gebhart/patrepeval huggingface dataset:
Altered Gene Expression Pattern in the Fatty Liver Dystrophy Mouse Reveals Impaired Insulin-mediated Cytoskeleton Dynamics (1999)

The mouse fatty liver dystrophy (fld) mutation is characterized by transient hypertriglyceridemia and fatty liver during the neonatal period, followed by development of a peripheral neuropathy. To uncover the metabolic pathway that is disrupted by the fld mutation, we analyzed the altered pattern of gene expression in the fatty liver of fld neonates by representational difference analysis of cDNA. Differentially expressed genes detected include a novel member of the Ras superfamily of small GTP-binding proteins, a novel Ser/Thr kinase, and several actin cytoskeleton-associated proteins including actin, profilin, alpha-actinin, and myosin light chain. Because these proteins have a potential functional link in the propagation of hormone signals, we investigated cytoskeleton dynamics in fld cells in response to hormone treatment. These studies revealed that preadipocytes from fld mice exhibit impaired formation of actin membrane ruffles in response to insulin treatment. These findings suggest that the altered mRNA expression levels detected in fld tissue represent a compensatory response for the nonfunctional fld gene and that the fld gene product may be required for development of normal insulin response.
Modulation of electrically evoked acetylcholine release in cultured rat septal neurones (2001)

The electrically evoked release of acetylcholine and its modulation via auto- and heteroreceptors were studied in primary cell cultures prepared from embryonic rat septum (ED 17). Cultures were grown for 1, 2 or 3 weeks on circular, poly D-lysine-coated glass coverslips. They developed a dense network of non-neuronal and neuronal cells, only some of which were immunopositive for choline acetyltransferase. To measure acetylcholine release, the cells on the coverslips were pre-incubated with [3H]choline (0.1 micromol/L), superfused with modified Krebs-Henseleit buffer at 25 degrees C and electrically stimulated twice for 2 min (S1, S2; 3 Hz, 0.5 ms, 90-100 mA). The electrically evoked overflow of [3H] from the cells consisted of approximately 80% of authentic [3H]Ach, was largely Ca2+-dependent and tetrodotoxin sensitive, and hence represents an action potential-evoked, exocytotic release of acetylcholine. Using pairs of selective agonists and antagonist added before S2, muscarinic autoreceptors, as well as inhibitory adenosine A1- and opioid mu-receptors, could be detected, whereas delta-opioid receptors were not found. Evoked [3H] overflow from cultures grown for 1 week, although Ca2+ dependent and tetrodotoxin sensitive, was insensitive to the muscarinic agonist oxotremorine, whereas the effect of oxotremorine on cells grown for 3 weeks was even more pronounced than that in 2-week-old cultures. In conclusion, similar to observations on rat septal tissue in vivo, acetylcholine release from septal cholinergic neurones grown in vitro is inhibited via muscarinic, adenosine A1 and mu-opioid receptors. This in vitro model may prove useful in the exploration of regulatory mechanisms underlying the expression of release modulating receptors on septal cholinergic neurones.
Adjuvant Activity of CpG Oligodeoxynucleotides (2006)

Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs directly stimulate human B cells and plasmacytoid dendritic cells (pDCs), thereby promoting the production of Th1 and proinflammatory cytokines and the maturation/activation of professional antigen-presenting cells. These activities enable CpG ODNs to act as immune adjuvants, accelerating and boosting antigen-specific immune responses by 5- to 500-fold. The CpG motifs present in bacterial DNA plasmids may contribute to the immunogenicity of DNA vaccines. Ongoing clinical studies indicate that CpG ODNs are safe and well tolerated when administered as adjuvants to humans and can improve vaccine-induced immune responses.
Antisense-mediated inhibition of BCL2 protooncogene expression and leukemic cell growth and survival: comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides. (1990)

Antisense oligodeoxynucleotides specific for sequences in mRNAs from the B-cell lymphoma/leukemia-2 (BCL2) gene were used to inhibit the growth in culture of a human leukemia cell line, 697. Normal phosphodiester (PO) and nuclease-resistant phosphorothioate (PS) oligodeoxynucleotides were compared with regard to specificity, potency, and kinetics. Both PO and PS antisense BCL2 oligodeoxynucleotides were specific inhibitors of cellular proliferation, since sense versions of these synthetic DNAs were inactive at similar concentrations. Specificity was further confirmed by quantitative immunofluorescence studies, showing that PO and PS antisense BCL2 oligodeoxynucleotides (when used at appropriate concentrations) reduced levels of BCL2 protein without influencing expression of HLA-DR and other control antigens. The onset of inhibition by PO oligodeoxynucleotides was faster, with reductions in cell numbers occurring within 1 day of addition to cultures, in contrast to phosphorothioates, which were ineffective until 3-4 days. Phosphorothioates were more potent that phosphodiesters, however, with half-maximal inhibition of leukemic cell growth occurring at concentrations 5-10 times lower. As expected from previous studies demonstrating the importance of BCL2 for regulating lymphoid cell survival, BCL2 antisense oligodeoxynucleotides also led to 697 leukemic cell death through sequence-specific mechanisms, with reductions in cellular viability generally lagging the inhibitory effects on cellular growth by about 2 days. Taken together, these data indicate that PO and PS oligodeoxynucleotides targeted against the human BCL2 protooncogene can be sequence-specific inhibitors of leukemic cell growth and survival.
The U14 snoRNA is required for 2'-O-methylation of the pre-18S rRNA in Xenopus oocytes. (1998)

We have studied the role of the U14 small nucleolar RNA (snoRNA) in pre-rRNA methylation and processing in Xenopus oocytes. Depletion of U14 in Xenopus oocytes was achieved by co-injecting two nonoverlapping antisense oligonucleotides. Focusing on the earliest precursor, depletion experiments revealed that the U14 snoRNA is essential for 2'-O-ribose methylation at nt 427 of the 18S rRNA. Injection of U14-depleted oocytes with specific U14 mutant snoRNAs indicated that conserved domain B, but not domain A, of U14 is required for the methylation reaction. When the effect of U14 on pre-rRNA processing is assayed, we find only modest effects on 18S rRNA levels, and no effect on the type or accumulation of 18S precursors, suggesting a role for U14 in a step in ribosome biogenesis other than cleavage of the pre-rRNA. Xenopus U14 is, therefore, a Box C/D fibrillarin-associated snoRNA that is required for site-specific 2'-O-ribose methylation of pre-rRNA.
Single-chain antibodies as diagnostic tools and therapeutic agents (2009)

Over three decades after the generation of the first mouse monoclonal antibodies by Kohler and Milstein, recombinant antibodies are the fastest growing class of therapeutic proteins. Furthermore, antibodies are key detection reagents in research and diagnostics. Technology improvements have provided several approaches to manufacturing human antibodies with high affinity for biologically relevant targets. Approximately 300 development programs for therapeutic antibodies have been reported in industrial and academic laboratories, and this clearly demonstrates the expectations towards antibody technology. Antibody fragments are a subclass with growing clinical importance. This review focuses on single-chain antibodies as one of the smallest possible format for recombinant antibodies and their use as diagnostic tools and therapeutic agents. We describe the structure, selection and production of single-chain antibodies. Furthermore, we review current applications of antibody fragments focusing on thrombus targeting using fibrin- and platelet-specific single-chain antibodies as well as describing novel noninvasive imaging approaches for the diagnosis of thrombosis and inflammation.
Red blood cell micromanipulation with elliptical laser beam profile optical tweezers in different osmolarity conditions (2011)

In this work optical tweezers with elliptical beam profiles have been developed in order to examine the effect of optical force on fresh red blood cells (RBC) in isotonic, hypertonic and hypotonic buffer solutions. Considering that the optical force depends essentially on the cell surface and the cytoplasmic refractive index, it is obvious that biochemical modifications associated with different states of the cell will influence its behaviour in the optical trap. Line optical tweezers were used to manipulate simultaneously more than one red blood cell. After we have been manipulated a RBC with an elliptical laser beam profile in an isotonic or hypertonic buffer, we noticed that it rotates by itself when gets trapped by optical tweezers and undergoes folding. Further shape deformations can be observed attributed to the competition between alignment and rotational torque which are transferred by laser light to the cell. In hypotonic buffer RBCs become spherical and do not rotate or fold since the resultant force due to rays emerging from diametrically opposite points of the cell leads to zero torque. Manipulation of fresh red blood cells in isotonic solution by line optical tweezers leads to folding and elongation of trapped RBCs. Membrane elasticity properties such as bending modulus can be estimated by measuring RBC's folding time in function with laser power.
A subcellular map of the human proteome (2017)

Resolving the spatial distribution of the human proteome at a subcellular level can greatly increase our understanding of human biology and disease. Here we present a comprehensive image-based map of subcellular protein distribution, the Cell Atlas, built by integrating transcriptomics and antibody-based immunofluorescence microscopy with validation by mass spectrometry. Mapping the in situ localization of 12,003 human proteins at a single-cell level to 30 subcellular structures enabled the definition of the proteomes of 13 major organelles. Exploration of the proteomes revealed single-cell variations in abundance or spatial distribution and localization of about half of the proteins to multiple compartments. This subcellular map can be used to refine existing protein-protein interaction networks and provides an important resource to deconvolute the highly complex architecture of the human cell.
Association of DISC1/TRAX Haplotypes With Schizophrenia, Reduced Prefrontal Gray Matter, and Impaired Short- and Long-term Memory (2005)

Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission.
Using Hemoglobin A1C as a Predicting Model for Time Interval from Pre-Diabetes Progressing to Diabetes (2014)

This prediction model is very useful to help prioritize the diagnosis at an early stage for targeting individuals with risk of diabetes. Using patients' HbA1C before anti-diabetes drugs are used we predicted the time interval from pre-diabetes progression to diabetes is 2.49 years without any influence of age and gender. Additional studies are needed to support this model for a long term prediction.
Influences on the resolution of GPR velocity analyses and a Monte Carlo simulation for establishing velocity precision (2011)

ABSTRACT The precision of ground‐penetrating radar velocity models is seldom reported, despite their common use for quantifying subsurface properties. We explore influences on the resolution of ground‐penetrating radar velocity analysis and demonstrate a Monte Carlo method for obtaining the implied precision in velocity estimates. A series of synthetic common‐midpoint gathers, which assume Ricker wavelets of 50 MHz, 100 MHz and 200 MHz frequencies as source pulses, simulate hyperbolic reflections from the bases of three horizontal layers, each with interval velocity and thickness of 0.1 m/ns and 2 m, respectively. With these, we use coherence analysis to show that the principal influence on stacking velocity resolution is the traveltime moveout, normalized by the wavelet period, exhibited across some offset range. Where moveout exceeds the period by factors of, e.g., 3 and 6, is resolved to [–6.5, +8.2]% to [–3.6, +4.0]%, respectively, at the 50% coherence threshold. The temporal duration of coherence responses is expressed as a one‐quarter wavelet period either side of the stacking traveltime. Coherence resolutions are used in Monte Carlo simulations to derive the implied precision in the interval stacking velocity and its derivative properties. These analyses are repeated for field common‐midpoint data, acquired using 50 MHz antennas, on Quaternary glacio‐fluvial media overlying a Cambrian basement (&lt;15 m deep). For three reflections identified in these data, the velocity and temporal resolution of coherence responses vary in a quantitatively similar way to events in the synthetic data. For the corresponding layers, Monte Carlo simulations yield precision estimates for , layer thickness and fractional water content. The procedure predicts a reasonable model of water content decreasing with depth, in accordance with increasing pore compaction and provides a robust error analysis; the uncertainty in estimates of the fractional water content of two (assumed) water‐saturated layers is ±2.6% and ±2.1% (shallower and deeper, respectively). Monte Carlo simulations are recommended as an efficient means of establishing the precision in quantitative estimates of subsurface properties derived from ground‐penetrating radar velocities, particularly where ground‐truth data are unavailable.
Preparation of Spherical Titanium Powders from Polygonal Titanium Hydride Powders by Radio Frequency Plasma Treatment (2013)

This paper describes a novel dehydrogenation and spheroidization method using in-situ radio frequency (RF) thermal plasma treatment process to prepare spherical titanium (Ti) powders. Polygonal titanium hydride (TiH2) powders were successfully converted into spherical Ti powders and the size of the powders decreased from 30 to 21 µm by means of evaporation at the powder surface during the plasma treatment. Contaminants in the final products were drastically decreased due to the evaporation and emission of vapors during the plasma treatment.
Interactive reconstruction of Monte Carlo image sequences using a recurrent denoising autoencoder (2017)

We describe a machine learning technique for reconstructing image sequences rendered using Monte Carlo methods. Our primary focus is on reconstruction of global illumination with extremely low sampling budgets at interactive rates. Motivated by recent advances in image restoration with deep convolutional networks, we propose a variant of these networks better suited to the class of noise present in Monte Carlo rendering. We allow for much larger pixel neighborhoods to be taken into account, while also improving execution speed by an order of magnitude. Our primary contribution is the addition of recurrent connections to the network in order to drastically improve temporal stability for sequences of sparsely sampled input images. Our method also has the desirable property of automatically modeling relationships based on auxiliary per-pixel input channels, such as depth and normals. We show significantly higher quality results compared to existing methods that run at comparable speeds, and furthermore argue a clear path for making our method run at realtime rates in the near future.
AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations (2017)

Somatic gain-of-function mutations in isocitrate dehydrogenases (<i>IDH</i>) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (<i>R</i>)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. <i>In vitro</i> studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human <i>IDH2</i> mutation-positive acute myeloid leukemia (AML) cells <i>ex vivo</i> and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2<sup>R140Q</sup>-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with <i>IDH2</i> mutation-positive advanced hematologic malignancies.<b>Significance:</b> Mutations in <i>IDH1/2</i> are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. <i>Cancer Discov; 7(5); 478-93. ©2017 AACR.</i><i>See related commentary by Thomas and Majeti, p. 459</i><i>See related article by Shih et al., p. 494</i><i>This article is highlighted in the In This Issue feature, p. 443</i>.
Prostacyclin Inhibits Non-Small Cell Lung Cancer Growth by a Frizzled 9-Dependent Pathway That Is Blocked by Secreted Frizzled-Related Protein 1 (2010)

The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human non-small cell lung cancer (NSCLC) and to define the mechanism of iloprost's tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with the expression of the cell surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9) and the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma). Silencing of Fzd 9 blocked PPARgamma activation by iloprost, and expression of Fzd 9 in cells lacking the protein resulted in iloprost's activation of PPARgamma and inhibition of transformed growth. Interestingly, soluble Frizzled-related protein-1, a well-known inhibitor of Wnt/Fzd signaling, also blocked the effects of iloprost and Fzd 9. Moreover, mice treated with iloprost had reduced lung tumors and increased Fzd 9 expression. These studies define a novel paradigm, linking the eicosanoid pathway and Wnt signaling. In addition, these data also suggest that prostacyclin analogs may represent a new class of therapeutic agents in the treatment of NSCLC where the restoration of noncanonical Wnt signaling maybe important for the inhibition of transformed cell growth.
Clinical application of functional glycoproteomics – dissection of glycotopes carried by soluble CD44 variants in sera of patients with cancers (2008)

We provide here an example of clinical application of functional glycoproteomics for cancer diagnosis. Sialyl Lewis a and sialyl Lewis x glycotopes, which are the specific ligands for selectins, and variant forms of CD44, which are the adhesion molecules recognizing hyaluronate, are both implicated in cancer metastasis. The CD44 variants modified by the sialyl Lewis a and sialyl Lewis x glycotopes are expected to have dual functions, serving as ligands for vascular selectins, and simultaneously having binding activity to vascular bed hyaluronate, and are expected to figure heavily in cancer metastasis. We developed a heterogeneous sandwich assay system to detect soluble CD44v specifically modified by the cancer-associated sialyl Lewis a/x glycotopes, using the extracellular domain of CD44v cleaved by the metalloproteinase ADAM10 as standard molecules. We also developed the assay system for CD44v modified by normal epithelial glycotopes including disialyl Lewis a and sialyl 6-sulfo Lewis x. The results indicated that serum levels of soluble CD44v modified by cancer-associated glycotopes were frequently increased in patients with cancers, while those of CD44v modified by the nonmalignant glycotopes tended to be elevated in patients with benign disorders.
Models of Immunity (2014)

This chapter provides a thorough discussion of the naturally occurring immune response to chlamydial infection of the genital tract, respiratory tract, and conjunctiva, including the events leading to resolution of infection, the mechanisms involved in resolution, and the events and mechanisms participating in the immune response to reinfection. The chapter addresses the ongoing development of a chlamydial vaccine including a review of vaccine studies, potential immunogens, and strategies of immunization. Unquestionably, there is a strong immune response in humans resulting from genital, ocular, or respiratory infection with relevant species of Chlamydia. As with many infections, immunity is seldom an all-or-none matter; therefore, a section explores some of the potential parameters which contribute to the resistance or susceptibility to reinfection. In addition, since immunity, particularly in adolescents, appears to be short-lived, any vaccine that is developed must do better than the natural infection, which is something that has proven to be extremely difficult. The chapter further reviews attempts at immunization with different immunogens or forms of immunogens, as well as the effect of the immunization route. Finally, the chapter discusses the potential immunization strategies, based on one's knowledge of the immune response and disease pathogenesis. In evaluating possible vaccine strategies for chlamydial disease, it is important to remember that we are dealing with the prevention of different disease entities. It is unlikely that a single vaccination protocol will be effective against trachoma, genital disease, pneumonia, coronary artery disease, and veterinary diseases.
P21-dependent G1arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228 (2000)

Depsipeptide, FR901228, a novel cyclic peptide inhibitor of histone deacetylase with a unique cytotoxicity profile is currently in phase I clinical trials. Here we demonstrate that, in addition to G2/M arrest, FR901228 causes G1 arrest with Rb hypophosphorylation. In vitro kinase assays demonstrated no direct inhibition of CDK activity, however, an inhibition was observed in CDKs extracted from cells exposed to FR901228. Cyclin D1 protein disappeared between 6 and 12 hours after treatment with FR901228, whereas cyclin E was upregulated. While it did not induce wt p53, FR901228 did induce p21(WAF1/CIP1)in a p53-independent manner. Cell clones lacking p21 were not arrested in G1 phase, but continued DNA synthesis and were arrested in G2/M phase following FR901228 treatment. Finally, FR901228 blunted ERK-2/MAPK activation by EGF whereas early signal transduction events remained intact since overall cellular tyrosine phosphorylation after EGF stimulation was unaffected. Thus, FR901228, while not directly inhibiting kinase activity, causes cyclin D1 downregulation and a p53-independent p21 induction, leading to inhibition of CDK and dephosphorylation of Rb resulting in growth arrest in the early G1 phase. In contrast to the G1 arrest, the G2/M arrest is p21-independent, but is associated with significant cytotoxicity.