gebhart/patrepeval huggingface dataset:
Regulation of co‐ and post‐translational myristoylation of proteins during apoptosis: interplay of N ‐myristoyltransferases and caspases (2012)

Myristoylation occurs cotranslationally on nascent proteins and post-translationally during apoptosis after caspase cleavages expose cryptic myristoylation sites. We demonstrate a drastic change in the myristoylated protein proteome in apoptotic cells, likely as more substrates are revealed by caspases. We show for the first time that both N-myristoyltransferases (NMTs) 1 and 2 are cleaved during apoptosis and that the caspase-3- or -8-mediated cleavage of NMT1 at Asp-72 precedes the cleavage of NMT2 by caspase-3 mainly at Asp-25. The cleavage of NMTs did not significantly affect their activity in apoptotic cells until the 8 h time point. However, the cleavage of the predominantly membrane bound NMT1 (64%) removed a polybasic domain stretch and led to a cytosolic relocalization (>55%), whereas predominantly cytosolic NMT2 (62%) relocalized to membranes when cleaved (>80%) after the removal of a negatively charged domain. The interplay between caspases and NMTs during apoptosis is of particular interest since caspases may not only control the rates of substrate production but also their myristoylation rate by regulating the location and perhaps the specificity of NMTs. Since apoptosis is often suppressed in cancer, the reduced caspase activity seen in cancer cells might also explain the higher NMT levels observed in many cancers.
Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond (2013)

Many current chemotherapies function by damaging genomic DNA in rapidly dividing cells ultimately leading to cell death. This therapeutic approach differentially targets cancer cells that generally display rapid cell division compared to normal tissue cells. However, although these treatments are initially effective in arresting tumor growth and reducing tumor burden, resistance and disease progression eventually occur. A major mechanism underlying this resistance is increased levels of cellular DNA repair. Most cells have complex mechanisms in place to repair DNA damage that occurs due to environmental exposures or normal metabolic processes. These systems, initially overwhelmed when faced with chemotherapy induced DNA damage, become more efficient under constant selective pressure and as a result chemotherapies become less effective. Thus, inhibiting DNA repair pathways using target specific small molecule inhibitors may overcome cellular resistance to DNA damaging chemotherapies. Non-homologous end joining a major mechanism for the repair of double-strand breaks (DSB) in DNA is regulated in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK). The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and recruiting other repair molecules. It also has enzymatic activity that may be involved in DNA damage signaling. Because of its' central role in repair of DSBs, DNA-PK has been the focus of a number of small molecule studies. In these studies specific DNA-PK inhibitors have shown efficacy in synergizing chemotherapies in vitro. However, compounds currently known to specifically inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor solubility and have high metabolic lability in vivo leading to short serum half-lives. Future improvement in DNA-PK inhibition will likely be achieved by designing new molecules based on the recently reported crystallographic structure of DNA-PK. Computer based drug design will not only assist in identifying novel functional moieties to replace the metabolically labile morpholino group but will also facilitate the design of molecules to target the DNA-PKcs/Ku80 interface or one of the autophosphorylation sites.
ERK Activation Following Macrophage FcγR Ligation Leads to Chromatin Modifications at the IL-10 Locus (2005)

We have previously demonstrated that macrophages stimulated in the presence of immune complexes produce high levels of IL-10. We now examine the mechanism of IL-10 superinduction. We report that the enhanced production of IL-10 correlates with a rapid and enhanced activation of two MAPKs, ERK and p38. The inhibition of either ERK or p38 prevented IL-10 induction, indicating that both MAPKs were required for IL-10 synthesis. By chromatin immunoprecipitation assay, we demonstrate that activation of ERK leads to the phosphorylation of serine 10 on histone H3 at the il-10 gene, making the promoter more accessible to transcription factors generated in response to p38 activation. Inhibition of ERK activation prevented histone modifications, and decreased the binding of Sp1 and STAT3 to the IL-10 promoter. We conclude that the activation of ERK following FcgammaR ligation leads to a remodeling of the chromatin at the il-10 locus, making it more accessible to transcription factors. The rapid and transient regulation of transcription factor accessibility to the IL-10 promoter by MAPK activation represents a novel way that the production of this cytokine is regulated.
The κB and V(D)J Recombination Signal Sequence Binding ProteinKRC Regulates Transcription of the Mouse Metastasis-associated Gene S100A4/mts1 (2000)

A kappaB-like sequence, Sb, is integral to the composite enhancer located in the first intron of the metastasis-associated gene, S100A4/mts1. Oligonucleotides containing this sequence form three specific complexes with nuclear proteins prepared from S100A4/mts1-expressing CSML100 adenocarcinoma cells. Protein studies show the Sb-interacting complexes include NF-kappaB/Rel proteins, p50.p50 and p50.p65 dimers. Additionally, the Sb sequence was bound by an unrelated approximately 200-kDa protein, p200. Site-directed mutagenesis in conjunction with transient transfections indicate that p200, but not the NF-kappaB/Rel proteins, transactivates S100A4/mts1. To identify candidate genes for p200, double-stranded DNA probes containing multiple copies of Sb were used to screen a randomly primed lambdagt11 cDNA expression library made from CSML100 poly(A)(+) RNA. Two clones corresponding to the DNA-binding proteins KRC and Alf1 were identified. KRC encodes a large zinc finger protein that binds to the kappaB motif and to the signal sequences of V(D)J recombination. In vitro DNA binding assays using bacterially expressed KRC fusion proteins, demonstrate specific binding of KRC to the Sb sequence. In addition, introduction of KRC expression vectors into mammalian cells induces expression of S100A4/mts1 and reporter genes driven by S100A4/mts1 gene regulatory sequences. These data indicate that KRC positively regulates transcription of S100A4/mts1.
A study on investment decision making model: genetic algorithms approach (2003)

Genetic algorithms (GAs) are becoming a paramount research method because of their robustness due to mimicking the natural evolution mechanism. Genetic algorithms can easily learn to adapt to complex environments. The paper studies the application of genetic algorithms on a user-oriented "investment decision-making model". The portfolio selection considers users' preferences in addition to the common return and risk factors. Preliminary results show that the portfolios generated by GAs outperform some of the better mutual funds and the index.
Sensory Issues in Children with Asperger Syndrome and Autism (2004)

The purpose of this study was to examine whether children with Asperger Syndrome and children with autism exhibit difference sensory profiles. The Sensory Profile (Dunn, 1999), completed on 86 individuals with Asperger Syndrome and 86 persons with autism matched for age, revealed differences in three of 23 areas evaluated: (a) Emotional/Social Responses, (b) Emotional Reactivity, and (c) Inattention/Distractibility. Implications regarding these similarities and differences in profile are discussed.
Monoclonal antibody to transferrin receptor blocks transferrin binding and inhibits human tumor cell growth in vitro. (1982)

A murine hybridoma has been obtained that produces a monoclonal antibody against the human transferrin receptor. In contrast to previously characterized monoclonal antibodies that recognize the transferrin receptor, this antibody, designated 42/6, blocks the binding of transferrin to its receptor and inhibits the growth of the human T leukemic cell line, CCRF-CEM, in vitro. Inhibition of cell growth was dose dependent, and as little as 2.5 micrograms of purified antibody per ml had a detectable effect, even though transferrin was present in the tissue culture medium in large molar excess. Cells grown in the presence of antibody for 7 days accumulated in S phase of the cell cycle. The addition of iron to antibody-treated cultures in the form of ferric complexes or ferrous sulfate did not overcome the growth inhibitory effects of the anti-transferrin-receptor antibodies. This result suggests that either transferrin is the only means by which CCRF-CEM leukemic cells can be provided with sufficient iron in vitro or that other factors in addition to iron starvation are involved in the antibody-mediated growth inhibition. The inhibition of cell growth by 42/6 monoclonal antibody suggests that monoclonal antibodies against proliferation-associated cell surface antigens, such as the transferrin receptor, may be useful pharmacological reagents to modify cell growth in vitro.
Interleukin-11 Drives Early Lung Inflammation during Mycobacterium tuberculosis Infection in Genetically Susceptible Mice (2011)

IL-11 is multifunctional cytokine whose physiological role in the lungs during pulmonary tuberculosis (TB) is poorly understood. Here, using in vivo administration of specific antibodies against IL-11, we demonstrate for the first time that blocking IL-11 diminishes histopathology and neutrophilic infiltration of the lung tissue in TB-infected genetically susceptible mice. Antibody treatment decreased the pulmonary levels of IL-11 and other key inflammatory cytokines not belonging to the Th1 axis, and down-regulated IL-11 mRNA expression. This suggests the existence of a positive feedback loop at the transcriptional level, which is further supported by up-regulation of IL-11 mRNA expression in the presence of rIL-11 in in vitro cultures of lung cells. These findings imply a pathogenic role for IL-11 during the early phase of Mycobacterium tuberculosis-triggered disease in a genetically susceptible host.
Intensification of Water Electrolysis in a Centrifugal Field (2002)

The intensification of the production of hydrogen and oxygen, i.e., water electrolysis, was achieved in a centrifugal acceleration field. This was demonstrated by measuring the cell voltage and the electrode potentials for cells operated with and without centrifugal fields, as a function of current density. Under industrial electrolysis conditions, greater reductions in cell voltage and in electrode potentials were achieved at a relative acceleration rate of compared to those in stationary conditions. The relationships between the cell performance and relative acceleration rate, applied value, for different anode materials, temperature, and NaCl concentration are reported. The data is obtained in acid, neutral, and highly alkaline electrolyte solutions using linear sweep voltammetry, galvanostatic, and potentiostatic polarization techniques. A cell voltage reduction of up to 700 mV, an anode potential reduction of up to 500 mV, and a cathode potential reduction of up to 350 mV at are achieved at a relative acceleration rate of and 80°C, compared to those in stationary conditions. The saving in cell voltage, and thus energy consumption, are significantly larger than the small amount of energy required to rotate the cells. © 2002 The Electrochemical Society. All rights reserved.
Cyclosporin in Atopic Dermatitis (1999)

This paper reflects the consensus reached among Belgian professors of dermatology on the place of cyclosporin (CsA) in the treatment of atopic dermatitis (AD). Existing therapeutic modalities and ways to evaluate efficacy of treatment are reviewed briefly. Based on data from the literature and personal experience, guidelines for the use of CsA in AD are proposed. CsA can be prescribed in recalcitrant cases of AD on a short-term basis, both in adults and children. Long-term treatment, up to 1 year, should be considered only in exceptional cases that cannot be controlled by short-time therapy. Contraindications, drug interactions and necessary controls during treatment are also discussed.
Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent. (2001)

Bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)methane (taurolidine) is a synthetic broad-spectrum antibiotic that reacts with bacterial cell membrane components to prevent adhesion to epithelial cell surfaces. Reflecting the key role of adhesion in the growth and development of human solid tumors, studies were initiated to assess the antiproliferative activity of this agent in selected human and murine tumor cell lines. A 3-day exposure to Taurolidine inhibited the growth of all of the cell lines evaluated with IC(50)s ranging from 9.6-34.2 microM. Studies to identify the mechanism responsible for this effect were conducted in NIH-3T3 murine fibroblasts and the PA-1 and SKOV-3 human ovarian tumor cells. These studies revealed that a 48-h exposure to taurolidine had little effect on cell cycle distribution in PA-1 and SKOV-3 cells but significantly increased the appearance of DNA debris in the sub-G(0)/G(1) region, an effect consistent with an induction of apoptosis. In contrast, in NIH-3T3 cells, taurolidine exposure did not increase DNA debris in the sub-G(0)/G(1) region. Additional studies assessed phosphotidylserine externalization after a 24-h exposure to taurolidine using annexin-V binding as a cell surface marker. These studies revealed that taurolidine increased the percentage of annexin-V-positive cells by 4-fold and 3-fold in PA-1 and SKOV-3 cells, respectively. In NIH-3T3 cells, taurolidine exposure slightly increased ( approximately 5%) annexin-V binding. Parallel studies revealed that exposure to taurolidine also resulted in poly(ADP-ribose) polymerase cleavage in both ovarian tumor cell lines but not in NIH-3T3 cells. Finally, murine-based studies were conducted to assess the antineoplastic activity of three consecutive daily i.p. bolus injections of taurolidine at doses ranging from 5-mg injection/mouse to 30-mg injection/mouse. The 20-mg injection dose produced approximately 10% mortality and was identified as the maximally tolerated dose in this model. Administration of this regimen to nude mice bearing i.p. human ovarian tumor xenografts significantly inhibited both tumor formation and growth. These findings are discussed in light of their clinical implications.
Polarized Human Immunodeficiency Virus Budding in Lymphocytes Involves a Tyrosine-Based Signal and Favors Cell-to-Cell Viral Transmission (1999)

Maturation and release of human immunodeficiency virus type 1 (HIV-1) is targeted at the pseudopod of infected mononuclear cells. However, the intracellular mechanism or targeting signals leading to this polarized viral maturation are yet to be identified. We have recently demonstrated the presence of a functional YXXL motif for specific targeting of HIV-1 virions to the basolateral membrane surface in polarized epithelial Madin-Darby canine kidney cells (MDCK). Site-directed mutagenesis was used to demonstrate that the membrane-proximal tyrosine in the intracytoplasmic tail of the HIV-1 transmembrane glycoprotein (gp41) is an essential component of this signal. In the present study, immunolocalization of viral budding allowed us to establish that this tyrosine-based signal is involved in determining the exact site of viral release at the surface of infected mononuclear cells. Substitution of the critical tyrosine residue was also shown to increase the amount of envelope glycoprotein at the cell surface, supporting previous suggestions that the tyrosine-based motif can promote endocytosis. Although alteration of the dual polarization-endocytosis motif did not affect the infectivity of cell-free virus, it could play a key role in cell-to-cell viral transmission. Accordingly, chronically infected lymphocytes showed a reduced ability to transmit the mutant virus to a cocultivated cell line. Overall, our data indicate that the YXXL targeting motif of HIV is active in various cell types and could play an important role in viral propagation; this may constitute an alternative target for HIV therapeutics and vaccine development.
Linkage Analysis of IL4 and Other Chromosome 5q31.1 Markers and Total Serum Immunoglobulin E Concentrations (1994)

Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (IgE) concentration. No linkage was found between these markers and specific IgE antibody concentrations. Analysis of total IgE within a subset of 128 IgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion.
Identification and Optimization of Pteridinone Toll-like Receptor 7 (TLR7) Agonists for the Oral Treatment of Viral Hepatitis (2013)

Pteridinone-based Toll-like receptor 7 (TLR7) agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogues were optimized for the immunomodulatory activity and selectivity versus other TLRs, based on differential induction of key cytokines including interferon α (IFN-α) and tumor necrosis factor α (TNF-α). In addition, physicochemical properties were adjusted to achieve desirable in vivo pharmacokinetic and pharmacodynamic properties. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.
Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. (1997)

The zinc finger transcription factor GATA4 has been implicated in heart development based on its early expression in precardiogenic splanchnic mesoderm and its ability to activate the expression of a number of cardiac-specific genes. To determine the role of GATA4 in embryogenesis, we generated mice homozygous for a GATA4 null allele. Homozygous GATA4 null mice arrested in development between E7.0 and E9.5 because of severe developmental abnormalities. Mutant embryos most notably lacked a primitive heart tube and foregut and developed partially outside the yolk sac. In the mutants, the two bilaterally symmetric promyocardial primordia failed to migrate ventrally but instead remained lateral and generated two independent heart tubes that contained differentiated cardiomyocytes. We show that these deformities resulted from a general loss in lateral to ventral folding throughout the embryo. GATA4 is most highly expressed within the precardiogenic splanchnic mesoderm at the posterior lip of the anterior intestinal portal, corresponding to the region of the embryo that undergoes ventral fusion. We propose that GATA4 is required for the migration or folding morphogenesis of the precardiogenic splanchnic mesodermal cells at the level of the AIP.
Engineering Robust and Functional Vascular Networks In Vivo With Human Adult and Cord Blood–Derived Progenitor Cells (2008)

The success of therapeutic vascularization and tissue engineering will rely on our ability to create vascular networks using human cells that can be obtained readily, can be expanded safely ex vivo, and can produce robust vasculogenic activity in vivo. Here we describe the formation of functional microvascular beds in immunodeficient mice by coimplantation of human endothelial and mesenchymal progenitor cells isolated from blood and bone marrow. Evaluation of implants after 1 week revealed an extensive network of human blood vessels containing erythrocytes, indicating the rapid formation of functional anastomoses within the host vasculature. The implanted endothelial progenitor cells were restricted to the luminal aspect of the vessels; mesenchymal progenitor cells were adjacent to lumens, confirming their role as perivascular cells. Importantly, the engineered vascular networks remained patent at 4 weeks in vivo. This rapid formation of long-lasting microvascular networks by postnatal progenitor cells obtained from noninvasive sources constitutes an important step forward in the development of clinical strategies for tissue vascularization.
Purification and Characterization of a Novel Thermostable Lipase from Pseudomonas cepacia (1992)

A thermostable lipase from Pseudomonas cepacia has been purified to homogeneity as judged by SDS-PAGE and isoelectric focusing. The purification included treatment of the culture supernatant with acrinol, hydrophobic interaction chromatography, and gel filtration. The enzyme was a monomeric protein with M(r) of 36,500 and pI of 5.1. The optimal pH at 50 degrees C and optimal temperature at pH 6.5 were 5.5-6.5 and 55-60 degrees C, respectively, when olive oil was used as the substrate. Simple triglycerides of short and middle chain fatty acids (C < or = 12) were the preferred substrates over those of long chain fatty acids. The enzyme cleaved all the ester bonds of triolein, with some preference for the 1,3-ester bonds. The enzyme retained all its activity even after incubation at 75 degrees C (pH 6.5) for 30 min. Further, the activity was not impaired during 21 h storage at pH 6.5 in 40% water-miscible solvents including methanol, ethanol, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, and dioxane. The addition of dimethylsulfoxide or acetone to the assay mixture in the range of 0-35% stimulated the enzyme, whereas benzene or n-hexane had an inhibitory effect. These properties together with the N-terminal amino acid sequence confirmed that the enzyme differs from the known Pseudomonas sp. lipases.
Accelerated atherosclerosis in hyperlipidemic C57BL/6 mice treated with cyclosporin A. (1993)

We and others have demonstrated that T lymphocytes are prominent components of atherosclerotic lesions. We hypothesized that if T cells were necessary for the development of atherosclerosis it would be possible to demonstrate its prevention or retardation in T-cell-suppressed mice. To test this hypothesis, CyA, a potent suppressor of T-cell activation, was used to treat C57BL/6 mice undergoing lipid hyperalimentation. Mice receiving normal mouse chow were completely free of atherosclerotic lesions. In mice receiving the atherogenic diet plus control oil injections, lesions of the aorta and coronary arteries were observed at 135 days and increased progressively in area until 310 days. Somewhat surprisingly, mice given the atherogenic diet plus CyA injections displayed even larger lesions at all three observed time intervals. Although CyA did suppress T-cell reactivity sufficiently to obtain the expected prolongation of skin allografts, it did not suppress the development or progression of atherosclerotic lesions.
Presence and Origin of Human IgG Subclass Proteinsin Newborns (1973)

Using haemagglutination inhibition tests specific for Gm types connected with IgGl, IgG2 and IgG3, and similar tests specific for Fc IgG4, the four subclasses of IgG were present in all of 29 human cord sera. The inhibition titres were similar to those in maternal sera. The Gm phenotype of a cord serum was always identical to that in the corresponding maternal serum. Some cord sera in addition contained small amounts of IgG with Gm types differing from that of the mother, these were probably produced by the fetus in utero. In sera obtained from the same children at 9 months of age, cases were found where Gm types, present at birth, had disappeared. The results indicate that both IgGl, IgG2 and IgG3 are transferred from mother to fetus before birth, and they are consistent with a similar transport also for IgG4.