gebhart/patrepeval huggingface dataset:
Inhibition of the Phosphoinositide 3-Kinase Pathway Induces a Senescence-like Arrest Mediated by p27Kip1 (2000)

A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K). We observed that senescence-like growth arrest is correlated with an increase in p27(Kip1) but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, including p15(INK4b), p16(INK4a), p19( INK4d), and p21(Cip1) as well as other negative cell cycle regulators such as p53 and p19(ARF), implies that this senescence-related growth arrest is independent of the activity of p53, p19(ARF), p16(INK4a), and p21(Cip1), which are associated with replicative senescence. The p27(Kip1) binds to the cyclin/CDK2 complexes and causes a decrease in CDK2 kinase activity. We demonstrated that ectopic expression of p27(Kip1) can induce permanent cell cycle arrest and a senescence-like phenotype in wild-type mouse embryo fibroblasts. We also obtained results suggesting that the kinase inhibitors LY294002 and Wortmannin arrest cell growth and induce a senescence-like phenotype, at least partially, through inhibition of PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, and up-regulation of p27(Kip1)expression. In summary, these observations taken together suggest that p27(Kip1) is an important mediator of the permanent cell cycle arrest induced by PI3K inhibitors. Our data suggest that repression of CDK2 activity by p27(Kip1) is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived from p27(Kip1-/-) mice entered cell cycle arrest after treatment with LY294002. We show that this is due to a compensatory mechanism by which p130 functionally substitutes for the loss of p27(Kip1). This is the first description that p130 may have a role in inhibiting CDK activity during senescence.
An antibody transesterase derived from reactive immunization that utilizes a wide variety of alcohol substrates (1998)

C. Lin, T. Z. Hoffman and Y. Xie, Chem. Commun., 1998, 1075 DOI: 10.1039/A801569D
John Harbison’s Use of Music of the Past in Three Selected Compositions (2013)

John Harbison’s music is rich in allusions to music of the past. Many of his compositions incorporate excerpts from pre-existing works or newly written passages in earlier styles, predominantly jazz. This article discusses the interaction of pre-existing and new music in three compositions by Harbison (Twilight Music, the Gatsby Etudes, and November 19, 1828), as well as three modes of borrowing used by Harbison (misreading, pastiche, and quotation). Each analysis examines how Harbison transforms pre-existing tonal material to create a post-tonal work, and shows that Harbison’s integration of tonal and post-tonal materials varies depending on the mode of borrowing.
Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. (1996)

Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1- and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B- and T-cell development are overtly normal. Nevertheless, B-cell responses to low and high doses of a T-cell-dependent antigen are impaired with decreased titers of antigen-specific IgM and IgG isotypes. This defect is not complete because there is still partial activation of B lymphocytes during the primary immune response, with generation of splenic germinal centers and a detectable, although reduced, secondary antibody response. These data suggest that certain T-dependent antigens manifest an absolute dependence on complement receptors for the initiation of a normally robust immune response.
On chip wide angle beam steering Ami (2014)

We demonstrate an on-chip optical phased array fabricated in a CMOS compatible process with continuous, fast (100 kHz), wide-angle (51°) beam-steering that is suitable for applications such as low-cost lidar systems.
IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells (1992)

Murine IL-10 has been reported originally to be produced by the Th2 subset of CD4+ T cell clones. In this study, we demonstrate that human IL-10 is produced by Th0, Th1-, and Th2-like CD4+ T cell clones after both Ag-specific and polyclonal activation. In purified peripheral blood T cells, low, but significant, levels of IL-10 were found to be produced by the CD4+CD45RA+ population, whereas CD4+CD45RA- "memory" cells secreted 5- to 20-fold higher levels of IL-10. In addition, IL-10 was produced by activated CD8+ peripheral blood T cells. Optimal induction of IL-10 was observed after activation by specific Ag and by the combination of anti-CD3 mAb and the phorbol ester tetradecanoyl phorbol acetate, whereas the combination of calcium ionophore A23187 and 12-O-tetradecanoylphorbol-13-acetate acetate was a poor inducer of IL-10 production. Kinetic studies indicated that IL-10 was produced relatively late as compared with other cytokines. Maximal IL-10 mRNA expression in CD4+ T cell clones and purified peripheral blood T cells was obtained after 24 h, whereas maximal IL-10 protein synthesis occurred between 24 h and 48 h after activation. No differences were observed in the kinetics of IL-10 production among Th0, Th1-, and Th2-like subsets of CD4+ T cell clones. The results indicate a regulatory role for IL-10 in later phases of the immune response.
Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat (1996)

Recent reports suggest a relationship between traumatic brain injury and the precocious development of neurodegenerative cascades, including diffuse deposits of beta-amyloid peptides (A beta) in the injured brain. Because the lateral fluid-percussion (FP) model of experimental brain injury produces clinically relevant neuropathological sequelae in the rat brain, we used this model together with a series of antibodies specific for amyloid precursor proteins (APPs), APP-like proteins (APLPs), or A beta to identify acute neurodegenerative changes after brain trauma. Male Sprague-Dawley rats were anesthetized and subjected to lateral FP brain injury of moderate to high severity. At 1 hr, 2 hr, 48 hr, 1 week, or 2 weeks after injury, animals were killed and their brains were removed for immunohistochemical analysis. APP/APLP immunoreactivity increased in specific brain regions as early as 1 hr after injury and persisted for at least 2 weeks. Axons in the thalamus and subcortical white matter showed the greatest APP/APLP accumulation. Injured cortex, striatum, cingulum, and hippocampus also demonstrated significant axonal accumulations of APP/APLP. Accumulation of APP/APLPs occurred primarily ipsilateral to the injury, although bilateral changes were observed in some brain regions. No deposition of A beta was observed in any brain region at any time point examined. These results demonstrate a pattern of widespread axonal pathology after lateral FP brain injury in the rat, characterized by intra-axonal accumulations of APP/APLP immunoreactivity in the absence of plaque-like deposits of A beta in the traumatized brain.
Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors (2013)

Localized Fgf10 expression in the distal mesenchyme adjacent to sites of lung bud formation has long been thought to drive stereotypic branching morphogenesis even though isolated lung epithelium branches in the presence of non-directional exogenous Fgf10 in Matrigel. Here, we show that lung agenesis in Fgf10 knockout mice can be rescued by ubiquitous overexpression of Fgf10, indicating that precisely localized Fgf10 expression is not required for lung branching morphogenesis in vivo. Fgf10 expression in the mesenchyme itself is regulated by Wnt signaling. Nevertheless, we found that during lung initiation simultaneous overexpression of Fgf10 is not sufficient to rescue the absence of primary lung field specification in embryos overexpressing Dkk1, a secreted inhibitor of Wnt signaling. However, after lung initiation, simultaneous overexpression of Fgf10 in lungs overexpressing Dkk1 is able to rescue defects in branching and proximal-distal differentiation. We also show that Fgf10 prevents the differentiation of distal epithelial progenitors into Sox2-expressing airway epithelial cells in part by activating epithelial β-catenin signaling, which negatively regulates Sox2 expression. As such, these findings support a model in which the main function of Fgf10 during lung development is to regulate proximal-distal differentiation. As the lung buds grow out, proximal epithelial cells become further and further displaced from the distal source of Fgf10 and differentiate into bronchial epithelial cells. Interestingly, our data presented here show that once epithelial cells are committed to the Sox2-positive airway epithelial cell fate, Fgf10 prevents ciliated cell differentiation and promotes basal cell differentiation.
Sequence-Specific DNA Binding by the αNAC Coactivator Is Required for Potentiation of c-Jun-Dependent Transcription of the Osteocalcin Gene (2005)

Since the c-Jun coactivator alphaNAC was initially identified in a differential screen for genes expressed in differentiated osteoblasts, we examined whether the osteocalcin gene, a specific marker of terminal osteoblastic differentiation, could be a natural target for the coactivating function of alphaNAC. We had also previously shown that alphaNAC can specifically bind DNA in vitro, but it remained unclear whether the DNA-binding function of alphaNAC is expressed in vivo or if it is required for coactivation. We have identified an alphaNAC binding site within the murine osteocalcin gene proximal promoter region and demonstrated that recombinant alphaNAC or alphaNAC from ROS17/2.8 nuclear extracts can specifically bind this element. Using transient transfection assays, we have shown that alphaNAC specifically potentiated the c-Jun-dependent transcription of the osteocalcin promoter and that this activity specifically required the DNA-binding domain of alphaNAC. Chromatin immunoprecipitation confirmed that alphaNAC occupies its binding site on the osteocalcin promoter in living osteoblastic cells expressing osteocalcin. Inhibition of the expression of endogenous alphaNAC in osteoblastic cells by use of RNA interference provoked a decrease in osteocalcin gene transcription. Our results show that the osteocalcin gene is a target for the alphaNAC coactivating function, and we propose that alphaNAC is specifically targeted to the osteocalcin promoter through its DNA-binding activity as a means to achieve increased specificity in gene transcription.
Glucocorticoid Regulation of Endothelial Cell Tight Junction Gene Expression: Novel Treatments for Diabetic Retinopathy (2005)

Loss of blood-retinal barrier (BRB) integrity and vascular permeability characterizes diabetic retinopathy, and new therapies to reverse or prevent vascular permeability are needed to treat this debilitating disease. Glucocorticoids are currently under investigation for use as a local therapeutic treatment for diabetic retinopathy. This review examines the changes that occur to barrier properties in diabetic retinopathy and the potential to use glucocorticoids to restore vascular barrier properties in the retina. Glucocorticoids are useful in preserving the integrity of the blood-brain barrier in the treatment of brain tumors, and these steroids show similar effects on the retinal vasculature suggesting their potential usefulness in treating diabetic retinopathy. Recent progress has been made toward the goal of elucidating the precise mechanism underlying the protective effects of glucocorticoids on the retinal vasculature. Glucocorticoids may act by both suppressing inflammation and by directly affecting the endothelial cells by regulating phosphorylation, organization, and content of tight junction proteins. Further work will advance our understanding of glucocorticoid regulation of barrier properties allowing the ultimate goal of developing a specific and safe therapy to treat or prevent loss of the blood-neural barrier in a number of diseases, including brain tumors and diabetic retinopathy.
Prospective Pilot Study of Recombinant Granulocyte-Macrophage Colony-Stimulating Factor and Interferon-γ in Patients With Inoperable Hepatocellular Carcinoma (2002)

Interferon (IFN)-gamma and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) enhance tumor immunogenicity. The authors assessed tolerability and effectiveness of a combination therapy of these recombinant human (rh) cytokines in patients with inoperable hepatocellular carcinoma (HCC). In a monocentric, open, nonrandomized pilot study, rhGM-CSF (5 microg/kg qd, Monday and Tuesday) and rhIFN-gamma (100 microg qd, Wednesday and Thursday) were subcutaneously administered in 9-week cycles. Primary objective was survival, as secondary outcomes volumetric changes of tumor mass and biologic parameters reflecting systemic immunologic or local tumor responses were measured. Only patients with complete response (CR), partial response (PR), or stable disease (SD) proceeded to new treatment cycles. Fifteen patients (median 63 years, range 46-74 years, all men) were enrolled. Survival after the first cycle was 80% with SD in 9 of 15 patients (60%). PR was detected in one patient after the second cycle. Two patients finished five treatment cycles. Overall survival at 26 and 52 weeks was 40% and 20%, respectively. Median survival in patients with inducible HLA-DR on hepatoma cells (40%) was increased (42 weeks, 27-100) as compared with HLA-DR negative cases (60%; 13 weeks, 8-23; p < 0.0001), and a control group (p = 0.01). Parameters reflecting systemic immunomodulatory activities were not associated with clinical outcome. In 13 of 15 patients (87%), adverse events were reported, all less than grade 2 and none requiring therapy discontinuation. Immunotherapeutic approaches hold promise to prolong survival in selected patients with advanced HCC who respond by enhanced tumor immunogenicity.
Intravascular Electroporation Markedly Attenuates Neointima Formation After Balloon Injury of the Carotid Artery in the Rat (2000)

The present study examined the use of electroporation (pulsed electric field application) to temporarily permeabilize vascular cell membranes and thereby deliver drugs directly into cells of the vessel wall to treat focal cardiovascular diseases (e.g., postangioplasty restenosis). A unique intravascular porous balloon electroporation catheter has been designed specifically to enhance drug uptake directly into the arterial wall. The effect of heparin on neointimal growth following balloon‐induced injury of the carotid arteries of rats was used as a measure of effective drug delivery. Histomorphometrical analysis of arteries showed that neointimal growth and lumen loss were significantly inhibited by heparin in combination with electroporation, but not by heparin delivered without electroporation. We conclude that the application of electroporation technology may be a viable approach to intramural drug delivery of potential therapeutic compounds for the treatment of neointimal growth and negative remodeling during postangioplasty restenosis.
PK/PD modeling of 5‐hydroxytryptophan (5‐HTP) challenge test with cortisol measurement in serum and saliva (2020)

This research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5-hydroxytryptophan (5-HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5-HTP challenge studies in healthy volunteers were collected. Serum 5-HTP, saliva, and serum cortisol were sampled as PK and PD marker. The population PK/PD modeling approach was applied. A baseline model of serum cortisol was built to assess the circadian rhythm before a pharmacodynamic model was used to evaluate the drug effect of the 5-HTP on cortisol. Finally, linear and power function relationships were tested to predict serum cortisol based on saliva cortisol. The PK of 5-HTP could be described using a one-compartment model with a transit compartment. The typical value for clearance was 20.40 L h<sup>-1</sup> and showed inter-study variability. A cosine function was chosen and properly described the circadian rhythm of serum cortisol. A linear approximation model was applied to fit the 5-HTP PD effect on cortisol data with a slope of 4.16 ng mL<sup>-1</sup> h. A power function provided a better description than a linear function to relate the saliva and serum cortisol. In conclusion, a circadian rhythm component was built in the PK/PD model of the 5-HTP challenge test which could better improve the understanding of the stimulating effect on HPA with cortisol change. After the 5-HTP challenge, saliva cortisol correlated well with serum cortisol and was predictable by a population PK-PD model.
Cell Wall-targeting Domain of Glycylglycine Endopeptidase Distinguishes among Peptidoglycan Cross-bridges (2005)

ALE-1, a homologue of lysostaphin, is a peptidoglycan hydrolase that specifically lyses Staphylococcus aureus cell walls by cleaving the pentaglycine linkage between the peptidoglycan chains. Binding of ALE-1 to S. aureus cells through its C-terminal 92 residues, known as the targeting domain, is functionally important for staphylolytic activity. The ALE-1-targeting domain belongs to the SH3b domain family, the prokaryotic counterpart of the eukaryotic SH3 domains. The 1.75 angstroms crystal structure of the targeting domain shows an all-beta fold similar to typical SH3s but with unique features. The structure reveals patches of conserved residues among orthologous targeting domains, forming surface regions that can potentially interact with some common features of the Gram-positive cell wall. ALE-1-targeting domain binding studies employing various bacterial peptidoglycans demonstrate that the length of the interpeptide bridge, as well as the amino acid composition of the peptide, confers the maximum binding of the targeting domain to the staphylococcal peptidoglycan. Truncation of the highly conserved first 9 N-terminal residues results in loss of specificity to S. aureus cell wall-targeting, suggesting that these residues confer specificity to S. aureus cell wall.
Detection of Als Proteins on the Cell Wall of Candida albicans in Murine Tissues (1999)

A murine model of disseminated candidiasis was utilized to determine whether Candida albicans Als proteins are produced in vivo. The kidneys, spleen, heart, liver, and lungs were collected from mice inoculated with one of three C. albicans strains (SC5314, B311, or WO-1). Immunohistochemical analysis of murine tissues by using a rabbit polyclonal anti-Als serum indicated that Als proteins were produced by each C. albicans cell in the tissues examined. Patterns of staining with the anti-Als serum were similar among the C. albicans strains tested. These data indicated that Als protein production was widespread in disseminated candidiasis and that, despite strain differences in ALS gene expression previously noted in vitro, Als protein production in vivo was similar among C. albicans strains. The extensive production of Als proteins in vivo and their presence on the C. albicans cell wall position these proteins well for a role in host-pathogen interaction.
Melanocytes: From Morphology to Application (2009)

Melanocytes in human skin are intricately regulated by keratinocytes and the surrounding stroma. The development of melanoma is thought to arise from disrupted melanocyte homeostasis. It is now known that microenvironment plays a major role in maintenance of cellular homeostasis and can contribute to tumor initiation and tumor progression. Historically, melanocyte studies have been performed in two-dimensional culture systems, and often with melanocytes cultured in the absence of keratinocytes. Here we present the biological basis for the use of organotypic, three-dimensional model systems in the study of melanoma, and highlight the features of the most utilized organotypic model systems.
Effects of A2ON Process on Denitrifying Dephosphatation (2010)

In combination with activated sludge process and biomembrance process, based on the principle of denitrifying dephosphatation, A2ON processes for biphase sequencing batch reactor biological nutrient removal (BNR) treatment have been developed, with an emphasis on the effects of the ratio of COD to TN (COD/TN) variations on the BNR treatment. Results indicated that the process possessed stable effects, showed strong flexibility for water quality, could attenuate the aerobic requirement and decrease the competition of denitrifying and dephosphation for carbon source to a greater degree, and meanwhile guaranteed that nitrifying bacteria about a generation time could grow stably.
Polyfunctional nanometric particles obtained from lignin, a woody biomass resource (2010)

Highly monodispersed nanometric particles, with a polyfunctional nature due to the presence of phenolic and aliphatic hydroxyl groups, were obtained by the simultaneous enzymatic saccharification and physical comminution of lignin, which is a woody biomass resource.
Peritonitis Increases MMP-9 Activity in Peritoneal Effluent from CAPD Patients (2001)

Patients undergoing long-term continuous ambulatory peritoneal dialysis (CAPD) sometimes experience ultrafiltration failure. Mesothelial basement membrane thickening and the accumulation of submesothelial fibrotic tissue are common features of the diseased peritoneum. Peritonitis can lead to ultrafiltration failure, but the precise mechanism is not clear. The key enzymes in extracellular matrix (ECM) remodeling, namely matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), are produced by human peritoneal mesothelial cells. Using peritoneal effluent from 13 CAPD patients with peritonitis and 7 noninfected CAPD control individuals, we examined MMP and TIMP activities by gelatin and reverse zymography. Latent and activated types of MMP-2 and -9, and TIMP-1 and -2 were identified in peritoneal effluent (from all CAPD patients). Levels of latent and activated type MMP-9, as well as of TIMP-1 activities were higher at the onset of peritonitis than either during the recovery phase of peritonitis and/ or in control individuals. Activated MMP-9 activity positively correlated with leukocyte numbers and IL-6 levels in peritoneal effluent. Activities of MMP-2 and TIMP-2 in peritoneal effluent did not change between the onset of peritonitis and recovery. We concluded that increased MMP-9 and TIMP-1 levels might be associated with peritoneal ECM remodeling during peritonitis.
Synthetic hexapeptide substrates and inhibitors of 3':5'-cyclic AMP-dependent protein kinase. (1976)

The substrate specificity of the catalytic subunit of rabbit skeletal muscle 3': 5'-cyclic AMP-dependent protein kinase (EC 2.7.1.37; ATP: protein phosphotransferase) has been studied using the synthetic peptide Arg-Gly-Tyr-Ser-Leu-Gly corresponding to the sequence around serine 24, a phosphorylation site in reduced, carboxymethylated, maleylated (RCMM) chicken egg white lysozyme. This peptide served as a substrate for the enzyme and exhibited a 6-fold higher Vmax and a 100-fold higher Km than RCMM-lysozyme. Replacement of the arginine with glycine, histidine, or lysine resulted in a dramatic reduction in the Vmax. These results support the concept that arginine is an important residue in determining the substrate specificity of the protein kinase, predominantly influencing the Vmax of the phosphorylation reaction. Two synthetic peptides in which serine was replaced by an alanine acted as competitive inhibitors of phosphorylation of the synthetic peptide substrate and RCMM-lysozyme.