gebhart/patrepeval huggingface dataset:
Inflammation-sleep interface in brain disease: TNF, insulin, orexin (2014)

The depth, pattern, timing and duration of unconsciousness, including sleep, vary greatly in inflammatory disease, and are regarded as reliable indicators of disease severity. Similarly, these indicators are applicable to the encephalopathies of sepsis, malaria, and trypanosomiasis, and to viral diseases such as influenza and AIDS. They are also applicable to sterile neuroinflammatory states, including Alzheimer's disease, Parkinson's disease, traumatic brain injury, stroke and type-2 diabetes, as well as in iatrogenic brain states following brain irradiation and chemotherapy. Here we make the case that the cycles of unconsciousness that constitute normal sleep, as well as its aberrations, which range from sickness behavior through daytime sleepiness to the coma of inflammatory disease states, have common origins that involve increased inflammatory cytokines and consequent insulin resistance and loss of appetite due to reduction in orexigenic activity. Orexin reduction has broad implications, which are as yet little appreciated in the chronic inflammatory conditions listed, whether they be infectious or sterile in origin. Not only is reduction in orexin levels characterized by loss of appetite, it is associated with inappropriate and excessive sleep and, when dramatic and chronic, leads to coma. Moreover, such reduction is associated with impaired cognition and a reduction in motor control. We propose that advanced understanding and appreciation of the importance of orexin as a key regulator of pathways involved in the maintenance of normal appetite, sleep patterns, cognition, and motor control may afford novel treatment opportunities.
Assembly of cyclin D-dependent kinase and titration of p27 Kip1 regulated by mitogen-activated protein kinase kinase (MEK1) (1998)

A constitutively active form of mitogen-activated protein kinase kinase (MEK1) was synthesized under control of a zinc-inducible promoter in NIH 3T3 fibroblasts. Zinc treatment of serum-starved cells activated extracellular signal-regulated protein kinases (ERKs) and induced expression of cyclin D1. Newly synthesized cyclin D1 assembled with cyclin-dependent kinase-4 (CDK4) to form holoenzyme complexes that phosphorylated the retinoblastoma protein inefficiently. Activation of the MEK1/ERK pathway neither triggered degradation of the CDK inhibitor kinase inhibitory protein-1 (p27(Kip1)) nor led to activation of cyclin E- and A-dependent CDK2, and such cells did not enter the DNA synthetic (S) phase of the cell division cycle. In contrast, zinc induction of active MEK1 in cells also engineered to ectopically overexpress cyclin D1 and CDK4 subunits generated levels of cyclin D-dependent retinoblastoma protein kinase activity approximating those achieved in cells stimulated by serum. In this setting, p27(Kip1) was mobilized into complexes containing cyclin D1; cyclin E- and A-dependent CDK2 complexes were activated; and serum-starved cells entered S phase. Thus, although the activity of p27(Kip1) normally is canceled through a serum-dependent degradative process, overexpressed cyclin D1-CDK complexes sequestered p27(Kip1) and reduced the effective inhibitory threshold through a stoichiometric mechanism. A fraction of these cells completed S phase and divided, but they were unable to continuously proliferate, indicating that other serum-responsive factors ultimately became rate limiting for cell cycle progression. Therefore, the MEK/ERK pathway not only acts transcriptionally to induce the cyclin D1 gene but functions posttranslationally to regulate cyclin D1 assembly with CDK4 and to thereby help cancel p27(Kip1)-mediated inhibition.
Strategies for identification and clinical evaluation of promising chemopreventive agents. (1996)

Strategies for chemopreventative drug development are based on the use of well-characterized agents, intermediate biomarkers correlating to cancer incidence, and suitable cohorts for efficacy studies. Since chemoprevention is applied over the long-term, chemopreventive drugs must have low toxicity. Strategies for enhancing chemopreventive drug efficacy and minimizing toxicity include combinations of drugs with complementary mechanisms and/or synergistic activity; coadministration of drugs to counter the toxicity of the chemopreventive agents; and pursuit of related compounds that retain efficacy with reduced side effects. Because of its slow development, cancer is not a feasible end point for clinical evaluation of chemoprevention, and so intermediate biomarkers that can serve as surrogate end points are crucial. Particularly important biomarkers are the morphometric and cytometric changes defining intraepithelial neoplasia (IEN). Cohorts for chemoprevention trials should have high incidences of the cancer or intermediate biomarker(s) under study within the trial duration.
Patterns of Synchrony in Neural Networks with Spike Adaptation (2001)

We study the emergence of synchronized burst activity in networks of neurons with spike adaptation. We show that networks of tonically firing adapting excitatory neurons can evolve to a state where the neurons burst in a synchronized manner. The mechanism leading to this burst activity is analyzed in a network of integrate-and-fire neurons with spike adaptation. The dependence of this state on the different network parameters is investigated, and it is shown that this mechanism is robust against inhomogeneities, sparseness of the connectivity, and noise. In networks of two populations, one excitatory and one inhibitory, we show that decreasing the inhibitory feedback can cause the network to switch from a tonically active, asynchronous state to the synchronized bursting state. Finally, we show that the same mechanism also causes synchronized burst activity in networks of more realistic conductance-based model neurons.
Equilibrium association constants for oligonucleotide-directed triple helix formation at single DNA sites: Linkage to cation valence and concentration (1993)

The linkage between the energetics of oligonucleotide-directed triple helix formation and the cationic solution environment has been investigated in mixed-valence salt solutions. Equilibrium constants for formation of the local pyrimidine.purine.pyrimidine structure afforded by binding of the oligonucleotide 5'-d(T*TTTTCTCTCTCTCT)-3' to a single site within a 339-bp plasmid fragment were measured using quantitative affinity cleavage titrations at pH 7.0 and 22 degrees C in the presence of various concentrations of KCl, MgCl2, and spermine tetrahydrochloride (SpmCl4). In a solution containing 10 mM NaCl, 140 mM KCl, 1.0 mM MgCl2, and 1.0 mM SpmCl4, the measured binding constant was 3.3 (+/- 1.4) x 10(5) M-1. The equilibrium constant previously reported for the same association reaction in 100 mM NaCl and 1 mM SpmCl4 at the same temperature and pH was 10-fold higher [Singleton, S. F., & Dervan, P. B. (1992) J. Am. Chem. Soc. 114, 6957-6965]. Further study demonstrated that varying the potassium ion concentration between 5.0 and 140 mM (in the presence of 10 mM NaCl, 1.0 mM MgCl2, and 1.0 mM SpmCl4) resulted in an overall 100-fold decrease in the binding affinity from the lowest to the highest concentration. In contrast, measured binding constants increased 500-fold as the spermine concentration was increased from 0.40 to 4.0 mM (in the presence of 10 mM NaCl, 140 mM KCl, and 1.0 mM MgCl2). There was a modest effect on the binding constant (a 3-fold decrease) upon varying the magnesium ion concentration from 0.10 to 10 mM (in the presence of 10 mM NaCl, 140 mM KCl, and 1.0 mM SpmCl4).(ABSTRACT TRUNCATED AT 250 WORDS)
Recombinant Human Laminin-10 (α5β1γ1) (2002)

The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. We determined the complete human cDNA sequence for the LN alpha5 chain and produced recombinant human LN-10 (rLN-10) in HEK293 cells by triple transfection of full-length cDNAs encoding the human LN alpha5, beta1, and gamma1 chains. The rLN-10 was purified using affinity chromatography and had an apparent molecular mass of approximately 800 kDa in SDS-PAGE and a native domain structure in rotary shadowing electron microscopy. By using function-blocking monoclonal antibodies, integrin alpha(3)beta(1) was found to be a major mediator of adhesion of HT-1080 and human saphenous vein endothelial cells. Human saphenous vein endothelial cells adhered more strongly to rLN-10 than to LN-1 and LN-8 and showed better migration on rLN-10, compared with several other matrices. Considering the cell adhesive and migration-promoting properties of rLN-10 on endothelial cells, this molecule could be useful in improving the biocompatibility and endothelialization of vascular grafts.
Indium incorporation and emission properties of nonpolar and semipolar InGaN quantum wells (2012)

We report indium incorporation properties on various nonpolar and semipolar free-standing GaN substrates. Electroluminescence characterization and x-ray diffraction (XRD) analysis indicate that the semipolar (202¯1¯) and (112¯2) planes have the highest indium incorporation rate among the studied planes. We also show that both indium composition and polarization-related electric fields impact the emission wavelength of the quantum wells (QWs). The different magnitudes and directions of the polarization-related electric fields for each orientation result in different potential profiles for the various semipolar and nonpolar QWs, leading to different emission wavelengths at a given indium composition.
An ex-vivo Human Intestinal Model to Study Entamoeba histolytica Pathogenesis (2009)

Amoebiasis (a human intestinal infection affecting 50 million people every year) is caused by the protozoan parasite Entamoeba histolytica. To study the molecular mechanisms underlying human colon invasion by E. histolytica, we have set up an ex vivo human colon model to study the early steps in amoebiasis. Using scanning electron microscopy and histological analyses, we have established that E. histolytica caused the removal of the protective mucus coat during the first two hours of incubation, detached the enterocytes, and then penetrated into the lamina propria by following the crypts of Lieberkühn. Significant cell lysis (determined by the release of lactodehydrogenase) and inflammation (marked by the secretion of pro-inflammatory molecules such as interleukin 1 beta, interferon gamma, interleukin 6, interleukin 8 and tumour necrosis factor) were detected after four hours of incubation. Entamoeba dispar (a closely related non-pathogenic amoeba that also colonizes the human colon) was unable to invade colonic mucosa, lyse cells or induce an inflammatory response. We also examined the behaviour of trophozoites in which genes coding for known virulent factors (such as amoebapores, the Gal/GalNAc lectin and the cysteine protease 5 (CP-A5), which have major roles in cell death, adhesion (to target cells or mucus) and mucus degradation, respectively) were silenced, together with the corresponding tissue responses. Our data revealed that the signalling via the heavy chain Hgl2 or via the light chain Lgl1 of the Gal/GalNAc lectin is not essential to penetrate the human colonic mucosa. In addition, our study demonstrates that E. histolytica silenced for CP-A5 does not penetrate the colonic lamina propria and does not induce the host's pro-inflammatory cytokine secretion.
The Thrombin Receptor Second Cytoplasmic Loop Confers Coupling to Gq-like G Proteins in Chimeric Receptors (1997)

Thrombin cleavage of this receptor's amino-terminal exodomain unmasks a new amino terminus. This then binds intramolecularly to the body of the receptor to trigger transmembrane signaling and activation of G iand G q -like G proteins. Toward identifying the domains responsible for thrombin receptor-G protein interactions, we examined the signaling properties of chimeric receptors in which thrombin receptor cytoplasmic sequences replaced the cognate sequences in the G s -coupled 2 -adrenergic receptor ( 2 AR) or the G i -coupled dopamine D 2 receptor (D 2 R). In Xenopus oocytes, a chimeric 2 AR bearing the thrombin receptor second cytoplasmic (C2) loop gained the ability to trigger intracellular Ca 2 release in response to adrenergic agonist, whereas a 2 AR bearing the cognate C2 loop from the D 2 R did not. Similarly, in COS-7 cells, a chimeric D 2 R bearing the thrombin receptor C2 loop gained the ability to trigger phosphoinositide hydrolysis in response to dopaminergic agonist, apparently by coupling to a G qlike G protein. No detectable G s coupling was seen. Thus, the thrombin receptor C2 loop was able to confer G q -like coupling in several different receptor contexts. These observations suggest that the thrombin receptor C2 loop specifies G q coupling by directly contacting G q or by contributing to a structure required for G q coupling. The ability of the thrombin receptor C2 loop to function in the context of the D 2 R and 2 AR strongly suggests that the transmembrane switching and G protein activation strategies used by the thrombin receptor must be very similar to those used by the D 2 R and 2 AR despite the thrombin receptor's strikingly different liganding mechanism.
Comparison of Variable Region Primary Structures within an Anti-fluorescein Idiotype Family (1989)

Previous reports described the properties of a high affinity (Ka = 1.7 X 10(10) M-1) prototype anti-fluorescein monoclonal antibody 4-4-20, an intermediate affinity (Ka = 3.7 X 10(7) M-1) prototype 9-40, and Ig members of the 9-40 idiotype family (comprised of 3-24, 5-14, 5-27, 10-25 and 12-40). Although the seven monoclonal anti-fluorescein antibodies expressed similar active site structural determinants (idiotypes) as determined serologically, each was characterized by different affinities for fluorescein and fine specificity binding patterns. Partial heavy (H)- and light (L)-chain N-terminal amino acid sequence analyses revealed all antibodies (except 5-27) were composed of highly homologous VHIII(C) and V kappa II subgroup genes, respectively. Antibody 5-27 utilized a VHIII(B) and a V kappa V subgroup genes and shared low V-region sequence homology with 4-4-20, 9-40 and the remaining 9-40 idiotype family. In addition, complete 4-4-20, VH- and VL-region primary structures were determined to better understand antibody-antigen interactions. Antibody 4-4-20 utilized a VHIII(C) subgroup VH-gene, a truncated Sp2 D gene segment, JH4, a V kappa II subgroup VL-gene, and J kappa 1. Antibody 4-4-20 VH and VL complementarity-determining regions contained many basic and aromatic amino acid residues capable of interaction with fluorescein. Results are discussed in terms of idiotypic and fluorescein-binding characteristics as well as antibody structural and functional diversity in the immune response.
Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins (2000)

Genetic factors have a substantial contribution to RA in the population, accounting for approximately 60% of the variation in liability to disease. Although tempered by power considerations, there is no evidence in these twin data that the overall genetic contribution to RA differs by sex, age, age at disease onset, and disease severity.
A 31 GHz f/sub max/ lateral BJT on SOI using self-aligned external base formation technology (2002)

A novel device structure and simple process technology for realizing low-power/high-performance SOI lateral BJTs are presented. Low base resistance has been achieved by employing a self-aligned external base formation process. Due to reduced parasitics, the fabricated device exhibited an f/sub max/ of 31 GHz, the highest value for an SOI BJT reported so far.
Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. (1984)

We have created mouse-human antibody molecules of defined antigen-binding specificity by taking the variable region genes of a mouse antibody-producing myeloma cell line with known antigen-binding specificity and joining them to human immunoglobulin constant region genes using recombinant DNA techniques. Chimeric genes were constructed that utilized the rearranged and expressed antigen-binding variable region exons from the myeloma cell line S107, which produces an IgA (kappa) anti-phosphocholine antibody. The heavy chain variable region exon was joined to human IgG1 or IgG2 heavy chain constant region genes, and the light chain variable region exon from the same myeloma was joined to the human kappa light chain gene. These genes were transfected into mouse myeloma cell lines, generating transformed cells that produce chimeric mouse-human IgG (kappa) or IgG (kappa) anti-phosphocholine antibodies. The transformed cell lines remained tumorigenic in mice and the chimeric molecules were present in the ascitic fluids and sera of tumor-bearing mice.
Detection of Marek's disease virus DNA in Japanese quail susceptible to atherosclerosis (1986)

Marek's disease virus (MDV) was demonstrated as an etiological agent which causes atherosclerosis in the chicken. Since herpes viruses are ubiquitous, incidences of viral atherogenesis in humans and other animals were speculated. In this laboratory, the atherosclerosis susceptible (SUS) and resistant (RES) Japanese quail were developed as the animal model for atherosclerosis research. The susceptibility of the animal might be due to an infection of MDV or a related quail herpes virus (QHV). An initial attempt to isolate viruses from quail and an agar gel precipitin test for MDC were not positive. A DNA hybridization technique was used to determine whether the MDC-DNA existed in the quail cell. The gene library of MDV EcoRl DNA fragments was used to prepare the DNA probe, labeled with (/sup 32/P) by nick translation. Dot hybridizations were carried out by mixing the MDV-DNA probe with DNAs isolated from quail tissues. A high stringent condition was used. From this experiment it was found that the tissues from the SUS quail were hybridization positive, but most of them from RES quail were negative. When aortas were compared, the severe atherosclerotic had a strong hybridization (3-4 cop. of genome/cell) whereas the others hybridized moderately (1 cop./cell). Itmore » was concluded that genes from MDV or a QHV indeed existed in Japanese quail.« less
An Investigation of the Mechanisms of Electronic Sensing of Protein Adsorption on Carbon Nanotube Devices (2004)

It has been reported that protein adsorption on single-walled carbon nanotube field effect transistors (FETs) leads to appreciable changes in the electrical conductance of the devices, a phenomenon that can be exploited for label-free detection of biomolecules with a high potential for miniaturization. This work presents an elucidation of the electronic biosensing mechanisms with a newly developed microarray of nanotube "micromat" sensors. Chemical functionalization schemes are devised to block selected components of the devices from protein adsorption, self-assembled monolayers (SAMs) of methoxy(poly(ethylene glycol))thiol (mPEG-SH) on the metal electrodes (Au, Pd) and PEG-containing surfactants on the nanotubes. Extensive characterization reveals that electronic effects occurring at the metal-nanotube contacts due to protein adsorption constitute a more significant contribution to the electronic biosensing signal than adsorption solely along the exposed lengths of the nanotubes.
Supercontinuum generation in ultraviolet-irradiated fibers (2004)

We demonstrate that UV exposure of highly nonlinear, germanosilicate fibers causes a strong change in their chromatic dispersion and can significantly alter the infrared supercontinuum generation in these fibers. By varying the level of UV exposure to the fiber, we show that the dispersion zero and the short-wavelength edge of the supercontinuum can be changed by more than 100 nm. A nonlinear Schrödinger equation model of the continuum generation in the nonlinear fiber shows that the short-wavelength behavior of the continuum is primarily controlled by changes in the fiber dispersion caused by the UV-induced change in the refractive index of the fiber core.
Improved knockdown from artificial microRNAs in an enhanced miR-155 backbone: a designer's guide to potent multi-target RNAi (2015)

Artificial microRNA (amiRNA) sequences embedded in natural microRNA (miRNA) backbones have proven to be useful tools for RNA interference (RNAi). amiRNAs have reduced off-target and toxic effects compared to other RNAi-based methods such as short-hairpin RNAs (shRNA). amiRNAs are often less effective for knockdown, however, compared to their shRNA counterparts. We screened a large empirically-designed amiRNA set in the synthetic inhibitory BIC/miR-155 RNA (SIBR) scaffold and show common structural and sequence-specific features associated with effective amiRNAs. We then introduced exogenous motifs into the basal stem region which increase amiRNA biogenesis and knockdown potency. We call this modified backbone the enhanced SIBR (eSIBR) scaffold. Using chained amiRNAs for multi-gene knockdown, we show that concatenation of miRNAs targeting different genes is itself sufficient for increased knockdown efficacy. Further, we show that eSIBR outperforms wild-type SIBR (wtSIBR) when amiRNAs are chained. Finally, we use a lentiviral expression system in cultured neurons, where we again find that eSIBR amiRNAs are more potent for multi-target knockdown of endogenous genes. eSIBR will be a valuable tool for RNAi approaches, especially for studies where knockdown of multiple targets is desired.
Cytotoxic T Cells in Cytomegalovirus Infection (1982)

We studied 58 recipients of bone-marrow transplants to evaluate immune responses to cytomegalovirus infection. Such infection developed in 43 patients; it was fatal in 12, nonfatal in 23, and present at death from other causes in eight. All patients had low or absent cytomegalovirus-specific cytotoxic lymphocyte activity before the onset of infection. Cytomegalovirus-specific cytotoxic responses developed in all survivors, whereas only two patients with fatal infection had even low-level cytomegalovirus-specific cytotoxic responses. Natural and antibody-dependent killer-cell activities were depressed both before and during infection in patients with fatal infections, but not in those who survived. The outcome of the infection did not correlate with the nature of the underlying disease, the type of transplant received, the pretransplantation cytomegalovirus-antibody status, or lymphocyte-proliferation responses to cytomegalovirus antigens or concanavalin A. The correlation between effective virus-specific cytotoxic response and recovery from infection indicates that these effector cells probably mediate recovery from cytomegalovirus infection.