to suggest that further research and understanding in the area of phase II metabolism and the SULT enzyme will have a great benefit in a clinical setting. Already research in the field is finding links with cancer and sulfonation-related disease, promising to deliver great advances in clinical practice in the future.
Multiplexed measurements of gene signatures in different analytes using the Nanostring nCounter™ Assay System (2009)

The nCounter Analysis System generated robust data for multi-gene expression signatures across three different sample preparation conditions.