gebhart/patrepeval huggingface dataset:
Progress with retroviral gene vectors (2000)

Retroviral vectors have become a standard tool for gene transfer technology. Compared with other gene transfer systems, retroviral vectors have several advantages, including their ability to transduce a variety of cell types, to integrate efficiently into the genomic DNA of the recipient cells and to express the transduced gene at high levels. The relatively well understood biology of retroviruses has made possible the development of packaging cell lines which provide in trans all the viral proteins required for viral particle formation. The design of different types of packaging cells has evolved to reduce the possibility of helper virus production. The host range of retroviruses has been expanded by pseudotyping the vectors with heterologous viral glycoproteins and receptor-specific ligands. The development of lentivirus vectors has allowed efficient gene transfer to quiescent cells. This review describes different strategies adopted for developing vectors to be used in gene therapy applications.
Adenosine receptors in brain membranes: binding of N6-cyclohexyl[3H]adenosine and 1,3-diethyl-8-[3H]phenylxanthine. (1980)

N6-Cyclohexyl[3H]adenosine ([3H]CHA) and 1,3-diethyl-8-[3H]phenylxanthine ([3H]DPX) to bind to adenosine receptors in brain membranes. The agonist [3H]CHA has high affinity in both bovine and guinea pig brain (Kd, 0.7 nM and 6 nM, respectively). [3H]CHA binding kinetics are slow (dissociation t1/2;60 min); binding is much higher at 25 degrees C than at 0 degrees C and is inhibited by guanine nucleotides. Potencies of nucleosides and xanthines in competing for [3H]CHA sites indicate that specific binding is entirely to A1 adenosine receptors. In bovine brain, the antagonist [3H]DPX exhibits high-affinity binding (Kd, 5 nM) to the same A1 receptors that bind [3H]CHA. Binding kinetics are rapid (dissociation t1/2, 1 min), and binding is moderately higher at 0 degrees C than at 25 degrees C. In guinea pig brain, [3H]DPX binding has only moderate affintiy (Kd 50 nM), and about 60% of specific binding is to sites that resemble A2 adenosine receptors.
Metalloproteinase inhibitors as therapeutics. (1993)

Matrix metalloproteinases (MMPs) are a family of enzymes which contain zinc at their active site and can degrade most of the matrix macromolecules found in connective tissues. These MMPs are secreted by connective tissue cells and infiltrating leucocytes in response to inflammatory mediators. There is now widespread recognition that MMPs are the major class of proteinases responsible for the excessive degradation of cartilage that leads to joint dysfunction in rheumatoid arthritis. The properties of the MMPs are reviewed and a therapeutic role for synthetic, zinc-binding pseudopeptide MMP inhibitors in the treatment of arthritis is proposed.
Design Considerations for Collaborative Visual Analytics (2008)

Visualizations leverage the human visual system to support the process of sensemaking, in which information is collected, organized, and analyzed to generate knowledge and inform action. Although most research to date assumes a single-user focus on perceptual and cognitive processes, in practice, sensemaking is often a social process involving parallelization of effort, discussion, and consensus building. Thus, to fully support sensemaking, interactive visualization should also support social interaction. However, the most appropriate collaboration mechanisms for supporting this interaction are not immediately clear. In this article, we present design considerations for asynchronous collaboration in visual analysis environments, highlighting issues of work parallelization, communication, and social organization. These considerations provide a guide for the design and evaluation of collaborative visualization systems.
Gene expression profiling of isogenic cells with different TP53 gene dosage reveals numerous genes that are affected by TP53 dosage and identifies CSPG2 as a direct target of p53 (2002)

TP53 does not fully comply with the Knudson model [Knudson, A. G., Jr. (1971) Proc. Natl. Acad. Sci. USA 68, 820-823] in that a reduction of constitutional expression of p53 may be sufficient for tumor predisposition. This finding suggests a gene-dosage effect for p53 function. To determine whether TP53 gene dosage affects the transcriptional regulation of target genes, we performed oligonucleotide-array gene expression analysis by using human cells with wild-type p53 (p53 +/+), or with one (p53 +/-), or both (p53 -/-) TP53 alleles disrupted by homologous recombination. We identified 35 genes whose expression is significantly correlated to the dosage of TP53. These genes are involved in a variety of cellular processes including signal transduction, cell adhesion, and transcription regulation. Several of them are involved in neurogenesis and neural crest migration, developmental processes in which p53 is known to play a role. Motif search analysis revealed that of the genes highly expressed in p53 +/+ and +/- cells, several contain a putative p53 consensus binding site (bs), suggesting that they could be directly regulated by p53. Among those genes, we chose CSPG2 (which encodes versican) for further study because it contains a bona fide p53 bs in its first intron and its expression highly correlates with TP53 dosage. By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53. In conclusion, we developed a strategy to demonstrate that many genes are affected by TP53 gene dosage for their expression. We report several candidate genes as potential downstream targets of p53 in nonstressed cells. Among them, CSPG2 is validated as being directly transactivated by p53. Our method provides a useful tool to elucidate additional mechanisms by which p53 exerts its functions.
Direct identification of residues of the epidermal growth factor receptor in close proximity to the amino terminus of bound epidermal growth factor. (1992)

We have recently developed a kinetically controlled, step-wise affinity cross-linking technique for specific, high-yield, covalent linkage of murine epidermal growth factor (mEGF) via its N terminus to the EGF receptor. EGF receptor from A431 cells was cross-linked to radiolabeled mEGF (125I-mEGF) by this technique and the 125I-mEGF-receptor complex was purified and denatured. Tryptic digestion of this preparation gave rise to a unique radiolabeled peptide that did not comigrate with trypsin-treated 125I-mEGF in SDS/Tricine gels but that could be immunoprecipitated with antibodies to mEGF. The immunoprecipitated peptide was isolated by electrophoresis in SDS/Tricine gels, eluted, and sequenced. The sequence was found to correspond to that of a tryptic peptide of the EGF receptor beginning with Gly-85, which is in domain I, a region N terminal to the first cysteine-rich region of the receptor. Selective loss of signal in the 17th sequencing cycle suggests that the point of attachment of N-terminally modified 125I-mEGF to the receptor is Tyr-101. The data presented here provide identification by direct protein microsequencing of a site of interaction of EGF and the EGF receptor.
Pathogenic role of anti-endothelial cell antibodies in systemic vasculitis. (2000)

Antiendothelial cell antibodies (AECA), a heterogeneous group of antibodies quite distinct from the ANCA family, have been detected in variety of diseases which share a varying degree of vessel wall damage. This review is mainly focused on Wegener's granulomatosis, Takayasu's arteritis and Kawasaki syndrome, which provide the best examples to evaluate the pathogenic and prognostic value of AECA. There is increasing evidence to show that AECA might be pathogenic in inducing autoimmune vascular disease. It is relevant to note that the presence and titre of AECA has been correlated with disease activity in systemic vasculitis. Experimental in vitro and in vivo models support a potential pathogenic role for AECA in sustaining immune-mediated vessel inflammation. Rather than being cytotoxic to endothelial cells, AECA are able to up-regulate the expression of adhesion molecules (E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and to induce the secretion of cytokine and chemokine which, in turn, cause leukocyte recruitment and adhesion. A recent idiotypic animal model has provided further evidence that AECA can be pathogenic.
Endotoxin-Neutralizing Antimicrobial Proteins of the Human Placenta (2002)

Microbial colonization and infection of placental tissues often lead to adverse pregnancy outcomes such as preterm birth, a leading cause of neonatal morbidity and mortality. The fetal membranes of the placenta, a physical and active barrier to microbial invasion, encapsulate the fetus and secure its intrauterine environment. To examine the innate defense system of the human placenta, antimicrobial peptides were isolated from the fetal membranes of human placenta and characterized biochemically. Two salt-resistant antimicrobial host proteins were purified to homogeneity using heparin-affinity and reversed-phase HPLC. Characterization of these proteins revealed that they are identical to histones H2A and H2B. Histones H2A and H2B showed dose-dependent inhibition of the endotoxin activity of LPS and inhibited this activity by binding to and therefore blocking both the core and lipid A moieties of LPS. Consistent with a role for histones in the establishment of placental innate defense, histones H2A and H2B were highly expressed in the cytoplasm of syncytiotrophoblasts and amnion cells, where the histone proteins were localized mainly to the epithelial surface. Furthermore, culturing of amnion-derived WISH cells led to the constitutive release of histone H2B, and histones H2A and H2B contribute to bactericidal activity of amniotic fluid. Our studies suggest that histones H2A and H2B may endow the epithelium of the placenta with an antimicrobial and endotoxin-neutralizing barrier against microorganisms that invade this immune-privileged site.
BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation (2010)

Oncogenic BRAF mutations are found in several tumor types, including melanomas and colorectal cancers. Tumors with BRAF mutations have increased mitogen-activated protein kinase pathway activity and heightened sensitivity to BRAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) inhibitors. To identify potential mechanisms of acquired drug resistance, we generated clones resistant to the allosteric MEK inhibitor AZD6244 from two BRAF V600E mutant colorectal cancer cell lines that are highly sensitive to MEK or BRAF inhibition. These AZD6244-resistant (AR) clones, which exhibited cross-resistance to BRAF inhibitors, acquired resistance through amplification of the BRAF gene. A small percentage of treatment-naïve parental cells showed preexisting BRAF amplification. We observed similar amplification in a subset of cells in a BRAF-mutant colorectal cancer. In cell lines, BRAF amplification increased the abundance of phosphorylated MEK and impaired the ability of AZD6244 to inhibit ERK (extracellular signal-regulated kinase) phosphorylation. The ability of AZD6244 to inhibit ERK phosphorylation in AR cells was restored by treatment with a BRAF inhibitor at low concentrations that reduced the abundance of phosphorylated MEK to amounts observed in parental cells. Combined MEK and BRAF inhibition fully overcame resistance to MEK or BRAF inhibitors alone and was also more effective in parental cells compared to treatment with either inhibitor alone. These findings implicate BRAF amplification as a mechanism of resistance to both MEK and BRAF inhibitors and suggest combined MEK and BRAF inhibition as a clinical strategy to overcome, or possibly prevent, this mechanism of resistance.
A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis (2006)

NIP-004 is a novel synthetic compound developed to display human thrombopoietin (TPO) receptor (c-Mpl) agonist activity. NIP-004 displays species specificity, stimulating proliferation or differentiation of human c-Mpl-expressing cells such as UT-7/TPO and human CD34(+) cells but not murine c-Mpl-expressing cells or cynomolgus monkey cells. To test the mechanism of its action, we constructed mutant forms of c-Mpl; murine c-Mpl(L490H) dis-played a response to NIP-004, whereas human c-Mpl(H499L) lost this response, indicating that histidine in the transmembrane domain of c-Mpl is essential for its activity. Because histidine is not present in the c-Mpl transmembrane domain of rats, hamsters, rhesus macaques, and cynomolgus monkeys, we examined the in vivo efficacy of NIP-004 using mice that received xenotransplants. In immunodeficient nonobese diabetic (NOD)/Shi-scid, IL-2Rgamma(null) (NOG) mice receiving transplants of umbilical cord blood-derived CD34(+) cells, NIP-004 increased human megakaryoblasts, mature megakaryocytes, and circulating human platelets 6-fold, the latter being morphologically and functionally indistinguishable from normal human platelets. These observations indicate that NIP-004 is a novel human c-Mpl activator and induces human thrombopoiesis.
The prohormone convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a strict temporal order during proopiomelanocortin biosynthetic processing. (1993)

Two subtilisin-like endoproteases called PC1 and PC2 are distributed in a tissue-specific manner in the pituitary and in the brain. AtT-20 cells and corticotropes of the anterior pituitary express primarily PC1 and perform a limited number of cleavages of the proopiomelanocortin (POMC) precursor during biosynthesis. Melanotropes of the intermediate pituitary express both PC1 and PC2 and perform a more extensive set of cleavages during the biosynthetic processing of POMC. To investigate the role of PC2 in the biosynthetic processing of POMC, AtT-20 mouse corticotropes were stably transfected with a full length PC2 cDNA. The AtT-20 cells expressing PC2 acquired the ability to perform all the additional cleavages seen in the intermediate pituitary, but did not acquire the ability to alpha-N-acetylate the product peptides. The kinetics of the earliest steps in biosynthetic processing were unaltered by the expression of PC2, and the changes due to PC2 expression were seen only in the middle and late steps in biosynthetic processing. Thus, both the identity of the final product peptides and the kinetics of the processing steps in the AtT-20 cells expressing PC2 fit the patterns expected for melanotropes of the intermediate pituitary.
Radiolabeled Cell Distribution After Intramyocardial, Intracoronary, and Interstitial Retrograde Coronary Venous Delivery (2005)

The majority of delivered cells is not retained in the heart for each delivery modality. The clinical implications of these findings are potentially significant, because cells with proangiogenic or other therapeutic effects could conceivably have effects in other organs to which they are not primarily targeted but to which they are distributed. Also, we found that although IM injection was more efficient, it was less consistent in the delivery of PBMNCs compared with IC and IRV techniques.
Basics of broadband impedance spectroscopy measurements using periodic excitations (2012)

Measuring the impedance frequency response of systems by means of frequency sweep electrical impedance spectroscopy (EIS) takes time. An alternative based on broadband signals enables the user to acquire simultaneous impedance response data collection. This is directly reflected in a short measuring time compared to the frequency sweep approach. As a result of this increase in the measuring speed, the accuracy of the impedance spectrum is compromised. The aim of this paper is to study how the choice of the broadband signal can contribute to mitigate this accuracy loss. A review of the major advantages and pitfalls of four different periodic broadband excitations suitable to be used in EIS applications is presented. Their influence on the instrumentation and impedance spectrum accuracy is analyzed. Additionally, the signal processing tools to objectively evaluate the quality of the impedance spectrum are described. In view of the experimental results reported, the impedance spectrum signalto- noise ratio (SNR Z) obtained with multisine or discrete interval binary sequence signals is about 20-30 dB more accurate than maximum length binary sequence or chirp signals. © 2012 IOP Publishing Ltd.
Fiber cladding mode sensitivity characterization for long-period gratings (2003)

We propose a simple method of characterizing the sensitivities of the cladding modes of an optical fiber to environmental conditions through the analysis of a single device. These sensitivities to conditions such as temperature, strain, and the refractive index of the surrounding medium are of particular relevance to the fabrication of long-period gratings (LPGs). The inferred sensitivities are all valid around the design wavelength of the analyzed fiber Bragg grating (FBG) device, and so can provide important design information for the manufacture of a LPG device that couples to a single or several cladding modes. To demonstrate the method, we use a FBG with a design wavelength of 1550 nm to determine the sensitivity of the cladding modes of a standard telecomm fiber to both temperature and strain. Using this information we infer the environmental sensitivity of any LPG fabricated in this fiber that operates around this wavelength. We design and fabricate LPGs to couple to selected cladding modes and measure the sensitivities of these devices directly. We find good agreement between the directly measured and inferred sensitivities.
Short Hairpin RNA Knockdown of the Androgen Receptor Attenuates Ligand-Independent Activation and Delays Tumor Progression (2006)

Progression to androgen independence is the lethal end stage of prostate cancer. We used expression of androgen receptor (AR)-targeted short hairpin RNAs (shRNA) to directly test the requirement for AR in ligand-independent activation of androgen-regulated genes and hormone-independent tumor progression. Transient transfection of LNCaP human prostate cancer cells showed that AR shRNA decreased R1881 induction of the prostate-specific antigen (PSA)-luciferase reporter by 96%, whereas activation by forskolin, interleukin-6, or epidermal growth factor was inhibited 48% to 75%. Whereas the antiandrogen bicalutamide provided no further suppression, treatment with the mitogen-activated protein kinase (MAPK) inhibitor U0126 completely abrogated the residual activity, indicating a MAPK-dependent, AR-independent pathway for regulating the PSA promoter. Expression of doxycycline-inducible AR shRNA expression in LNCaP cells resulted in decreased levels of AR and PSA as well as reduced proliferation in vitro. When these cells were grown as xenografts in immunocompromised mice, induction of AR shRNA decreased serum PSA to below castration nadir levels and significantly retarded tumor growth over the entire 55-day experimental period. This is the first demonstration that, by inducibly suppressing AR expression in vivo, there is an extensive delay in progression to androgen independence as well as a dramatic inhibition of tumor growth and decrease in serum PSA, which exceeds that seen with castration alone. Based on these findings, we propose that suppressing AR expression may provide superior therapeutic benefit in reducing tumor growth rate than castration and may additionally be very effective in delaying progression to androgen independence.
Trapdoors for hard lattices and new cryptographic constructions (2008)

We show how to construct a variety of "trapdoor" cryptographic tools assuming the worst-case hardness of standard lattice problems (such as approximating the length of the shortest nonzero vector to within certain polynomial factors). Our contributions include a new notion of trapdoor function with preimage sampling, simple and efficient "hash-and-sign" digital signature schemes, and identity-based encryption. A core technical component of our constructions is an efficient algorithm that, given a basis of an arbitrary lattice, samples lattice points from a discrete Gaussian probability distribution whose standard deviation is essentially the length of the longest Gram-Schmidt vector of the basis. A crucial security property is that the output distribution of the algorithm is oblivious to the particular geometry of the given basis.
The role of mitochondria in aging. (1996)

Aging is a process drawing attention of many researchers, and at present many theories exists, which try to explain this chain of inevitable events leading to death of organism. In this article we focused our attention on a theory explaining the degenerative changes occurring during aging by the effect of oxygen free radicals. These highly reactive radicals are produced during oxidative phosphorylation in mitochondria. All cellular components appear to be sensitive to oxygen-radical damage. Lipids, proteins and nucleic acids are probably the most susceptible to this injury. Lipoperoxidation of lipids together with cross-linking of proteins with phospholipids and nucleic acids caused changes in membrane fluidity. Mitochondrial DNA coding several subunits of respiratory chain enzymes can be also damaged by these radicals. All these changes together have negative impact on mitochondrial metabolism resulting progressive decrease of the efficiency of oxidative phosphorylation and thus of the whole organism.
Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-kappa B mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. (1994)

Cell adhesion to endothelial cells stimulated by tumor necrosis factor-alpha (TNF) is due to induction of surface receptors, such as vascular cell adhesion molecule-1 (VCAM-1). The antioxidant pyrrolidine dithiocarbamate (PDTC) specifically inhibits activation of nuclear factor-kappa B (NF-kappa B). Since kappa B motifs are present in VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) promoters, we used PDTC to study the regulatory mechanisms of VCAM-1 and ICAM-1 induction and subsequent monocyte adhesion in TNF-treated human umbilical vein endothelial cells (HUVECs). PDTC or N-acetylcysteine dose dependently reduced TNF-induced VCAM-1 but not ICAM-1 surface protein (also in human umbilical arterial endothelial cells) and mRNA expression (by 70% at 100 mumol/L PDTC) in HUVECs as assessed by flow cytometry and polymerase chain reaction. Gel-shift analysis in HUVECs demonstrated that PDTC prevented NF-kappa B mobilization by TNF, suggesting that only VCAM-1 induction was controlled by NF-kappa B. Since HUVECs released superoxide anions in response to TNF, and H2O2 induces VCAM-1, PDTC may act as a radical scavenger. Although ICAM-1 induction was unaffected, inhibitors of NADPH oxidase (apocynin) or cytochrome P-450 (SKF525a) suppressed VCAM-1 induction by TNF, revealing that several radical-generating systems are involved in its regulation. PDTC, apocynin, or SKF525a decreased adhesion of monocytic U937 cells to TNF-treated HUVECs (by 75% at 100 mumol/L PDTC). Inhibition by anti-VCAM-1 monoclonal antibody 1G11 indicated that U937 adhesion was VCAM-1 dependent and suppression by antioxidants was due to reduced VCAM-1 induction.(ABSTRACT TRUNCATED AT 250 WORDS)