gebhart/patrepeval huggingface dataset:
p75NTR‐mediated signaling promotes the survival of myoblasts and influences muscle strength (2005)

During muscle development, the p75(NTR) is expressed transiently on myoblasts. The temporal expression pattern of the receptor raises the possibility that the receptor is influencing muscle development. To test this hypothesis, p75(NTR)-deficient mutant mice were tested for muscle strength by using a standard wire gripe strength test and were found to have significantly decreased strength relative to that of normal mice. When normal mybolasts were examined in vivo for expression of NGF receptors, p75(NTR) was detected on myoblasts but the high affinity NGF receptor, trk A, was not co-expressed with p75(NTR). In vitro, proliferating C2C12 and primary myoblasts co-expressed the p75(NTR) and MyoD, but immunofluorescent analysis of primary myoblasts and RT-PCR analysis of C2C12 mRNA revealed that myoblasts were devoid of trk A. In contrast to the cell death functions that characterize the p75(NTR) in neurons, p75(NTR)-positive primary and C2C12 myoblasts did not differentiate or undergo apoptosis in response to neurotrophins. Rather, myoblasts survived and even proliferated when grown at subconfluent densities in the presence of the neurotrophins. Furthermore, when myoblasts treated with NGF were lysed and immunoprecipitated with antibodies against phosphorylated I-kappaB and AKT, the cells contained increased levels of both phospho-proteins, both of which promote cell survival. By contrast, neurotrophin-treated myoblasts did not induce phosphorylation of Map Kinase p42/44 or p38, indicating the survival was not mediated by the trk A receptor. Taken together, the data indicate that the p75(NTR) mediates survival of myoblasts prior to differentiation and that the activity of this receptor during myogenesis is important for developing muscle.
Pharmacokinetics and Short-Term Metabolic Effects of Mammalian Cell-Derived Biosynthetic Human Growth Hormone in Man (1992)

The pharmacokinetics and acute effects of an authentic recombinant DNA-derived human growth hormone (rhGH) produced by genetically engineered mammalian cells were determined in 12 healthy volunteers following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration of 4 IU (1.3 mg) hGH/m2 body surface area. Following i.v. administration, apparent elimination half-life of rhGH was 18 min. Following i.m. administration, a mean peak serum concentration of 36.9 ng/ml (range 13-61 ng/ml) occurred at 3 h, and following s.c. administration, more sustained but lower serum concentrations occurred, with mean peak concentrations of 16.4 and 16.3 ng/ml at 4 and 6 h (ranges 9.0-27.5 ng/ml and 6.5-35.5 ng/ml at 4 and 6 h, respectively). The mean area under the curves was lower after s.c. (134 +/- 48 ng.h.ml-1) than after i.m. (194 +/- 48 ng.h.ml-1) injections (p < 0.03). Comparable results were obtained for the same dose of rhGH given subcutaneously in concentrations of either 4 IU/ml or 10 IU/ml. Both i.m. and s.c. administrations caused similar increases in free fatty acids at 4 h and insulin-like growth factor I at 24 h. Insulin, C-peptide and blood glucose were almost unchanged during the first 4 h after administration, whereas leukocytes increased significantly (p < 0.0001). Local and systemic tolerance were good, and no adverse reactions were observed. In a GH-deficient child, hGH serum levels between 10 and 20 ng/ml were demonstrated for a period of 8 h after s.c. administration of 0.07 IU rhGH/kg body weight.
<p>IDH1-mutated relapsed or refractory AML: current challenges and future prospects</p> (2019)

Abstract: The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is discouraging with salvage standard approaches. Mutations of isocitrate dehydrogenase 1 (IDH1 mut, ), present in 7–14% of AML patients, have been discovered recently, opening the door to targeted agents aiming to improve the outcomes in this setting. Several oral selective IDH1 mut, inhibitors are under investigation, ivosidenib being the first approved for R/R AML. We performed a systematic review to analyze the clinical outcomes and safety reported with IDH1 mut, inhibitors and other agents in adult patients with IDH1 mut, R/R AML. Ivosidenib in monotherapy achieved complete remission (CR) of 24%, overall response of 42%, and median overall survival of 9 months in R/R AML, and promising outcomes were reported with IDH305 and FT-2102. IDH1 mut, inhibitors were generally well tolerated, but some therapy-related toxicities should be monitored, including IDH-differentiation syndrome, prolongation of the QT interval, and leukocytosis, all manageable and reversible. Also, venetoclax, CB-839, PARP inhibitors, and IDH1 peptide vaccine are being studied in IDH1mut, AML. The results of the ongoing and upcoming clinical trials will bring new evidence to establish the role of IDH1 mut, inhibitors in therapeutic strategies of AML. Keywords: isocitrate dehydrogenase 1, acute myeloid leukemia, relapsed/refractory, ivosidenib, FT-2102, venetoclax
Apoptosis Triggered by Myc-Induced Suppression of Bcl-XL or Bcl-2 Is Bypassed during Lymphomagenesis (2001)

Enforced Bcl-2 expression inhibits Myc-induced apoptosis and cooperates with Myc in transformation. Here we report that the synergy between Bcl-2 and Myc in transforming hematopoietic cells in fact reflects a Myc-induced pathway that selectively suppresses the expression of the Bcl-X(L) or Bcl-2 antiapoptotic protein. Myc activation suppresses Bcl-X(L) RNA and protein levels in cultures of primary myeloid and lymphoid progenitors, and Bcl-X(L) and Bcl-2 expression is inhibited by Myc in precancerous B cells from Emu-myc transgenic mice. The suppression of bcl-X RNA levels by Myc requires de novo protein synthesis, indicating that repression is indirect. Importantly, the suppression of Bcl-2 or Bcl-X(L) by Myc is corrupted during Myc-induced tumorigenesis, as Bcl-2 and/or Bcl-X(L) levels are markedly elevated in over one-half of all lymphomas arising in Emicro-myc transgenic mice. Bcl-2 and/or Bcl-X(L) overexpression did not correlate with loss of ARF or p53 function in tumor cells, indicating that these two apoptotic pathways are inactivated independently. Therefore, the suppression of Bcl-X(L) or Bcl-2 expression represents a physiological Myc-induced apoptotic pathway that is frequently bypassed during lymphomagenesis.
Learning to Communicate to Solve Riddles with Deep Distributed Recurrent Q-Networks (2016)

We propose deep distributed recurrent Q-networks (DDRQN), which enable teams of agents to learn to solve communication-based coordination tasks. In these tasks, the agents are not given any pre-designed communication protocol. Therefore, in order to successfully communicate, they must first automatically develop and agree upon their own communication protocol. We present empirical results on two multi-agent learning problems based on well-known riddles, demonstrating that DDRQN can successfully solve such tasks and discover elegant communication protocols to do so. To our knowledge, this is the first time deep reinforcement learning has succeeded in learning communication protocols. In addition, we present ablation experiments that confirm that each of the main components of the DDRQN architecture are critical to its success.
Streptokinase Inhibits Acute Platelet Thrombus Formation in Stenosed Dog Coronary Arteries (1991)

Previous evidence has suggested that plasmin, in addition to its proteolytic action on fibrin, may affect platelet function. To test the effects of plasmin generated in vivo by the thrombolytic agent streptokinase (SK) on platelet-dependent vascular occlusion, we have used a well-established canine model of experimental coronary artery stenosis which produces platelet aggregate-dependent cyclical variations in coronary blood flow. Infusion of SK into 22 dogs at doses sufficient to cause a systemic lytic state led to complete abolition of cyclical blood flow reductions (CFR's) at sites of coronary artery injury. Inhibition of coronary platelet occlusion was associated with marked prolongations of the bleeding time (from 3.2 ± 0.6 min before to 14 ± 5 min after SK infusion, mean ± SD, n = 22). Despite the striking effects of SK on in vivo platelet-vessel wall interactions, only platelet aggregation in response to collagen was diminished among the ex vivo parameters of platelet function that were studied simultaneously. Platelet aggregation in response to other agonists, thromboxane A2 production, monoclonal antibody binding to platelet membrane glycoprotein (Gp) IIb-IIIa, Gp Ib-dependent botrocetin-induced platelet aggregation and platelet levels of cyclic AMP were not significantly altered. Therefore the thrombolytic agent streptokinase appears to cause important inhibitory effects on in vivo platelet reactivity with injured vascular intimal surfaces, possibly due to localised changes in platelet aggregate formation in the microenvironment of exposed collagen. These findings suggest that plasmin generated by thrombolytic agents may exhibit platelet inhibitory activity, and that this effect may be important in reestablishing blood flow in certain forms of platelet-mediated arterial thromboses.
Comparison of Binding Characteristics and In Vitro Activities of Three Inhibitors of Vascular Endothelial Growth Factor A (2014)

The objectives of this study were to evaluate the relative binding and potencies of three inhibitors of vascular endothelial growth factor A (VEGF), used to treat neovascular age-related macular degeneration, and assess their relevance in the context of clinical outcome. Ranibizumab is a 48 kDa antigen binding fragment, which lacks a fragment crystallizable (Fc) region and is rapidly cleared from systemic circulation. Aflibercept, a 110 kDa fusion protein, and bevacizumab, a 150 kDa monoclonal antibody, each contain an Fc region. Binding affinities were determined using Biacore analysis. Competitive binding by sedimentation velocity analytical ultracentrifugation (SV-AUC) was used to support the binding affinities determined by Biacore of ranibizumab and aflibercept to VEGF. A bovine retinal microvascular endothelial cell (BREC) proliferation assay was used to measure potency. Biacore measurements were format dependent, especially for aflibercept, suggesting that biologically relevant, true affinities of recombinant VEGF (rhVEGF) and its inhibitors are yet to be determined. Despite this assay format dependency, ranibizumab appeared to be a very tight VEGF binder in all three formats. The results are also very comparable to those reported previously.1-3 At equivalent molar ratios, ranibizumab was able to displace aflibercept from preformed aflibercept/VEGF complexes in solution as assessed by SV-AUC, whereas aflibercept was not able to significantly displace ranibizumab from preformed ranibizumab/VEGF complexes. Ranibizumab, aflibercept, and bevacizumab showed dose-dependent inhibition of BREC proliferation induced by 6 ng/mL VEGF, with average IC50 values of 0.088 ± 0.032, 0.090 ± 0.009, and 0.500 ± 0.091 nM, respectively. Similar results were obtained with 3 ng/mL VEGF. In summary Biacore studies and SV-AUC solution studies show that aflibercept does not bind with higher affinity than ranibizumab to VEGF as recently reported,4 and both inhibitors appeared to be equipotent with respect to their ability to inhibit VEGF function.
Spectrum and Image Texture Features Analysis for Early Blight Disease Detection on Eggplant Leaves (2016)

This study investigated both spectrum and texture features for detecting early blight disease on eggplant leaves. Hyperspectral images for healthy and diseased samples were acquired covering the wavelengths from 380 to 1023 nm. Four gray images were identified according to the effective wavelengths (408, 535, 624 and 703 nm). Hyperspectral images were then converted into RGB, HSV and HLS images. Finally, eight texture features (mean, variance, homogeneity, contrast, dissimilarity, entropy, second moment and correlation) based on gray level co-occurrence matrix (GLCM) were extracted from gray images, RGB, HSV and HLS images, respectively. The dependent variables for healthy and diseased samples were set as 0 and 1. K-Nearest Neighbor (KNN) and AdaBoost classification models were established for detecting healthy and infected samples. All models obtained good results with the classification rates (CRs) over 88.46% in the testing sets. The results demonstrated that spectrum and texture features were effective for early blight disease detection on eggplant leaves.
Total synthesis of (+)-rosaramicin aglycone and its diacetate. (1986)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal synthesis of (+)-rosaramicin aglycone and its diacetate.R. H. Schlessinger, M. A. Poss, and S. RichardsonCite this: J. Am. Chem. Soc. 1986, 108, 11, 3112–3114Publication Date (Print):May 1, 1986Publication History Published online1 May 2002Published inissue 1 May 1986https://pubs.acs.org/doi/10.1021/ja00271a055https://doi.org/10.1021/ja00271a055research-articleACS PublicationsRequest reuse permissionsArticle Views538Altmetric-Citations39LEARN 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
Ubiquitin-Specific Protease 8 Links the PTEN-Akt-AIP4 Pathway to the Control of FLIPS Stability and TRAIL Sensitivity in Glioblastoma Multiforme (2010)

The antiapoptotic protein FLIP(S) is a key suppressor of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human glioblastoma multiforme (GBM) cells. We previously reported that a novel phosphatase and tensin homologue (PTEN)-Akt-atrophin-interacting protein 4 (AIP4) pathway regulates FLIP(S) ubiquitination and stability, although the means by which PTEN and Akt were linked to AIP4 activity were unclear. Here, we report that a second regulator of ubiquitin metabolism, the ubiquitin-specific protease 8 (USP8), is a downstream target of Akt, and that USP8 links Akt to AIP4 and the regulation of FLIP(S) stability and TRAIL resistance. In human GBM xenografts, levels of USP8 correlated inversely with pAkt levels, and genetic or pharmacologic manipulation of Akt regulated USP8 levels in an inverse manner. Overexpression of wild-type USP8, but not catalytically inactive USP8, increased FLIP(S) ubiquitination, decreased FLIP(S) half-life, decreased FLIP(S) steady-state levels, and decreased TRAIL resistance, whereas short interfering RNA (siRNA)-mediated suppression of USP8 levels had the opposite effect. Because high levels of the USP8 deubiquitinase correlated with high levels of FLIP(S) ubiquitination, USP8 seemed to control FLIP(S) ubiquitination through an intermediate target. Consistent with this idea, overexpression of wild-type USP8 decreased the ubiquitination of the FLIP(S) E3 ubiquitin ligase AIP4, an event previously shown to increase AIP4-FLIP(S) interaction, whereas siRNA-mediated suppression of USP8 increased AIP4 ubiquitination. Furthermore, the suppression of FLIP(S) levels by USP8 overexpression was reversed by the introduction of siRNA targeting AIP4. These results show that USP8, a downstream target of Akt, regulates the ability of AIP4 to control FLIP(S) stability and TRAIL sensitivity.
Structural and Biochemical Characterization of the Human Cyclophilin Family of Peptidyl-Prolyl Isomerases (2010)

Peptidyl-prolyl isomerases catalyze the conversion between cis and trans isomers of proline. The cyclophilin family of peptidyl-prolyl isomerases is well known for being the target of the immunosuppressive drug cyclosporin, used to combat organ transplant rejection. There is great interest in both the substrate specificity of these enzymes and the design of isoform-selective ligands for them. However, the dearth of available data for individual family members inhibits attempts to design drug specificity; additionally, in order to define physiological functions for the cyclophilins, definitive isoform characterization is required. In the current study, enzymatic activity was assayed for 15 of the 17 human cyclophilin isomerase domains, and binding to the cyclosporin scaffold was tested. In order to rationalize the observed isoform diversity, the high-resolution crystallographic structures of seven cyclophilin domains were determined. These models, combined with seven previously solved cyclophilin isoforms, provide the basis for a family-wide structure:function analysis. Detailed structural analysis of the human cyclophilin isomerase explains why cyclophilin activity against short peptides is correlated with an ability to ligate cyclosporin and why certain isoforms are not competent for either activity. In addition, we find that regions of the isomerase domain outside the proline-binding surface impart isoform specificity for both in vivo substrates and drug design. We hypothesize that there is a well-defined molecular surface corresponding to the substrate-binding S2 position that is a site of diversity in the cyclophilin family. Computational simulations of substrate binding in this region support our observations. Our data indicate that unique isoform determinants exist that may be exploited for development of selective ligands and suggest that the currently available small-molecule and peptide-based ligands for this class of enzyme are insufficient for isoform specificity.
Climate Protection by an Alternative Use of Methane—The Carbon Moratorium (2009)

Despite a rising output, in the last few decades the known reserves of fossil energy resources have steadily increased. Additionally, there are in all likelihood tremendous reserves of methane hydrate. In view of the climate change, new means must be explored for its use as an energy source. Starting with an assessment of various options for dealing with the carbon cycle and thermodynamic considerations of methane chemistry, a new approach for the use of methane as energy source is developed in this Concept. After thermal methane cracking, only the energy content of the hydrogen is used and the carbon is stored safely and retrievably in disused coal beds. Arguments for the viability of a carbon moratorium of this kind are discussed.
Virgin olive oil and coenzyme Q10 protect heart mitochondria from peroxidative damage during aging (1999)

The mitochondrial theory of aging suggests that this phenomenon is the consequence of random somatic mutations in mitochondrial DNA, induced by long-term exposure to free radical attack. There are two potential dietary means of delaying the effects of free radicals on cellular aging, i.e., enrichment of mitochondrial membranes with monounsaturated fatty acids and supplementation with antioxidants. We have performed a preliminary study on male rats, 6 or 12 month old, fed with diets differing in the nature of the fat (virgin olive oil or sunflower oil) and/or with antioxidant supplementation (coenzyme Q10), analysing hydroperoxide and coenzyme Q9 and Q10 in heart mitochondria. Preliminary results allow us to conclude that the CoQ10 dietetic supplementation as well as the enrichment of the cellular membranes with monounsaturated fatty acids, successfully protect mitochondrial membranes from aged rats against the free radical insult.
Light-Driven Activation of β2-Adrenergic Receptor Signaling by a Chimeric Rhodopsin Containing the β2-Adrenergic Receptor Cytoplasmic Loops (2005)

Structure-function studies of rhodopsin indicate that both intradiscal and transmembrane (TM) domains are required for retinal binding and subsequent light-induced structural changes in the cytoplasmic domain. Further, a hypothesis involving a common mechanism for activation of G-protein-coupled receptor (GPCR) has been proposed. To test this hypothesis, chimeric receptors were required in which the cytoplasmic domains of rhodopsin were replaced with those of the beta(2)-adrenergic receptor (beta(2)-AR). Their preparation required identification of the boundaries between the TM domain of rhodopsin and the cytoplasmic domain of the beta(2)-AR necessary for formation of the rhodopsin chromophore and its activation by light and subsequent optimal activation of beta(2)-AR signaling. Chimeric receptors were constructed in which the cytoplasmic loops of rhodopsin were replaced one at a time and in combination. In these replacements, size of the third cytoplasmic (EF) loop critically determined the extent of chromophore formation, its stability, and subsequent signal transduction specificity. All the EF loop replacements showed significant decreases in transducin activation, while only minor effects were observed by replacements of the CD and AB loops. Light-dependent activation of beta(2)-AR leading to Galphas signaling was observed only for the EF2 chimera, and its activation was further enhanced by replacements of the other loops. The results demonstrate coupling between light-induced conformational changes occurring in the transmembrane domain of rhodopsin and the cytoplasmic domain of the beta(2)-AR.
Assessment of the Pathological Stages of Alzheimer’s Disease in Thin Paraffin Sections: A Comparative Study (1998)

The staging method proposed by Braak and Braak allows the objective and reliable assessment of Alzheimer-related neurofibrillary pathology. Originally the method was designed for 100-microm thick sections. However, the use of thick sections proved to present difficulties in a routine neuropathology laboratory. In order to adapt the staging method for thin paraffin-embedded sections, we performed an inter- and intrarater study analysing the reliability of the staging method in thin sections. Statistical analysis of the data provided by six independent examiners in two rating sessions reveal kappa values of 0.6-0.8 for both the interrater and the intrarater reliability. The average rate of mistake of the examiners was rarely bigger than a half stage. We conclude that the adapted staging method in thin sections is strongly reliable and we recommend it for staging purposes in institutions where the preparation of thick sections would be difficult.
Cloning and Expression of an HIV‐1 Specific Single‐Chain Fv Region Fused to Escherichia coli Alkaline Phosphatasea (1991)

We have constructed a single-chain Fv fragment representing the variable domain of the human monoclonal antibody 3D6, binding specifically to HIV-1 gp41. This gene was fused to the coding region of E. coli alkaline phosphatase (EcPhoA) and expressed in E. coli. The EcPhoA signal peptide was used to direct the recombinant fusion protein to the periplasmic space of the bacteria, from where it was purified by hydrophobic interaction chromatography and gel filtration followed by antigen-affinity chromatography using a synthetic HIV-1 peptide as ligand. The purified fusion protein was bifunctional, showing both phosphatase activity as well as antigen-binding specificity identical to that of the original antibody.