gebhart/patrepeval huggingface dataset:
Differential genome-wide array–based methylation profiles in prognostic subsets of chronic lymphocytic leukemia (2009)

Global hypomethylation and regional hypermethylation are well-known epigenetic features of cancer; however, in chronic lymphocytic leukemia (CLL), studies on genome-wide epigenetic modifications are limited. Here, we analyzed the global methylation profiles in CLL, by applying high-resolution methylation microarrays (27,578 CpG sites) to 23 CLL samples, belonging to the immunoglobulin heavy-chain variable (IGHV) mutated (favorable) and IGHV unmutated/IGHV3-21 (poor-prognostic) subsets. Overall, results demonstrated significant differences in methylation patterns between these subgroups. Specifically, in IGHV unmutated CLL, we identified methylation of 7 known or candidate tumor suppressor genes (eg, VHL, ABI3, and IGSF4) as well as 8 unmethylated genes involved in cell proliferation and tumor progression (eg, ADORA3 and PRF1 enhancing the nuclear factor-kappaB and mitogen-activated protein kinase pathways, respectively). In contrast, these latter genes were silenced by methylation in IGHV mutated patients. The array data were validated for selected genes using methylation-specific polymerase chain reaction, quantitative reverse transcriptase-polymerase chain reaction, and bisulfite sequencing. Finally, the significance of DNA methylation in regulating gene promoters was shown by reinducing 4 methylated tumor suppressor genes (eg, VHL and ABI3) in IGHV unmutated samples using the methyl-inhibitor 5-aza-2'-deoxycytidine. Taken together, our data for the first time reveal differences in global methylation profiles between prognostic subsets of CLL, which may unfold epigenetic silencing mechanisms involved in CLL pathogenesis.
Diseases of protein aggregation and the hunt for potential pharmacological agents (2007)

Protein aggregation is a ubiquitous phenomenon significant to all aspects of science. Notably, the formation of protein aggregates is frequently encountered in biochemical research and biopharmaceutical industry. Formation of protein aggregates is generally regarded to be associated with partially folded intermediate species that are susceptible to self-association due to the exposure of hydrophobic core. Evidence supports the concept that the formation of aggregates in vitro is a generic property of proteins. In human etiology, more than 20 different devastating human diseases have been reported to be associated with protein aggregation. Although protein aggregation diseases have been the center of intense research, much remains to be learned regarding the underlying molecular mechanisms. In this review, the general background information on protein aggregation is first provided. Next, we summarize the properties, characteristics and causes of protein aggregates. Finally, from the perspectives of epidemiology, pathogenesis, existing mechanisms, relevant hypotheses, and current as well as potential therapeutic approaches, two examples of protein aggregation diseases, Alzheimer's disease and cataract, are briefly discussed. Importantly, while a variety of molecules have been suggested, the effective therapeutic drugs for curing the diseases involving protein aggregation have yet to be identified. We believe that a better understanding of the mechanisms of protein aggregation process and an extensive investigation into the drug penetration, efficacy, and side effects will certainly aid in developing the successful pharmacological agents for these diseases.
Pannexin1 is part of the pore forming unit of the P2X7 receptor death complex (2007)

The purinergic receptor P2X(7) is part of a complex signaling mechanism participating in a variety of physiological and pathological processes. Depending on the activation scheme, P2X(7) receptors in vivo are non-selective cation channels or form large pores that can mediate apoptotic cell death. Expression of P2X(7)R in Xenopus oocytes results exclusively in formation of a non-selective cation channel. However, here we show that co-expression of P2X(7)R with pannexin1 in oocytes leads to the complex response seen in many mammalian cells, including cell death with prolonged ATP application. While the cation channel activity is resistant to carbenoxolone treatment, this gap junction and hemichannel blocking drug suppressed the currents induced by ATP in pannexin1/P2X(7)R co-expressing cells. Thus, pannexin1 appears to be the molecular substrate for the permeabilization pore (or death receptor channel) recruited into the P2X(7)R signaling complex.
Age of calf at weaning of spring-calving beef cows and the effect on cow and calf performance and production economics. (2000)

Over a 5-yr period, spring-calving cows were used in a carry-over design experiment to evaluate effects of calf age at weaning on cow and calf performance and production economics. Weaning management groups were early (n = 60, calf age 150 d, EW), traditional (n = 60, calf age 210 d, NW), and late (n = 60, calf age 270 d, LW). Cow body condition score (BCS) and weights at the last weaning date were different (P < .05) for EW (5.8, 583 kg), NW (5.5, 560 kg), and LW (5.2, 541 kg) management groups. Pregnancy rates among groups were similar. Days on feed for groups differed (P = .001) and was 247 for EW, 204 for NW, and 164 d for LW steers. Average daily gain in the feedlot differed (P = .01) among groups and averaged 1.5 kg for LW, 1.4 kg for NW, and 1.3 kg for EW steers. Dry matter intake while steers were in the feedlot was greater (P = .001) for LW than for NW and EW calves. Hot carcass weight was greater (P = .01) for EW (328 kg) and NW (332 kg) calves than for LW (321 kg) steers, and fat depth was greater (P = .05) for EW and NW steers than for LW steers. When carcass data for the NW and LW steers were adjusted to the fat depth of EW steers, carcass characteristics among groups were similar. Net income per steer at slaughter for the feedlot phase was greater (P < .001) for the EW ($75.36) and NW ($62.16) steers than for the LW ($10.09) steers. Again, when carcass data for the NW and LW steers were adjusted to the same fat depth of the EW steers, net income differences among groups were reduced. Replacement heifers were developed in a drylot and costs were higher (P < .001) for the EW than for NW and LW heifers. Annual cow costs were greater (P < .10) for the LW ($443.45) than for the EW ($410.09) and NW ($421.35) groups. Break-even for each system on a steer financial basis was not different between the NW and LW groups, and both the NW and LW groups had lower (P = .08) break-evens than the EW group. Age of the calf at weaning affects cow weight and BCS. Net income in each system is influenced by cow costs, month of the year that steer calves are purchased into the feedlot and finished steers are sold, month of the year cull cows are marketed, and replacement heifer development costs.
Gut-Enriched Krüppel-Like Factor Interaction with Smad3 Inhibits Myofibroblast Differentiation (2006)

Gut-enriched Krüppel-like factor (GKLF) has been reported to partially inhibit alpha-smooth muscle actin (alpha-SMA) gene transcription by competing for binding to the TGF-beta control element (TCE) with known activators such as Sp1 and other Krüppel-like factors. This incomplete inhibition via the TCE suggests an additional mechanism, which was evaluated in this study. The results showed that an alpha-SMA promoter mutated in the TCE remained susceptible to inhibition by GKLF in rat lung fibroblasts consistent with the existence of an additional TCE-independent mechanism. Since TGF-beta- induced alpha-SMA expression is Smad3-dependent, potential interaction between GKLF and Smad3 was examined as a basis for this additional inhibitory mechanism. Co-immunoprecipitation and yeast two-hybrid assays revealed that GKLF could bind Smad3 through the Smad3 MH2 domain. Electrophoretic mobility shift assays and ChIP assay indicated that this GKLF-Smad3 interaction inhibited Smad3 binding to the Smad3-binding element (SBE) in the alpha-SMA promoter, and the activity of an SBE containing artificial promoter. Further analysis using smad3(-/-) fibroblasts confirmed that the TCE-independent inhibition by GKLF was dependent on Smad3. These data taken together suggest that in addition to inhibition via the TCE, GKLF represses alpha-SMA gene expression by interacting with Smad3 to prevent Smad3 binding to the SBE. It represents the first evidence to directly link GKLF with Smad3, a key intracellular mediator of TGF-beta signaling, which should lead to a clearer understanding of the mechanism of how GKLF regulates TGF-beta-induced gene expression.
In vivo genome editing with a small Cas9 orthologue derived from Campylobacter jejuni (2017)

Several CRISPR-Cas9 orthologues have been used for genome editing. Here, we present the smallest Cas9 orthologue characterized to date, derived from Campylobacter jejuni (CjCas9), for efficient genome editing in vivo. After determining protospacer-adjacent motif (PAM) sequences and optimizing single-guide RNA (sgRNA) length, we package the CjCas9 gene, its sgRNA sequence, and a marker gene in an all-in-one adeno-associated virus (AAV) vector and produce the resulting virus at a high titer. CjCas9 is highly specific, cleaving only a limited number of sites in the human or mouse genome. CjCas9, delivered via AAV, induces targeted mutations at high frequencies in mouse muscle cells or retinal pigment epithelium (RPE) cells. Furthermore, CjCas9 targeted to the Vegfa or Hif1a gene in RPE cells reduces the size of laser-induced choroidal neovascularization, suggesting that in vivo genome editing with CjCas9 is a new option for the treatment of age-related macular degeneration.
Peptide Mimetics of Thyrotropin-Releasing Hormone Based on a Cyclohexane Framework: Design, Synthesis, and Cognition-Enhancing Properties (1995)

The design and synthesis of peptide mimetics of thyrotropin-releasing hormone (TRH) in which the peptide backbone is entirely replaced by a cyclohexane framework are described. The cis-1,3,5-trisubstituted ring was expected to permit key pharmacophoric groups to adopt conformations consistent with proposed bioactive conformations of the peptide. Compounds were synthesized by a stereoselective synthesis starting from L-glutamic acid. In a behavioral model of cognition in which TRH is active, the mimetics are potent, active compounds, exhibiting oral activity. One analog (26, (1S,3R,5(2S),5S)-5-[[5-oxo-1-(phenylmethyl)-2-pyrrolidinyl]-methyl]-5- [(1H-imidazol-5-yl)methyl]cyclohexaneacetamide) was radiolabeled for binding studies and evaluated in other binding assays and pharmacological tests. Competition binding of 26 vs [3H]MeTRH to rat brain slices suggests a two-site model for ligand binding with IC50's of 1 microM and 3 mM. Direct binding of [3H]-26 shows a biphasic curve with IC50's of 80 and 49 microM, respectively. Further studies would be needed to establish a link between the novel binding site(s) and the behavioral activity of 26 and TRH analogs.
Point Defect Studies in Gold by Electron Irradiation at Low Temperatures. I. Threshold Displacement Energy and Displacement Cross Section (1964)

The damage production on 99.999% pure 0.00025-in.-thick gold foils was measured as a function of incident electron energy in the range from 1.3 to 2.2 MeV. The effective threshold displacement energy was measured to be near 35 eV. It was found that reasonable agreement between the experimental and theoretical values of the displacement cross section could only be achieved with an unusually low value of the resistivity of a Frenkel pair (${\ensuremath{\rho}}_{F}=0.89\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$ \ensuremath{\Omega}-cm/unit fractional concentration). By comparison, in copper the agreement between the theoretical and experimental cross section (${\ensuremath{\rho}}_{F}=1.2\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$ \ensuremath{\Omega}-cm/unit fractional concentration) is somewhat better. This is interpreted to indicate that directional effects in the displacement process are considerably more important in gold than in copper, and that, for energies near the threshold energy, displacements in gold are possible only in a small solid angle centered about one crystallographic direction, most likely the $〈100〉$ direction.
Novel synthesis and in vitro characterization of disulfide-linked ricin-monoclonal antibody conjugates devoid of galactose binding activity. (1988)

The use of tumor immunotherapy using whole ricin-antibody conjugates is complicated by the nonspecific lectin activity of the ricin B-chain which leads to toxic side effects. A novel method of coupling whole intact ricin to monoclonal antibody (MoAb) is described herein, where the nonspecific binding of the ricin B-chain is blocked. The coupling was done using the bifunctional reagents S-acetylmercaptosuccinic anhydride for antibody and succinimidyl 3-(2-pyridyldithio)propionate for ricin, and this resulted in the loss of B-chain binding activity, while impairing neither the toxic potential of the A-chain nor the activity of the MoAb. The purified immunotoxins could not bind to lactose-Sepharose and were equally cytotoxic in vitro to MoAb-reactive cell lines in the presence or absence of lactose. The coupling method was suitable for six different ricin-antibody conjugates and also using ricin deglycosylated by treatment with periodate. However, the blocking of the ricin B-chain was only effective with whole IgG molecules as F(ab')2-ricin immunotoxins could, like ricin, bind to lactose-Sepharose. Ricin-antibody conjugates reduced the [3H]leucine incorporation of appropriate target cells by 50% at a concentration of 6 to 45 ng/ml, whereas nonreactive antibody immunotoxins were not toxic to the target cells at concentrations as high as 10(4) ng/ml. The specific cytotoxicity of these immunotoxins could be inhibited by the addition of unconjugated reactive MoAb; the presence of lactose or a nonreactive MoAb did not significantly affect the observed cytotoxicity. Thus, whole ricin-antibody conjugates produced in this way do not bind nonspecifically to target cells, the most important implication being that such immunotoxins should be more potent that ricin A-chain conjugates and capable of being used in vivo.
Modulation of transforming growth factor beta receptor levels on microvascular endothelial cells during in vitro angiogenesis. (1996)

Microvascular endothelial cells (RFCs) cultured in two-dimensional (2D) cultures proliferate rapidly and exhibit an undifferentiated phenotype. Addition of transforming growth factor beta1 (TGFbeta1) increases fibronectin expression and inhibits proliferation. RFCs cultured in three-dimensional (3D) type I collagen gels proliferate slowly and are refractory to the anti-proliferative effects of TGF beta1. TGF beta1 promotes tube formation in 3D cultures. TGF beta1 increases fibronectin expression and urokinase plasminogen activator (uPA) activity and plasminogen activator inhibitor-1 (PAI-1) levels in 3D cultures. Since the TGF beta type I and II receptors have been reported to regulate different activities induced by TGF beta1, we compared the TGF beta receptor profiles on cells in 2D and 3D cultures. RFCs in 3D cultures exhibited a significant loss of cell surface type II receptor compared with cells in 2D cultures. The inhibitory effect of TGF beta1 on proliferation is suppressed in transfected 2D cultures expressing a truncated form of the type II receptor, while its stimulatory effect on fibronectin production is reduced in both 2D and 3D transfected cultures expressing a truncated form of the type I receptor. These data suggest that the type II receptor mediates the antiproliferative effect of TGF beta1 while the type I receptor mediates the matrix response of RFCs to TGF beta1 and demonstrate that changes in the matrix environment can modulate the surface expression of TGF beta receptors, altering the responsiveness of RFCs to TGF beta1.
Isolation, crystal structure determination and cholinesterase inhibitory potential of isotalatizidine hydrate from Delphinium denudatum (2016)

These results suggest that isotalatazidine hydrate is a potent dual cholinesterase inhibitor and can be used as a target drug in Alzheimer diseases. This is first report indicating isotalatazidine hydrate with anticholinesterase potential.
A system software structure for distributed multimedia systems (1992)

Digital audio and video data are different from traditional media in their time-criticalness and high bandwidth requirements. These requirements and the fact that typical multimedia applications perform only few operations on the continuous-media data suggest the use of new techniques for data handling in distributed, integrated, digital multimedia systems. This paper proposes a system software structure which encapsulates the processing of continuous-media data into stream handlers of a real-time environment. This environment is controlled by traditional non-real-time functions for resource, buffer and continuous-media data stream management. On top of this system, distributed multimedia applications can be built.
Identification of functionally important amino acids in the cellulose‐binding domain of Trichoderma reesei cellobiohydrolase I (1995)

Cellobiohydrolase I (CBHI) of Trichoderma reesei has two functional domains, a catalytic core domain and a cellulose binding domain (CBD). The structure of the CBD reveals two distinct faces, one of which is flat and the other rough. Several other fungal cellulolytic enzymes have similar two-domain structures, in which the CBDs show a conserved primary structure. Here we have evaluated the contributions of conserved amino acids in CBHI CBD to its binding to cellulose. Binding isotherms were determined for a set of six synthetic analogues in which conserved amino acids were substituted. Two-dimensional NMR spectroscopy was used to assess the structural effects of the substitutions by comparing chemical shifts, coupling constants, and NOEs of the backbone protons between the wild-type CBD and the analogues. In general, the structural effects of the substitutions were minor, although in some cases decreased binding could clearly be ascribed to conformational perturbations. We found that at least two tyrosine residues and a glutamine residue on the flat face were essential for tight binding of the CBD to cellulose. A change on the rough face had only a small effect on the binding and it is unlikely that this face interacts with cellulose directly.
Abstract 17492: Alirocumab, a Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibody, Reduces Cholesterol Concentrations of Serum Remnant Lipoprotein Fractions, Very Low-Density Lipoproteins and Triglycerides (2013)

Introduction: Increased very low-density lipoprotein (VLDL) levels form part of a pattern of atherogenic dyslipidemia which predisposes to premature atherosclerosis. Remnant lipoproteins are produc...
Wide-linewidth phase diversity homodyne receivers (1988)

The use of phase diversity homodyne receivers, which have excellent performance even when the laser linewidth is of the same order of magnitude as the bit rate, to construct coherent systems with semiconductor lasers and moderate bandwidth receivers is considered. Theoretical, experimental, and computer simulation results of a study of a linewidth homodyne phase-diversity receiver is presented. A 150-Mb/s system with an IF linewidth of more than 50% of the bit rate is investigated in depth and is experimentally shown to operate within 1.8 dB from its theoretical limit.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Nanometer-scale crystallinity in In–Ga–Zn-oxide thin film deposited at room temperature observed by nanobeam electron diffraction (2014)

We report a detailed analysis of the nanoscopic structure of an In–Ga–Zn-oxide (IGZO) thin film deposited at room temperature. Using nanobeam electron diffraction (NBED) with a 1-nm-diameter probe, we analyzed a nanoscopic region of the IGZO thin film in which the diffraction spots of crystal were unobservable in a macroscopic region using selected-area electron diffraction (SAED) with about 300-nm-diameter probe. However, they were clearly recognized in a NBED pattern. They indicate a minute crystalline structure in the film. We further confirm the presence of crystals by observing a NBED pattern with spots distributed with six-fold symmetry in a specimen thickness thinned down to10 nm. To check the effect of the electron-beam irradiation during a transmission electron microscopy (TEM) and NBED measurements, we examine changes in crystal size as a function of the cumulative electron dose. No crystal growth during the electron beam irradiation was observed in the film. These results allow us to conclude that the IGZO thin film is not amorphous but a nanocrystalline (nc)-IGZO thin film, composed of nanometer-size crystals.
Oxytocin and Vasopressin V1a and V2 Receptors Form Constitutive Homo- and Heterodimers during Biosynthesis (2003)

G protein-coupled receptor (GPCR) oligomerization is a growing concept that has emerged from several studies suggesting that GPCRs can form both homo- and heterodimers. Using both coimmunoprecipitation and bioluminescence resonance energy transfer (BRET) approaches, we established that the vasopressin V1a, V2, and the oxytocin receptors exist as homo- and hetero-dimers in transfected human embryonic kidney 293T cells. Each receptor protomer had a similar propensity to form homo- and heterodimers, indicating that their relative expression levels may determine the homo-/heterodimer ratio. The finding that immature forms of the receptor can be immunoprecipitated as homo- and heterodimers and the detection by BRET of such oligomer in endoplasmic reticulum-enriched fractions suggest that the oligomerization processes take place early during biosynthesis. Treatment with agonists or antagonists did not modify the BRET among any of the vasopressin and oxytocin receptor pairs studied, indicating that the dimerization state of the receptors is not regulated by ligand binding once they have reached the cell surface. Taken together, these results strongly support the notion that GPCR dimerization is a constitutive process.
Survival and Viability of Dirofilaria immitis Microfilariae in Defined and Undefined Culture Media (1986)

D. Abraham, S. Lauria, M. Mika-Grieve, J. B. Lok, R. B. Grieve, Survival and Viability of Dirofilaria immitis Microfilariae in Defined and Undefined Culture Media, The Journal of Parasitology, Vol. 72, No. 5 (Oct., 1986), pp. 776-777
Purification and antigenicity of a novel glucan-binding protein of Streptococcus mutans (1994)

A novel glucan-binding protein (GBP) having an apparent molecular mass of 59 kDa (GBP59) has been purified from Streptococcus mutans SJ by a combination of affinity chromatography on alpha-1,6-linked glucan, gel filtration chromatography, and ion-exchange chromatography. GBP59 was distinct from the quantitatively predominant S. mutans GBP (GBP74) on the basis of size, elution position in a salt gradient, and antigenicity. Rat antisera to purified GBP59 and GBP74 did not cross-react. GBP59 is apparently immunogenic in humans, since immunoglobulin A (IgA) antibody in 20 of 24 adult parotid saliva samples was shown to react with GBP59 in an enzyme-linked immunosorbent assay. The glucan-binding activity of GBP59 was confirmed by anti-GBP59 immunogold labelling of Sephadex G-50 that had been preincubated with S. mutans culture supernatant. GBP59 could be detected in culture supernatants of all laboratory strains of S. mutans (e.g., Ingbritt), as well as all strains of S. mutans that had been recently isolated from young children. GBP59 was often the only component in protease inhibitor-containing 4-h S. mutans culture supernatants that reacted with human parotid salivary IgA antibody in Western blot (immunoblot) analyses. These studies suggest that GBP59 is a structurally and antigenically distinct S. mutans GBP that can elicit significant levels of salivary IgA antibody in humans.