gebhart/patrepeval huggingface dataset:
Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy (2012)

The knockdown of myostatin, a negative regulator of skeletal muscle mass may have important implications in disease conditions accompanied by muscle mass loss like cancer, HIV/AIDS, sarcopenia, muscle atrophy, and Duchenne muscular dystrophy (DMD). In DMD patients, where major muscle loss has occurred due to a lack of dystrophin, the therapeutic restoration of dystrophin expression alone in older patients may not be sufficient to restore the functionality of the muscles. We recently demonstrated that phosphorodiamidate morpholino oligomers (PMOs) can be used to re-direct myostatin splicing and promote the expression of an out-of-frame transcript so reducing the amount of the synthesized myostatin protein. Furthermore, the systemic administration of the same PMO conjugated to an octaguanidine moiety (Vivo-PMO) led to a significant increase in the mass of soleus muscle of treated mice. Here, we have further optimized the use of Vivo-PMO in normal mice and also tested the efficacy of the same PMO conjugated to an arginine-rich cell-penetrating peptide (B-PMO). Similar experiments conducted in mdx dystrophic mice showed that B-PMO targeting myostatin is able to significantly increase the tibialis anterior (TA) muscle weight and when coadministered with a B-PMO targeting the dystrophin exon 23, it does not have a detrimental interaction. This study confirms that myostatin knockdown by exon skipping is a potential therapeutic strategy to counteract muscle wasting conditions and dual myostatin and dystrophin skipping has potential as a therapy for DMD.Molecular Therapy - Nucleic Acids (2012) 1, e62; doi:10.1038/mtna.2012.54; published online 18 December 2012.
Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries (2003)

FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.
Insulin-like growth factor-I inhibits insulin and amylin secretion in conscious rats (1994)

Human recombinant insulin-like growth factor-I (IGF-I) exerts insulin-like antidiabetic properties in vitro and in vivo. To determine the effects of IGF-I infusion on insulin and amylin release, plasma glucose of freely moving undisturbed rats was constantly maintained at 13.9 mmol/liter by variable glucose infusion for 120 min in three groups of fasted Sprague-Dawley rats (hyperglycemic clamp technique). Group A, vehicle infusion (control group); group B, bolus 0.39 nmol plus 0.39 nmol/h IGF-I continously; and group C, bolus 1.96 nmol plus 1.96 nmol/h IGF-I continuously. During the steady-state phase of the experiment, IGF-I dose dependently reduced plasma insulin (pmol/liter: A, 718 +/- 58; B, 613 +/- 35, NS vs. A; C, 408 +/- 21, P < 0.01 vs. A; dose-response effect: P < 0.0001), plasma amylin (pmol/liter: A, 10.2 +/- 0.6; B, 8.8 +/- 0.5, NS vs. A; C, 5.8 +/- 0.4, P < 0.01 vs. A; dose-response effect: P < 0.0001), and net glucose uptake (mumol/kg.min: A, 188 +/- 12; B, 160 +/- 12, NS vs. A; C, 134 +/- 7, P < 0.01 vs. A; dose-response effect: P < 0.0025). At the same time, the ratio of plasma insulin/plasma amylin (mol/mol: A, 72 +/- 6; B, 71 +/- 5; C, 74 +/- 9; NS), the ratio of net glucose uptake/plasma insulin (mumol/kg.min per pmol/liter: A, 0.28 +/- 0.03; B, 0.27 +/- 0.02; C, 0.36 +/- 0.04; NS), and glycogen content of liver, heart, and various hindlimb muscles remained unaffected. The results demonstrate that IGF-I is a potent inhibitor of insulin and amylin release in healthy rats exposed to hyperglycemia and suggest that IGF-I infusion inhibits hormone secretion from pancreatic beta cells at infusion rates that do not affect insulin-stimulated glucose uptake by peripheral tissues.
Electronic Circuits for the Generation and Transfer of High-Power Pulses in Nuclear Fusion Installations (1984)

The toroidal confinement and the ohmic heating of a thermonuclear plasma as used in tokamak experiments can be achieved by strong magnetic fields and by a heavy direct current flowing parallel to the axis of the plasma torus. This current can be induced with the aid of a transformer for which the plasma torus acts as the secondary winding. The high loop voltage required for start-up is obtained by commutation of the primary current to a resistor. This commutation can be achieved by a mechanical switch or by electronic circuits. New electronic commutation circuits are described which enable very heavy direct currents to be switched without contacts. The operation of the new circuits was checked by computer calculations. Experiments have not yet been performed.
At the Crossroads (2006)

Review| June 01 2006 At the Crossroads Book Arts Academic Educators Working Group Meeting, The University of Alabama, Tuscaloosa, Alabama, January 13-14, 2006 Tony White Tony White Tony White is interim director of Reader Services; an Arts & Architecture Librarian, and assistant professor at Pratt Institute in Brooklyn, New York. Search for other works by this author on: This Site PubMed Google Scholar Afterimage (2006) 33 (6): 10. https://doi.org/10.1525/aft.2006.33.6.10 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Tony White; At the Crossroads. Afterimage 1 June 2006; 33 (6): 10. doi: https://doi.org/10.1525/aft.2006.33.6.10 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAfterimage Search This content is only available via PDF. © 2006 by The Regents of the University of California2006 Article PDF first page preview Close Modal You do not currently have access to this content.
Mutants of Mucor hiemalis Endo-β-N-acetylglucosaminidase Show Enhanced Transglycosylation and Glycosynthase-like Activities (2007)

Endo-beta-N-acetylglucosaminidase from Mucor hiemalis (Endo-M), a family 85 glycoside hydrolase, acts on the beta1,4 linkage of N,N'-diacetylchitobiose moiety in the N-linked glycans of glycoproteins and catalyzes not only the hydrolysis reaction but also the transglycosylation reaction that transfers the releasing sugar chain to an acceptor other than water to form a new glycosidic linkage. The transglycosylation activity of Endo-M holds a great promise for the chemo-enzymatic synthesis and glyco-engineering of glycoproteins, but the inherent hydrolytic activity for product hydrolysis and low transglycosylation have hampered its broad applications. This paper describes the site-directed mutagenesis on residues in the putative catalytic region of Endo-M to generate mutants with superior transglycosylation activity. Two interesting mutants were discovered. The Y217F mutant was found to possess much enhanced transglycosylation activity and yet much diminished hydrolytic activity in comparison with the wild-type Endo-M. Kinetic analyses revealed that the Km value of Y217F for an acceptor substrate 4-methylumbelliferyl-beta-D-N-acetylglucosaminide was only one-tenth of that of the wild-type, implicating a much higher affinity of Y217F for the acceptor substrate than the wild-type. The other mutant, N175A, acts like a glycosynthase. It was found that mutation at Asn175"knocked out" the hydrolytic activity, but the mutant was able to take the highly active sugar oxazolines (the transition state mimics) as donor substrates for transglycosylation. This is the first glycosynthase derived from endo-beta-N-acetylglucosaminidases that proceed via a substrate-assisted mechanism. Our findings provide further insights on the substrate-assisted mechanism of GH85. The usefulness of the novel glycosynthase was exemplified by the efficient synthesis of a human immunodeficiency virus, type 1 (HIV-1) glycopeptide with potent anti-HIV activity.
N-acetyl-L-Cysteine Promotes T Cell Mediated Immunity In Allogeneic Settings IN VIVO And IN VITRO (2009)

N-acetyl-L-cysteine (NAC) is a thiol antioxidant which stimulates glutathione synthesis in cells. Several studies indicate that NAC exerts effects on the immune system in vitro, although with conflicting results. Whereas some studies indicate that NAC has an inhibitory effect on T cell proliferation and activation of NF-κB, others suggest an activating effect. The ability of NAC to protect cells against oxidative stress by inducing glutathione has provided a rationale for using it to prevent veno-occlusive disease of the liver and liver toxicity after allogeneic stem cell transplantation (ASCT). Unfortunately, a prospective randomized study failed to show a positive effect of NAC on hepatotoxicity in ASCT patients. However, we observed that patients who received NAC as a therapy to treat liver toxicity (n = 73) had an increased prevalence of acute GvHD compared to patients who had been randomized to not receive NAC (n = 87) (P = 0.04), indicating that NAC has an immunostimulatory effect in vivo. Importantly, the NAC-treated group only had an increased risk of grade II acute GvHD (30%) compared to the control group (10%), whereas severe acute GvHD grades III-IV in the groups were 8% vs 14%, respectively. These observations prompted us to thoroughly study the effect of NAC on T cell mediated immunity in vitro. We have found that low levels of NAC (0.4–3.2 mM) potentiate T cell proliferation and upregualtion of activation markers in response to alloantigens, whereas high concentrations (12.5–50 mM) are highly suppressive, which might explain the previously published conflicting data. Furthermore, T cells that have been stimulated in the presence of high concentrations of NAC (25 mM) in a primary mixed lymphocyte reaction (MLR) respond more vigorously when restimulated in a secondary MLR without NAC, compared to control secondary MLR which had been cultured without NAC during both stimulations. Preliminary data indicate that this observation partly can be explained by that NAC render T cells less apoptotic, and that T cells respond robustly when NAC has been metabolized. To summarize, we have found that NAC has an immunostimulatory effect on T cells under certain conditions, both in vitro and in vivo. These observations might be of clinical importance, as NAC potentially could be used as a therapeutic agent to promote T cell mediated immunity in immunocompromized ASCT patients with relapse of the underlying malignant disease.
Leukotriene A4 Hydrolase, Mutation of Tyrosine 378 Allows Conversion of Leukotriene A4 into an Isomer of Leukotriene B4 (1996)

Leukotriene A4 hydrolase catalyzes the final step in the biosynthesis of the proinflammatory compound leukotriene B4, a reaction which is accompanied by suicide inactivation of the enzyme by leukotriene A4. We have recently reported that Tyr-378 is a major structural determinant for suicide inactivation and that mutation of Tyr-378 into Phe or Gln protects leukotriene A4 hydrolase from this catalytic restriction (Mueller, M. J., Blomster, M., Opperman, U. C. T., Jörnvall, H., Samuelsson, B., and Haeggström, J. Z. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 5931-5935). In the present study, we show that both [Y378F]- and [Y378Q]leukotriene A4 hydrolase converts leukotriene A4 not only into leukotriene B4 but also into a second, previously unknown, product of the enzyme. From biophysical analyses and comparison with a synthetic standard, the structure of this product was determined to 5S,12R-dihydroxy-6,10-trans-8, 14-cis-eicosatetraenoic acid, i.e. Delta6-trans-Delta8-cis-leukotriene B4. The relative formation of Delta6-trans-Delta8-cis-leukotriene B4 versus leukotriene B4 by [Y378F]- and [Y378Q]leukotriene A4 hydrolase, was 18% and 32%, respectively. For [Y378F]leukotriene A4 hydrolase, the turnover of leukotriene A4 into leukotriene B4 or Delta6-trans-Delta8-cis-leukotriene B4 was calculated to 2.5 s-1 which is almost three times the kcat value of the wild type enzyme. Taken together, these findings indicate that Tyr-378 is located at the active site where it assists in the formation of the correct double-bond geometry in the product leukotriene B4.
Identification of the equine herpesvirus type 1 glycoprotein 17/18 as a homologue of herpes simplex virus glycoprotein D (1992)

The DNA sequence of the equine herpesvirus type 1 (EHV-1) gD gene homologue has been determined for the strain Ab1 and compared with previously published sequences. A portion of the gene has been located to a region of the genome which also encodes homologues of the herpes simplex virus type 1 genes for gE and gI and is known to encode an epitope of the virion protein gp17/18. Analysis of the EHV-1 strain Kentucky A (KyA) by DNA hybridization showed the presence of a gD gene homologue and established the absence of genes for gI and gE. Western blot analysis, however, showed that KyA virus particles contain gp17/18, thus indicating that this protein is encoded by the gD gene homologue. The KyA gp17/18 was found to be smaller than that detected in other strains and this is accounted for by a frameshift mutation in the KyA sequence relative to Ab1. The mutation in the KyA strain results in an altered C-terminal sequence and could explain the apparent structural differences suggested by the reactivities with monoclonal antibodies (MAbs). We have also expressed part of the Ab1 gD gene as a fusion protein with glutathione S-transferase in Escherichia coli and shown that this reacts with the MAb 5H6 originally used to map gp17/18. These experiments establish that gp17/18 is encoded by the gD gene homologue.
Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting (2015)

The ubiquitin system plays a critical role in muscle wasting. Previous work has focused on the roles of ubiquitination. However, a role for deubiquitination in this process has not been established. Because ubiquitin-specific protease (USP)19 deubiquitinating enzyme is induced in skeletal muscle in many catabolic conditions, we generated USP19 knockout (KO) mice. These mice lost less muscle mass than wild-type (WT) animals in response to glucocorticoids, a common systemic cause of muscle atrophy as well as in response to denervation, a model of disuse atrophy. KO mice retained more strength and had less myofiber atrophy with both type I and type IIb fibers being protected. Rates of muscle protein synthesis were similar in WT and KO mice, suggesting that the sparing of atrophy was attributed to suppressed protein degradation. Consistent with this, expression of the ubiquitin ligases MuRF1 and MAFbx/atrogin-1 as well as several autophagy genes was decreased in the muscles of catabolic KO mice. Expression of USP19 correlates with that of MuRF1 and MAFbx/atrogin-1 in skeletal muscles from patients with lung cancer or gastrointestinal cancer, suggesting that USP19 is involved in human muscle wasting. Inhibition of USP19 may be a useful approach to the treatment of many muscle-wasting conditions.
Clinical Studies with GHRH in Man (1986)

GHRH was isolated from two GHRH-secreting pancreatic tumors which resulted in clinical acromegaly. Over 98% of acromegalic patients have a pituitary adenoma; however, acromegaly may occasionally result from ectopic or eutopic GHRH secretion. Administration of GHRH to normal adults stimulates growth hormone (GH) secretion; it may also stimulate GH release in some adults with GH deficiency in childhood and in a majority of GH-deficient children. Continuous infusion of GHRH to normal men stimulates GH secretion which augments naturally occurring GH pulses. GHRH is effective when administered subcutaneously and intranasally, but requires 30- and 300-fold higher doses, respectively. Intermittent subcutaneous GHRH therapy promotes acceleration of linear growth in GH-deficient children and appears promising as a treatment for these children.
Peptide-YY and Neuropeptide-Y Inhibit Vasoactive Intestinal Peptide-Stimulated Adenosine 3′,5′-Monophosphate Production in Rat Small Intestine: Structural Requirements of Peptides for Interacting with Peptide-YY-Preferring Receptors* (1989)

Previous binding studies indicated that peptide-YY (PYY) and neuropeptide-Y (NPY) shared a common PYY-preferring receptor site in rat small intestinal epithelium. We showed here that PYY and NPY inhibited vasoactive intestinal peptide (VIP)-stimulated cAMP production in epithelial cells isolated from rat small intestine and examined their structure-activity relationship. Inhibition of VIP-stimulated cAMP by PYY or NPY is time and dose dependent; half-maximal effects were observed for 10 and 107 nM, respectively. In contrast, the structurally related peptide, pancreatic polypeptide, was only active at 1 microM. PYY or NPY reduced the efficacy of VIP by about 50% without altering its potency. Both peptides also suppressed prostaglandin E1-, prostaglandin E2-, and forskolin-stimulated cAMP production and reduced basal cAMP levels. Their inhibitory effects were observed throughout the small intestine, including duodenum, jejunum, and ileum, but not in large intestine. PYY or NPY and epinephrine (through alpha 2-adrenergic receptors) did not exert additive inhibitory effects on intestinal cAMP production. Several fragments of PYY and NPY were used to characterize their structural requirement for inhibiting VIP-stimulated cAMP production and competing with [125I]PYY for binding to intestinal membranes. A highly significant correlation was observed between IC50 values measured in the two assays. No partial sequence of PYY retained the full activity of intact PYY, but the C-terminal portion of PYY was shown to be much more important than the N-terminal portion. Deletion of 21 amino acids from the N-terminus [PYY-(22-36)] only resulted in a 4- to 5-fold decrease in potency compared to that of PYY-(1-36). In contrast, PYY-(27-36) exhibited a drastic loss of potency. The N-terminal fragments PYY-(1-22) and PYY-(1-28) also had very low potencies. Similar results were obtained with NPY fragments. These results provide the first insight on the negative coupling of PYY-preferring receptors with the cAMP production system in small intestine and evidence of the crucial role of the C-terminal portion of PYY in interaction with these receptors.
Soluble and Transmembrane Isoforms of Novel Interleukin-17 Receptor-like Protein by RNA Splicing and Expression in Prostate Cancer (2002)

Members of the interleukin-17 cytokine family are present in a variety of tissues (1-3), although the founding member, interleukin-17, is expressed exclusively in T cells and B cells (4-8). The cloning and characterization of a novel single-pass transmembrane protein with limited homology to the interleukin-17 receptor is reported. High mRNA levels were detected in prostate, cartilage, kidney, liver, heart, and muscle, whereas transcripts were barely detected in thymus and leukocytes. At least 11 RNA splice variants were found, transcribed from 19 exons on human chromosome 3p25.3-3p24.1. Differential exon usage was found in different tissues by quantitative reverse transcriptase-PCR. Predicted proteins range from 186 to 720 amino acids. Soluble secreted proteins lacking transmembrane and intracellular domains are predicted from several splice isoforms and may function as extracellular antagonists to cytokine signaling by functioning as soluble decoy receptors. Using antibodies directed at the cytoplasmic and extracellular domains of this protein, we investigated its localization and found that it was expressed in a variety of normal human tissues including prostate and in prostate cancer.
Annealed versus quenched diffusion coefficient in random media (1989)

We examine two a priori different definitions of a diffusion coefficient for tracer particles in static random media. The ``quenched'' diffusion coefficient ${D}^{Q}$ characterizes the spread of a packet in a single environment. The ``annealed'' coefficient ${D}^{A}$ characterizes the spread of the configuration-averaged packet. For one-dimensional diffusion with a drift ${D}^{A}$&gt;${D}^{Q}$ whereas d&gt;1${D}^{A}$=${D}^{Q}$. For some models displaying anomalous diffusion we also find ${D}^{A}$&gt;${D}^{Q}$. .AE
Identification and partial characterization of a unique marker for human basophils. (1995)

A unique marker for human basophils is needed to precisely determine the involvement of this cell type in clinical disease. To search for a marker of the basophil secretory granule, mouse hybridomas were generated against purified human basophils and screened for basophil-selective Ab. One hybridoma (2D7) produced an IgG1 kappa Ab that labeled basophils, but not lymphocytes, monocytes, eosinophils, neutrophils, and mast cells by an indirect immunoperoxidase procedure. The pattern of basophil staining was cytoplasmic and granular by light microscopy. By immunogold electron microscopy, the 2D7 ligand was localized to secretory granules. Activated basophils showed reduced 2D7-dependent staining intensity, consistent with a secretory granule localization. Tissue sections of normal skin, lung, and bowel showed no reactivity with 2D7, consistent with the anticipated absence of basophils in these tissues. 2D7 staining of basophils was clearly distinct from metachromatic staining, which was presumably dependent on proteoglycan. Extracts of normal human basophils subjected to Western blotting with 2D7 exhibited two predominant bands at apparent molecular masses of 76,150 and 72,260 Da. In summary, the 2D7 ligand appears to be a specific marker for human basophils and may facilitate the assessment of basophil involvement in diseases such as asthma, anaphylaxis, and atopic dermatitis.
Hyperfractionated Low-Dose Radiotherapy for High-Risk Neuroblastoma After Intensive Chemotherapy and Surgery (2001)

Hyperfractionated 21-Gy RT is well tolerated and, together with dose-intensive chemotherapy and surgery, may help in local control of high-risk neuroblastoma. Extending the RT field to definitively encompass regional nodal groups may improve results. Visible residual disease may warrant higher RT dosing. Patients with biologically unfavorable disease may be at increased risk for local failure. RT to the primary site may not be necessary when tumors are excised at diagnosis.
Weakly- and Semi-Supervised Panoptic Segmentation (2018)

We present a weakly supervised model that jointly performs both semantic- and instance-segmentation -- a particularly relevant problem given the substantial cost of obtaining pixel-perfect annotation for these tasks. In contrast to many popular instance segmentation approaches based on object detectors, our method does not predict any overlapping instances. Moreover, we are able to segment both "thing" and "stuff" classes, and thus explain all the pixels in the image. "Thing" classes are weakly-supervised with bounding boxes, and "stuff" with image-level tags. We obtain state-of-the-art results on Pascal VOC, for both full and weak supervision (which achieves about 95% of fully-supervised performance). Furthermore, we present the first weakly-supervised results on Cityscapes for both semantic- and instance-segmentation. Finally, we use our weakly supervised framework to analyse the relationship between annotation quality and predictive performance, which is of interest to dataset creators.