gebhart/patrepeval huggingface dataset:
Allele-specific recognition of the 3′ splice site of INS intron 1 (2010)

Genetic predisposition to type 1 diabetes (T1D) has been associated with a chromosome 11 locus centered on the proinsulin gene (INS) and with differential steady-state levels of INS RNA from T1D-predisposing and -protective haplotypes. Here, we show that the haplotype-specific expression is determined by INS variants that control the splicing efficiency of intron 1. The adenine allele at IVS1-6 (rs689), which rapidly expanded in modern humans, renders the 3' splice site of this intron more dependent on the auxiliary factor of U2 small nuclear ribonucleoprotein (U2AF). This interaction required both zinc fingers of the 35-kD U2AF subunit (U2AF35) and was associated with repression of a competing 3' splice site in INS exon 2. Systematic mutagenesis of reporter constructs showed that intron 1 removal was facilitated by conserved guanosine-rich enhancers and identified additional splicing regulatory motifs in exon 2. Sequencing of intron 1 in primates revealed that relaxation of its 3' splice site in Hominidae coevolved with the introduction of a short upstream open reading frame, providing a more efficient coupled splicing and translation control. Depletion of SR proteins 9G8 and transformer-2 by RNA interference was associated with exon 2 skipping whereas depletion of SRp20 with increased representation of transcripts containing a cryptic 3' splice site in the last exon. Together, these findings reveal critical interactions underlying the allele-dependent INS expression and INS-mediated risk of T1D and suggest that the increased requirement for U2AF35 in higher primates may hinder thymic presentation of autoantigens encoded by transcripts with weak 3' splice sites.
Leptin and Cellular and Innate Immunity in Abstinent Alcoholics and Controls (2003)

These data show that circulating levels of leptin are associated with NK activity in humans and suggest that abnormal in vivo concentrations of leptin may contribute to the declines of NK activity in alcoholics who are at risk for infectious diseases.
Antitumor Benzothiazoles. 14. Synthesis and in Vitro Biological Properties of Fluorinated 2-(4-Aminophenyl)benzothiazoles (2001)

Synthetic routes to a series of mono- and difluorinated 2-(4-amino-3-substituted-phenyl)benzothiazoles have been devised. Whereas mixtures of regioisomeric 5- and 7-fluoro-benzothiazoles were formed from the established Jacobsen cyclization of precursor 3-fluoro-thiobenzanilides, two modifications to this general process have allowed the synthesis of pure samples of these target compounds. Fluorinated 2-(4-aminophenyl)benzothiazoles were potently cytotoxic (GI(50) < 1 nM) in vitro in sensitive human breast MCF-7 (ER+) and MDA 468 (ER-) cell lines but inactive (GI(50) > 10 microM) against PC 3 prostate, nonmalignant HBL 100 breast, and HCT 116 colon cells. The biphasic dose-response relationship characteristically shown by the benzothiazole series against sensitive cell lines was exhibited by the 4- and 6-fluoro-benzothiazoles (10b,d) but not by the 5- and 7-fluoro-benzothiazoles (10h,i). The most potent broad spectrum agent in the NCI cell panel was 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (10h) which, unlike the 6-fluoro isomer (10d), produces no exportable metabolites in the presence of sensitive MCF-7 cells. Induction of cytochrome P450 CYP1A1, a crucial event in determining the antitumor specificity of this series of benzothiazoles, was not compromised. 10h is currently the focus of pharmaceutical and preclinical development.
Thinking and Writing (2004)

It is true to say that often one does not know what one thinks until one has written it. Writing is a discipline that leads to analytical, critical, and logical thinking. A good paper presents a structured argument that is based on sound evidence, and that leads inevitably to a logical thesis or conclusion.KeywordsPhysical ActivityAcademic PerformanceCritical ThinkingSecondary SourceStructure ArgumentThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Highly flexible, IgG-shaped, trivalent antibodies effectively target tumor cells and induce T cell-mediated killing (2018)

A novel bispecific antibody format was applied to generate T cell-engaging antibodies. The TriFab format is a trivalent IgG-shaped entity composed of two Fab arms that bind to antigens on the surface of tumor cells, which are linked via flexible peptides to a CD3 binding moiety that replaces the CH2 domains of conventional IgGs. The distinctive feature of these T cell recruiting bispecifics is that their CD3 variable regions are incorporated between domains, rather than N- or C-terminally fused to an Fc or antibody fragments. T cell recruiting TriFabs resemble in size and shape, are expressed and show biophysical properties similar to regular IgGs. Transmission electron microscopy (TEM) demonstrates high flexibility of the cell surface binding arms as well as target antigen accessibility of the interspersed CD3 binding domain. Functional co-culturing assays of peripheral blood mononuclear cells (PBMCs) and different tumor cell lines (MCF7 and A431) revealed a dose-dependent T cell-mediated cytotoxicity that was induced by the TriFabs targeting either LeY or EGFR cell surface antigens.
A Hierarchy of Nuclear Localization Signals Governs the Import of the Regulatory Factor X Complex Subunits and MHC Class II Expression (2004)

Comprised of RFX5, RFXAP, and RFX-B/ANK, the regulatory factor X (RFX) complex is an obligate transcription factor required for the expression of MHC class II genes. RFX functions by binding to the conserved X1 box sequence located upstream of all MHC class II genes. Using a mutagenesis scheme and a yeast heterologous reporter system, the mechanism by which the RFX complex is transported into the nucleus was examined. The results have identified specific nuclear localization signals (NLS) in both RFX5 and RFXAP that direct the nuclear translocation and expression of MHC class II genes. Additionally, a nuclear export signal was identified in the N terminus of RFXAP. RFX-B was poorly localized to the nucleus, and no specific NLS was identified. Whereas RFX5 could import an RFXAP NLS mutant into the nucleus, it had no effect on the import of RFX-B. The results suggest that although RFX5 and RFXAP could assemble before nuclear import, RFX-B association with the complex does not take place until after the subunits enter the nucleus. The identification of nuclear import and export sites on RFX molecules provides potential targets to modulate MHC class II expression.
The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients (2012)

This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.
Definition of an Fc receptor-related gene (FcRX) expressed in human and mouse B cells (2002)

The recent identification of five human Fc receptor (FcR) homologs, hFcRH1-5, has extended the known FcR family and identified an unanticipated richness of the chromosome 1q region in genes encoding potential Ig-binding proteins. In a database search for additional relatives of this family we identified expressed sequence tag representatives of a new FcR-related molecule (hFcRX) and its mouse ortholog (mFcRX). The FcRX cDNAs were cloned from human lymph node and mouse spleen cDNA libraries. hFcRX is located centromeric of FcgammaRII and FcgammaRIII at 1q23, and its mouse ortholog resides in a syntenic region of chromosome 1. The genes encode proteins with 67% interspecies identity that lack both N-linked glycosylation sites and transmembrane regions. Two of the four FcRX domains are Ig-like, and share characteristics similar to FcgammaRI domains 2 and 3, having 28% overall extracellular identity with hFcgammaRI and 27% identity with mFcgammaRI respectively. FcRX transcripts are found primarily in secondary lymphoid tissues, where they are expressed by B lineage cells. FcRX thus may function as a secreted or intracellular protein in normal and neoplastic B cells.
In situ detection of sequence-specific DNA binding activity specified by a recombinant bacteriophage. (1988)

We have used a recombinant bacteriophage that expresses the DNA-binding domain of C/EBP to optimize conditions for a screening technique that may facilitate the cloning of genes that encode sequence-specific DNA-binding proteins. The method relies on the expression of cDNA inserts in bacteriophage lambda gt11. Fusion protein adsorbed onto nitrocellulose filters is probed with radioactive, double-stranded DNA as a ligand. Two procedures greatly increase the level of binding between ligand and recombinant fusion protein. First, nitrocellulose filters are processed through a denaturation/renaturation regimen using 6 M guanidine hydrochloride. Second, synthetic DNA corresponding to the specific binding site is catenated extensively using DNA ligase. The combination of these procedures leads to remarkably strong detection signals. Specific DNA-binding signals can be detected on duplicate filters, and filters can be washed and reused by repeating the cycle of denaturation/renaturation.
In vivo activity of 4-methylcoumarin-7-O-sulfamate, a nonsteroidal, nonestrogenic steroid sulfatase inhibitor. (1996)

Steroid sulfatase regulates the formation of estrone from estrone sulfate (E1S) and dehydroepiandrosterone (DHA) from DHA sulfate. DHA can be converted to androstenediol, a steroid with potent estrogenic properties, and inhibition of steroid sulfatase activity is therefore an important therapeutic target. Because nonsteroidal steroid sulfatase inhibitors may offer some advantage for use in the treatment of breast cancer, 4-methylcoumarin-7-O-sulfamate (COUMATE) was synthesized and shown to be active in vitro. In this study, in vitro and in vivo techniques have been used to confirm that COUMATE, in contrast to the steroidal steroid sulfatase inhibitor estrone-3-O-sulfamate, is devoid of estrogenic activity. COUMATE did not stimulate the growth of MCF-7 breast cancer cells or uteri of ovariectomized rats, in contrast to estrone-3-O-sulfamate. COUMATE was orally active in vivo and after multiple dosing (10 mg/kg/day for 7 days) inhibited liver estrone sulfatase activity by 85%. Seven days after single or multiple dosing with COUMATE, liver estrone sulfatase activity was almost fully restored. Measurement of estrone sulfatase activity in WBCs revealed a degree of inhibition similar to that detected in liver samples. COUMATE was able to completely block the ability of E1S to stimulate uterine growth in ovariectomized rats. The development of a potent nonsteroidal, nonestrogenic steroid sulfatase inhibitor should allow the therapeutic potential of this type of therapy to be evaluated.
A different approach to treatment of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia lyase (1999)

Phenylketonuria (PKU), with its associated hyperphenylalaninemia (HPA) and mental retardation, is a classic genetic disease and the first to have an identified chemical cause of impaired cognitive development. Treatment from birth with a low phenylalanine diet largely prevents the deviant cognitive phenotype by ameliorating HPA and is recognized as one of the first effective treatments of a genetic disease. However, compliance with dietary treatment is difficult and when it is for life, as now recommended by an internationally used set of guidelines, is probably unrealistic. Herein we describe experiments on a mouse model using another modality for treatment of PKU compatible with better compliance using ancillary phenylalanine ammonia lyase (PAL, EC 4.3.1.5) to degrade phenylalanine, the harmful nutrient in PKU; in this treatment, PAL acts as a substitute for the enzyme phenylalanine monooxygenase (EC 1.14.16.1), which is deficient in PKU. PAL, a robust enzyme without need for a cofactor, converts phenylalanine to trans-cinnamic acid, a harmless metabolite. We describe (i) an efficient recombinant approach to produce PAL enzyme, (ii) testing of PAL in orthologous N-ethyl-N'-nitrosourea (ENU) mutant mouse strains with HPA, and (iii) proofs of principle (PAL reduces HPA)-both pharmacologic (with a clear dose-response effect vs. HPA after PAL injection) and physiologic (protected enteral PAL is significantly effective vs. HPA). These findings open another way to facilitate treatment of this classic genetic disease.
Prediction of Late Disease Recurrence and Extended Adjuvant Letrozole Benefit by the HOXB13/IL17BR Biomarker (2013)

In the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence.
Normal and abnormal pulmonary ventilation: visualization at hyperpolarized He-3 MR imaging. (1996)

To assess the feasibility of helium-3 magnetic resonance (MR) imaging with a three-dimensional fast low-angle shot (FLASH) sequence, He-3 gas (volume, 300 mL; pressure, 3 x 10(5) Pa; polarized up to 45% by means of optimal pumping) was inhaled by five healthy volunteers and five patients with pulmonary diseases. All breath-hold examinations (22-42 seconds) were completed successfully. Normal ventilation was depicted with homogeneous high signal intensity, lesions were depicted as causing defects, and obstructive lung disease was depicted with severely inhomogeneous signal intensity.
Group I aptazymes as genetic regulatory switches (2002)

Group I aptazymes may find applications as genetic regulatory switches for generating conditional knockouts at the level of mRNA or for developing economically viable gene therapies.
A high affinity calcium-stimulated magnesium-dependent adenosine triphosphatase in rat adipocyte plasma membranes. (1980)

N,N',N'-tetraacetic acid CDTA, trans-cyclohexane-1,2
Endogenous adenosine inhibits P-selectin-dependent formation of coronary thromboemboli during hypoperfusion in dogs. (1998)

The activation of platelets and the formation of neutrophil- platelet conjugates may lead to the development of thromboemboli. We studied whether blockade of adenosine receptors during coronary hypoperfusion may cause thromboemboli via P-selectin-dependent mechanisms in 30 open-chest dogs. When coronary blood flow was reduced to 20% of the control, it was stable at low levels with increases in adenosine levels. When 8-p-sulfophenyltheophylline, an adenosine receptor antagonist, was infused during coronary hypoperfusion, coronary blood flow decreased gradually and approached almost zero 20 min after its administration. Histological examination revealed thromboemboli in the small coronary vessels. During hypoperfusion in the presence of 8-p-sulfophenyltheophylline, the mAb against P-selectin attenuated both the reduction in coronary blood flow and the formation of thromboemboli, and improved contractile and metabolic dysfunction of the myocardium. Flow cytometric analysis indicated that the expression of P-selectin on platelet and neutrophil-platelet adhesion were increased during coronary hypoperfusion, and that both were further augmented by 8-p-sulfophenyltheophylline. Immunohistochemical examination showed no staining of P-selectin in the ischemic myocardium. Adenosine inhibited the thrombin-induced expression of P-selectin on platelet and neutrophil- platelet adhesion via adenosine A2 receptors. Adenosine appears to inhibit the formation of thromboemboli during coronary hypoperfusion by suppressing the expression of P-selectin on platelets and neutrophil-platelet adhesion.
Expression and characterization of DrrA and DrrB proteins of Streptomyces peucetius in Escherichia coli: DrrA is an ATP binding protein (1997)

Streptomyces peucetius, a microorganism that produces the anticancer drugs doxorubicin and daunorubicin, is itself resistant to the action of these drugs. The genes conferring resistance to doxorubicin and daunorubicin in S. peucetius have been sequenced (P. G. Guilfoile and R. Hutchinson, Proc. Natl. Acad. Sci. USA 88:8553-8557, 1991). Two open reading frames, drrA and drrB, were proposed to encode for an ABC (ATP-binding cassette) type of permease that carries out export of the antibiotics in an ATP-dependent manner. This article reports subcloning of the drrA and drrB genes into Escherichia coli expression vectors and characterization of their gene products. Upon induction from the lac promoter, a 36-kDa DrrA protein could be identified on Coomassie blue-stained gels. The DrrB protein was identified by use of a polyclonal antiserum generated against a synthetic peptide corresponding to a portion of the DrrB protein. Together, the DrrA and DrrB proteins conferred resistance to doxorubicin in E. coli. The DrrB protein was localized to the cell membrane. The DrrA protein bound ATP or GTP in a Mg2+-dependent fashion. ATP binding was enhanced on addition of doxorubicin or daunorubicin.
Effect of intensive i.v. + oral magnesium supplementation on circulating ion levels, lipid parameters and metabolic control in Mg-depleted insulin-dependent diabetic patients (IDDM). (1997)

Magnesium depletion in diabetic patients is a frequent observation and is involved in the pathogenesis of acute and chronic complications. In this study the effect of a 10 week intensive oral + i.v. supplementation of Mg was studied in 11 depleted IDDM patients with stable metabolic control. Ionized Mg decreased and erythrocyte Mg increased significantly together with an increased storage of Mg in the body demonstrated with a classical retention test. Normalization of the Mg parameters was however not obtained. Lipid parameters and metabolic control remained unchanged.
Evidence for a chair cyclohexane-1,4-radical cation intermediate in the single electron-transfer-induced Cope rearrangement of 2,5-diaryl-1,5-hexadienes (1988)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEvidence for a chair cyclohexane-1,4-radical cation intermediate in the single electron-transfer-induced Cope rearrangement of 2,5-diaryl-1,5-hexadienesTsutomu. Miyashi, Akinori. Konno, and Yasutake. TakahashiCite this: J. Am. Chem. Soc. 1988, 110, 11, 3676–3677Publication Date (Print):May 1, 1988Publication History Published online1 May 2002Published inissue 1 May 1988https://pubs.acs.org/doi/10.1021/ja00219a062https://doi.org/10.1021/ja00219a062research-articleACS PublicationsRequest reuse permissionsArticle Views264Altmetric-Citations47LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Soy Isoflavones Improve Systemic Arterial Compliance but Not Plasma Lipids in Menopausal and Perimenopausal Women (1997)

The possibility that the heightened cardiovascular risk associated with the menopause, which is said to be ameliorated by soybeans, can be reduced with soy isoflavones was tested in 21 women. Although several were perimenopausal, all have been included. A placebo-controlled crossover trial tested the effects of 80-mg daily isoflavones (45 mg genistein) over 5- to 10-week periods. Systemic arterial compliance (arterial elasticity), which declined with age in this group, improved 26% (P < .001) compared with placebo. Arterial pressure and plasma lipids were unaffected. The vasodilatory capacity of the microcirculation was measured in nine women; high acetylcholine-mediated dilation in the forearm vasculature was similar with active and placebo treatments. LDL oxidizability measured in vitro was unchanged. Thus, one important measure of arterial health, systemic arterial compliance, was significantly improved in perimenopausal and menopausal women taking soy isoflavones to about the same extent as is achieved with conventional hormone replacement therapy.
Selective targeting of G‐protein‐coupled receptor subtypes with venom peptides (2011)

The G-protein-coupled receptor (GPCR) family is one of the largest gene superfamilies with approx. 370 members responding to endogenous ligands in humans and a roughly equal amount of receptors sensitive to external stimuli from the surrounding. A number of receptors from this superfamily are well recognized targets for medical treatment of various disease conditions, whereas for many others the potential medical benefit of interference is still obscure. A general problem associated with GPCR research and therapeutics is the insufficient specificity of available ligands to differentiate between closely homologous receptor subtypes. In this context, venom peptides could make a significant contribution to the development of more specific drugs. Venoms from certain animals specialized in biochemical hunting contain a mixture of molecules that are directed towards a variety of membrane proteins. Peptide toxins isolated from these mixtures usually exhibit high specificity for their targets. Muscarinic toxins found from mamba snakes attracted much attention during the 1990s. These are 65-66 amino acid long peptides with a structural three-finger folding similar to the α-neurotoxins and they target the muscarinic acetylcholine receptors in a subtype-selective manner. Recently, several members of the three-finger toxins from mamba snakes as well as conotoxins from marine cone snails have been shown to selectively interact with subtypes of adrenergic receptors. In this review, we will discuss the GPCR-directed peptide toxins found from different venoms and how some of these can be useful in exploring specific roles of receptor subtypes.