gebhart/patrepeval huggingface dataset:
Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression (2020)

Our data establish essential roles for Tregs in resolving atherosclerotic cardiovascular disease and provide mechanistic insight into the pathways governing plaque remodeling and regression of disease.
The IGF system and breast cancer. (2001)

The IGF system components have been implicated in breast cancer progression. IGF-I and IGF-II are mitogenic and anti-apoptotic peptides that influence the proliferation of various cell types including normal and transformed breast epithelial cells. The IGF system is a key growth regulatory pathway in breast cancer. As various components of the IGF system have been directly or indirectly implicated in breast cancer, it is essential to gain a better understanding of these in order to develop more specific therapeutic strategies for treating breast cancer.
Effects of interleukin-3 on hematopoietic recovery after 5-fluorouracil or cyclophosphamide treatment of cynomolgus primates. (1990)

Interleukin-3 (IL-3) is a hematopoietic growth factor that supports the growth of early hematopoietic progenitors in vitro. In vivo administration of recombinant human interleukin-3 (rhIL-3) to normal primates results in a modest and delayed leukocytosis secondary to increases in neutrophils, basophils, and eosinophils. We postulated that the effects of rhIL-3 might be more pronounced in hematologically stressed primates, and therefore administered rhIL-3 to primates after intensive myelosuppressive therapy. Primates received either cyclophosphamide (CPM) at 60 mg/kg or 5-fluorouracil (5-FU) at 75 mg/kg i.v. on two consecutive days. Subsequently, rhIL-3 was administered intravenously or subcutaneously at 20 micrograms/kg per d for 14 d. Compared to controls, all rhIL-3 treated primates experienced higher absolute neutrophil count (ANC) nadirs and dramatic decreases in the period of severe neutropenia (ANC less than 500) after myelosuppressive therapy. RhIL-3 administration resulted in a significant basophilia and eosinophilia, which resolved after discontinuation of the drug. RhIL-3 did not enhance erythroid recovery. Platelet recovery was earlier in rhIL-3-treated animals. However, variations in the platelet recovery observed in control animals, precluded accurate estimation of this effect or its significance. Our results indicate that the administration of rhIL-3 following intensive myelosuppressive therapy dramatically enhances myeloid recovery and ablates the predicted period of prolonged severe neutropenia.
Efficient Heterogeneous Aerobic Oxidation of Amines by a Supported Ruthenium Catalyst (2003)

An inexpensive supported ruthenium catalyst (Ru/Al2O3) can be used to convert a broad range of primary (see scheme) and secondary amines into the corresponding nitriles and imines in high yields using either dioxygen or air as oxidants. The catalyst can be recycled and reused with no detectable loss of ruthenium and without an observed reduction in catalytic activity. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2003/z50779_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
The effect of elimination of intersubunit disulfide bonds on the activity, assembly, and secretion of recombinant human acetylcholinesterase. Expression of acetylcholinesterase Cys-580—-Ala mutant. (1991)

Site-directed mutagenesis was used to study the cysteine residue involved in the assembly of human acetylcholinesterase (HuAChE) catalytic subunits.Substitution of the cysteine at position 580 by alanine resulted in impairment of interchain disulfide bridge formation; the mutagenized enzyme (C580A) was secreted from recombinant cells in the monomeric form and failed to assemble into dimers.The mutant monomeric HuAChE did not differ from the native oligomeric enzyme neither in rate of catalysis nor in affinity to acetylthiocholine.Mutant monomers were also shown to retain the acetylcholinesterase characteristic sensitivity to high substrate concentrations.The mutation did not seem to affect the efficiencies of either synthesis or secretion of recombinant HuAChE polypeptides, as was demonstrated in cell lines derived from human embryonic kidney (293 cells) as well as from a human neuroblastoma (SK-N-SH).Furthermore, the mutation did not lead to an increase in accumulation of intracellular HuAChE polypeptides, suggesting that export of acetylcholinesterase from cells may not be coupled to subunit assembly.Acetylcholinesterase (EC 3.1.1.7;abbreviated herein AChE)' occurs in multiple molecular forms in different tissues of vertebrates and invertebrates.Some of these forms are soluble while others are associated with the extracellular surface of cells by different mechanisms of attachment (reviewed in Massoulie and Bon, 1982;Silman and Futerman, 1987; Chatonnet and Lockridge, 1989).Members of one subset of attached forms consists of two or three tetramers of catalytic subunits linked to a collagen-like structure that allows attachment to the basal lamina.A second class of cell-bound forms consists of tetramers of catalytic subunits attached to a 20-kDa non-catalytic subunit embedded in the plasma membrane.The AChE forms that are not associated with structural subunits can be divided into two classes: those composed
A Gain-of-function Polymorphism in a G-protein Coupling Domain of the Human β1-Adrenergic Receptor (1999)

The beta1-adrenergic receptor (beta1AR) is a key cell surface signaling protein expressed in the heart and other organs that mediates the actions of catecholamines of the sympathetic nervous system. A polymorphism in the intracellular cytoplasmic tail near the seventh transmembrane-spanning segment of the human beta1AR has been identified in a cohort of normal individuals. At amino acid position 389, Gly or Arg can be found (allele frequencies 0.26 and 0. 74, respectively), the former previously considered as the human wild-type beta1AR. Using site-directed mutagenesis to mimic the two variants, CHW-1102 cells were permanently transfected to express the Gly-389 and Arg-389 receptors. In functional studies with matched expression, the Arg-389 receptors had slightly higher basal levels of adenylyl cyclase activities (10.7 +/- 1.2 versus 6.1 +/- 0.4 pmol/min/mg). However, maximal isoproterenol-stimulated levels were markedly higher for the Arg-389 as compared to the Gly-389 receptor (63.3 +/- 6.1 versus 20.9 +/- 2.0 pmol/min/mg). Agonist-promoted [35S]guanosine 5'-O-(thiotriphosphate) binding was also increased with the Arg-389 receptor consistent with enhanced coupling to Gs and increased adenylyl cyclase activation. In agonist competition studies carried out in the absence of guanosine 5'-(beta, gamma-imido)triphosphate, high affinity binding could not be resolved with the Gly-389 receptor, whereas Arg-389 displayed an accumulation of the agonist high affinity receptor complex (RH = 26%). Taken together, these data indicate that this polymorphic variation of the human beta1AR results in alterations of receptor-Gs interaction with functional signal transduction consequences, consistent with its localization in a putative G-protein binding domain. The genetic variation of beta1AR at this locus may be the basis of interindividual differences in pathophysiologic characteristics or in the response to therapeutic betaAR agonists and antagonists in cardiovascular and other diseases.
Differential regulation of central vasopressin in transgenic rats harboring the mouse Ren-2 gene (1994)

The transgenic (TG) rat carrying the mouse renin gene (mRen-2d) has provided a unique opportunity to explore central interactions between the brain renin-angiotensin (RAS) and vasopressin (AVP) systems. To evaluate the hypothalamic vasopressin axis in the TG rat, we measured the central nervous system concentrations of AVP and determined the effect of angiotensin II (ANG II) and its NH2-terminal heptapeptide [angiotensin-(1-7)] on blood pressure, heart rate, and AVP release using brain microdialysis. Intracerebroventricular infusion of ANG II or ANG-(1-7) in control rats increased local AVP release from the paraventricular and supraoptic nuclei. The ANG II infusion was associated with a significant increase in blood pressure not observed with ANG-(1-7). In contrast, the angiotensin peptide-induced central AVP responses and the ANG II-induced blood pressure increase were absent in the TG animal. The plasma AVP responses to ANG II and ANG-(1-7) were comparable in the control and TG rats. The TG rats exhibited a 22-fold higher level of AVP in the dorsal lower brain stem but had lower AVP levels in the posterior pituitary and the median eminence compared with control rats. These results suggest that insertion of the mouse renin gene into the rat genome leads to alterations in the AVP axis in terms of AVP peptide content and angiotensin-induced cardiovascular and AVP responses.
Noncoding regions are the main source of targetable tumor-specific antigens (2018)

Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but few have been identified thus far. We therefore developed a proteogenomic approach to enable the high-throughput discovery of TSAs coded by potentially all genomic regions. In two murine cancer cell lines and seven human primary tumors, we identified a total of 40 TSAs, about 90% of which derived from allegedly noncoding regions and would have been missed by standard exome-based approaches. Moreover, most of these TSAs derived from nonmutated yet aberrantly expressed transcripts (such as endogenous retroelements) that could be shared by multiple tumor types. Last, we demonstrated that, in mice, the strength of antitumor responses after TSA vaccination was influenced by two parameters that can be estimated in humans and could serve for TSA prioritization in clinical studies: TSA expression and the frequency of TSA-responsive T cells in the preimmune repertoire. In conclusion, the strategy reported herein could considerably facilitate the identification and prioritization of actionable human TSAs.
Combined vaccine+axitinib therapy yields superior antitumor efficacy in a murine melanoma model (2012)

Axitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptors, has demonstrated modest efficacy when applied as a single agent in the setting of advanced-stage melanoma. On the basis of the reported ability of axitinib to 'normalize' the tumor vasculature, we hypothesize that combination therapy using axitinib plus specific peptide-based vaccination would promote superior activation and recruitment of protective T cells into the melanoma microenvironment, leading to enhanced treatment benefit. Using a subcutaneous M05 (B16.OVA) melanoma model, we observed that a treatment regimen consisting of a 7-day course of axitinib (0.5 mg/day provided orally) combined with a subcutaneous vaccine [ovalbumin (OVA) peptide-pulsed syngenic dendritic cells adenovirally engineered to produce IL-12p70] yielded superior protection against melanoma growth and extended overall survival when compared with animals receiving either single modality therapy. Treatment benefits were associated with: (a) a reduction in suppressor cell (myeloid-derived suppressor cells and Treg) populations in the tumor, (b) activation of tumor vascular endothelial cells, and (c) activation and recruitment of type-1, vaccine-induced CD8 T cells into tumors. These results support the therapeutic superiority of combined vaccine+axitinib immunotherapy and the translation of such approaches into the clinic for the treatment of patients with advanced-stage melanoma.
Electronic Money and the Future of Central Banks (2002)

Computers and telecommunications devices may replace paper currency and checks?some day. Indeed, electronic methods of transferring money have become widely used. Recently, however, discussion of ?electronic money? has taken a new turn, zeroing in on the extent to which holding new forms of electronic money eventually could make central banks obsolete, rendering them powerless to control inflation. This Commentary updates the old story of electronic funds transfers before introducing the new story of electronic money holdings, which may be a metaphor for a larger question about the future of central banking.
Probing Structure-Function Relations in Heme-Containing Oxygenases and Peroxidases (1988)

Structural factors that influence functional properties are examined in the case of four heme enzymes: cytochrome P-450, chloroperoxidase, horseradish peroxidase, and secondary amine mono-oxygenase. The identity of the axial ligand, the nature of the heme environment, and the steric accessibility of the heme iron and heme edge combine to play major roles in determining the reactivity of each enzyme. The importance of synthetic porphyrin models in understanding the properties of the protein-free metal center is emphasized. The conclusions described herein have been derived from studies at the interface between biological and inorganic chemistry.
Structure of coiled β‐β‐hairpins and β‐β‐corners (1991)

Two types of super-secondary structure, coiled beta-beta-hairpins and beta-beta-corners, are considered in this paper. A beta-beta-corner can be represented as a long beta-beta-hairpin folded orthogonally on itself so that the strands, when passing from one layer to the other, rotate in a right-handed direction about an imaginary axis. It is shown that a beta-beta-hairpin, forming a coiled coil structure or a beta-beta-corner, is right-handed when viewed from the concave side. These unique arrangements of beta-strands in the coiled beta-beta-hairpins and beta-beta-corners are of particular value in protein modelling and prediction.
The therapeutic potential of RNA interference (2005)

In recent years, we have witnessed the discovery of a new mechanism of gene regulation called RNA interference (RNAi), which has revitalized interest in the development of nucleic acid-based technologies for therapeutic gene suppression. This review focuses on the potential therapeutic use of RNAi, discussing the theoretical advantages of RNAi-based therapeutics over previous technologies as well as the challenges involved in developing RNAi for clinical use. Also reviewed, are the in vivo proof-of principle experiments that provide the preclinical justification for the continued development of RNAi-based therapeutics.
[The role of electrical neuromodulation in the therapy of chronic lower urinary tract dysfunction]. (2003)

The electrostimulation techniques may be used as a supplement or an alternative to standard therapy. Electrical therapy for chronic lower tract dysfunction comprises of non-invasive pudendal nerve neuromodulation and invasive sacral nerve stimulation. Short-term functional electrical stimulation seems favourable in selected patients with detrusor hyperreflexia. Sacral nerve stimulation may be a successful treatment option for patients with refractory detrusor overactivity and some forms of urinary retention.
Noise reduction and design methodology in mixed-signal systems with alternating impedance electromagnetic bandgap (AI-EBG) structure (2005)

This paper presents noise suppression and design methodology in mixed-signal systems with alternating impedance electromagnetic bandgap (AI-EBG) structure. The AI-EBG structure was developed recently and applied for noise isolation/suppression in mixed-signal systems. In this paper, the mixed-signal systems with and without the AI-EBG structure were designed and fabricated to see noise reduction effect due to AI-EBG structure. This AI-EBG structure showed excellent noise suppression in mixed-signal systems by suppressing all harmonic noise peaks due to digital circuits in a stopband range of -100 dB isolation (S/sub 21/) level. However, without carefully designing mixed-signal system with the AI-EBG structure, the use of the AI-EBG structure could cause problems associated with signal integrity as well as electromagnetic interference (EMI). In this paper, excellent noise suppression with AI-EBG structure is shown and design methodology in mixed-signal systems with AI-EBG structure is proposed to avoid possible problems associated with signal integrity as well as EMI.
Specificity of antiglobulin factors in normal human serum reacting with enzyme digested gamma-G-globulin. (1968)

Summary Papain agglutinator in normal human serum was found to react with erythrocytes sensitized with autologous and homologous Fab fragments of anti-Rh antibody. The incidence of agglutinator activity ranged from 24 to 93%. This broad range was attributed to the sensitivity of the hemagglutination assay, specificity of Fab sensitizor, age of the individuals and parental background. Papain agglutinator is similar to the previously described pepsin agglutinator in many respects, but differences in specificity were established by reciprocal absorption and inhibition experiments. Therefore a new buried antigenic determinant is exposed by digesting human γG-globulin with papain. This antigenic difference between the Fab and (Fab′) 2 fragments supports the concept that papain and pepsin cleaves the γG-globulin molecules at different sites.
Synthesis and Application of Submicrometer Fluorescence Sensing Particles for Lysosomal pH Measurements in Murine Macrophages (2000)

Phagocytosis of bioparticles such as bacteria and viruses by macrophages is a critical component of the immune response against infections. In this paper we describe the synthesis of submicrometer fluorescent particles with pH sensing capability. The particles are used to measure the pH and to monitor the effect of chloroquine, an antimalarial drug, on the pH in the lysosome, the cellular organelle involved in the phagocytosis process. The synthesis of the pH sensing particles is realized by the covalent attachment of amine reactive forms of Oregon Green (pH sensitive dye) and Texas Red (pH insensitive dye) to the surface of amino-modified submicrometer polystyrene particles. The particles are absorbed by J774 Murine Macrophages through phagocytosis and directed to lysosomes. Despite the high lysosomal levels of digestive enzymes and acidity, the absorbed particles remain stable for 12 h in the cells when they are stored in a PBS buffer solution at pH 7.4. The pH dynamic range of the sensing particles is between pH 4.5 and 7 with a sensitivity of 0.1 pH units. Exposure of the cells to chloroquine increases the lysosomal pH from 4.8 to 6.5. The effect is concentration-dependent.
Increased protein binding to a −530 mutation of the human β‐globin gene associated with decreased β‐globin synthesis (1991)

Although some cases of the syndrome of hereditary persistence of fetal hemoglobin (HPFH) have been correlated with mutations causing a change in the binding of trans-acting factors to DNA sequences flanking the gamma-globin gene, this mechanism has not been described in beta-thalassemias upstream of the canonical promoter of the beta-globin gene. In this report we describe such a change in binding of a protein that may explain a silent carrier phenotype of beta-thalassemia. We have previously demonstrated the binding of a protein (BP1) derived from a nuclear extract of human K562 cells to DNA 5' to the human beta-globin gene in a region having a negative regulatory function. The binding of BP1 in this region can be detected by DNAse I footprinting and by gel mobility shift analysis. We have now compared binding of BP1 to the normal sequence and a mutated sequence (+ATA/-T at -530 bp from the cap site) from the silent carrier of beta-thalassemia. Using mobility shift assays we show that BP1 binds about nine times more strongly to the mutated sequence than the normal sequence. These results suggest the possibility that the decreased expression of the beta-globin gene exhibited by the carrier may be due, at least in part, to tighter binding of a protein which functions as a negative control element or repressor.
Synthesis of fluorescent nucleotide analogues: 5'-mono-, di-, and triphosphates of linear-benzoguanosine, linear-benzoinosine, and linear-benzoxanthosine. (1979)

The fluorescent nucleotide analogues (the 5'-mono-, di-, and triphosphates of lin-benzoguanosine, lin-benzoxanthosine, and lin-benzoinosine) have been prepared for use as dimensional probes of enzyme binding sites. They have quantum yields in aqueous solution of 0.39, 0.55, and 0.04 and fluorescent lifetimes of 6, 9, and approximately equal to 1.5 nsec, respectively. lin-Benzoinosine 5'-monophosphate is a substrate for xanthine oxidase (xanthine:oxygen oxidoreductase, EC 1.2.3.2), providing lin-benzoxanthosine 5'-monophosphate, and lin-benzoinosine 5'-diphosphate is a substrate for polynucleotide phosphorylase (polyribonucleotide:orthophosphate nucleotidyltransferase. EC 2.7.7.8), giving poly(lin-benzoinosinic acid). The benzologues of the purine diphosphates are substrates for pyruvate kinase (ATP:pyruvate 2-O-phosphotransferase, EC 2.7.1.40), which is used to prepare the triphosphates.
TIM3+FOXP3+regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer (2013)

T-cell immunoglobulin mucin 3 (TIM3) is an inhibitory molecule that has emerged as a key regulator of dysfunctional or exhausted CD8<sup>+</sup> T cells arising in chronic diseases such as cancer. In addition to exhausted CD8<sup>+</sup> T cells, highly suppressive regulatory T cells (Tregs) represent a significant barrier against the induction of antitumor immunity. We have found that the majority of intratumoral FOXP3<sup>+</sup> Tregs express TIM3. TIM3<sup>+</sup> Tregs co-express PD-1, are highly suppressive and comprise a specialized subset of tissue Tregs that are rarely observed in the peripheral tissues or blood of tumor-bearing mice. The co-blockade of the TIM3 and PD-1 signaling pathways in vivo results in the downregulation of molecules associated with TIM3<sup>+</sup> Treg suppressor functions. This suggests that the potent clinical efficacy of co-blocking TIM3 and PD-1 signal transduction cascades likely stems from the reversal of T-cell exhaustion combined with the inhibition of regulatory T-cell function in tumor tissues. Interestingly, we find that TIM3<sup>+</sup> Tregs accumulate in the tumor tissue prior to the appearance of exhausted CD8<sup>+</sup> T cells, and that the depletion of Tregs at this stage interferes with the development of the exhausted phenotype by CD8<sup>+</sup> T cells. Collectively, our data indicate that TIM3 marks highly suppressive tissue-resident Tregs that play an important role in shaping the antitumor immune response in situ, increasing the value of TIM3-targeting therapeutic strategies against cancer.