gebhart/patrepeval huggingface dataset:
Hypoxia promotes chondrogenesis in rat mesenchymal stem cells: A role for AKT and hypoxia‐inducible factor (HIF)‐1α (2008)

Mesenchymal stem cells (MSCs) are multipotent cells capable of developing along the chondrogenic, osteogenic and adipogenic lineages. As such, they have received interest as a potential cell source for tissue engineering strategies. Cartilage is an avascular tissue and thus resides in a microenvironment with reduced oxygen tension. The aim of this study was to examine the effect of a low oxygen environment on MSC differentiation along the chondrogenic route. In MSCs exposed to chondrogenic growth factors, transforming growth factor-beta and dexamethasone, in a hypoxic environment (2% oxygen), the induction of collagen II expression and proteoglygan deposition was significantly greater than that observed when cells were exposed to the chondrogenic growth factors under normoxic (20% oxygen) conditions. The transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha), is a crucial mediator of the cellular response to hypoxia. Following exposure of MSCs to hypoxia (2% oxygen), HIF-1alpha translocated from the cytosol to the nucleus and bound to its target DNA consensus sequence. Similarly, hypoxia evoked an increase in phosphorylation of both AKT and p38 mitogen activated protein kinase, upstream of HIF-1alpha activation. Furthermore, the PI3 kinase/AKT inhibitor, LY294002, and p38 inhibitor, SB 203580, prevented the hypoxia-mediated stabilisation of HIF-1alpha. To assess the role of HIF-1alpha in the hypoxia-induced increase in chondrogenesis, we employed an siRNA knockdown approach. In cells exposed to HIF-1alpha siRNA, the hypoxia-induced enhancement of chondrogenesis, as evidenced by upregulation of collagen II, sox-9 and proteoglycan deposition, was absent. This provides evidence for HIF-1alpha being a key mediator of the beneficial effect of a low oxygen environment on chondrogenesis.
Drug-Polymer Conjugates Containing Acid-Cleavable Bonds (1999)

Drug-polymer conjugates are potential candidates for the selective delivery of anticancer agents to tumor tissue. Incorporating acid-sensitive bonds between the drug and the polymer is an attractive approach because it ensures effective release of the polymer-bound drug at the tumor site. This release is either extracellular, resulting from the slightly acidic pH in tumor tissue, or intracellular, in acidic endosomes or lysosomes after cellular uptake of the drug-polymer conjugate. This paper reviews acid-sensitive drug-polymer conjugates developed during the past 20 years and outlines aspects for further development in this research field.
Identification and Characterization of a Novel Endoplasmic Reticulum (ER) DnaJ Homologue, Which Stimulates ATPase Activity of BiP in Vitro and Is Induced by ER Stress (2002)

The activity of Hsp70 proteins is regulated by accessory proteins, which include members of the DnaJ-like protein family. Characterized by the presence of a highly conserved 70-amino acid J domain, DnaJ homologues activate the ATPase activity of Hsp70 proteins and stabilize their interaction with unfolded substrates. DnaJ homologues have been identified in most organelles where they are involved in nearly all aspects of protein synthesis and folding. Within the endoplasmic reticulum (ER), DnaJ homologues have also been shown to assist in the translocation, secretion, retro-translocation, and ER-associated degradation (ERAD) of secretory pathway proteins. By using bioinformatic methods, we identified a novel mammalian DnaJ homologue, ERdj4. It is the first ER-localized type II DnaJ homologue to be reported. The signal sequence of ERdj4 remains uncleaved and serves as a membrane anchor, orienting its J domain into the ER lumen. ERdj4 co-localized with GRP94 in the ER and associated with BiP in vivo when they were co-expressed in COS-1 cells. In vitro experiments demonstrated that the J domain of ERdj4 stimulated the ATPase activity of BiP in a concentration-dependent manner. However, mutation of the hallmark tripeptide HPD (His --> Gln) in the J domain totally abolished this activation. ERdj4 mRNA expression was detected in all human tissues examined but showed the highest level of the expression in the liver, kidney, and placenta. We found that ERdj4 was highly induced at both the mRNA and protein level in response to ER stress, indicating that this protein might be involved in either protein folding or ER-associated degradation.
Expression of Salmonella typhimurium genes required for invasion is regulated by changes in DNA supercoiling (1990)

The ability to enter intestinal epithelial cells is an essential virulence factor of salmonellae. We have previously cloned a group of genes (invA, B, C, and D) that allow S. typhimurium to penetrate tissue culture cells (J. E. Galán and R. Curtiss III, Proc. Natl. Acad. Sci. USA 86:6383-6387, 1989). Transcriptional and translational cat and phoA fusions to invA (the proximal gene in the invABC operon) were constructed, and their expression was studied by measuring the levels of alkaline phosphatase or chloramphenicol acetyltransferase activity in mutants grown under different conditions. It was found that when strains containing the fusions were grown on media with high osmolarity, a condition known to increase DNA superhelicity, the level of invA transcription was approximately eightfold higher than that in strains grown on media with low osmolarity. The osmoinducibility of invA was independent of ompR, which controls the osmoinducibility of other genes. Strains grown in high-osmolarity media in the presence of subinhibitory concentrations of gyrase inhibitors (novobiocin or coumermycin A1), which reduce the level of DNA supercoiling, showed reduced expression of invA. Nevertheless, invA was poorly expressed in topA mutants of S. typhimurium, which have increased DNA superhelicity. In all cases, the differential expression of the invasion genes was correlated with the ability of S. typhimurium to penetrate tissue culture cells. These results taken together indicate that expression of S. typhimurium invasion genes is affected by changes in DNA supercoiling and suggest that this may represent a way in which this organism regulates the expression of these genes.
THE HISTORY OF INTRAVENOUS AND SUBCUTANEOUS ADMINISTRATION OF DRUGS (1916)

With the revival of interest in the treatment by drugs, and the epoch-making studies of pharmacology and experimental therapeutics in the past ten or twenty years, the administration of substances by subcutaneous or intravenous injection is being practiced on a large scale, both in experimental work on animals and in the treatment of patients. An inquiry into the historical development of these more exact and certainly more efficacious methods of drug administration may therefore be of considerable and timely interest. Curiously enough, although in the domain of surgery we find the names of numerous individuals perpetuated by being tagged to all kinds of minor and unimportant manipulations and operations, in the domain of internal medicine and more especially in connection with medicinal treatment, the origin of some of our most important and life-saving procedures and remedies is shrouded in obscurity. It is really our duty, therefore, to ascertain as far
A polynomial-transform based computation of the 2-D DCT with minimum multiplicative complexity (2002)

This paper provides a full description of a 2-D discrete cosine transform (DCT) which has the property of requiring only N 1-D DCT of size N for performing the 2-D algorithm. No multiplication is involved elsewhere in the algorithm, thus the multiplicative complexity is halved when compared to classical row/column algorithms. Compared to some other proposed algorithms, our approach has the characteristic of being formally very concise. Once the main result has been obtained, a remaining difficulty is the search for an in-place algorithm. This problem is also solved.
Leaching of tobramycin from PMMA bone cement beads (1985)

The in vitro leaching characteristics of tobramycin from acrylic resin (PMMA) bone cement beads have been determined by a radioimmune assay. Tobramycin was incorporated at two concentrations into bone cement beads fabricated from three commercial brands of acrylic resin. Antibiotic leaching followed a curvilinear relationship of the form X . Y = A . X + B . Y. All beads showed similar tobramycin leaching rates over time but the initial amount of leached material differed with the amount of tobramycin incorporated in the bead and the source of the PMMA bone cement. The data indicate that tobramycin-impregnated PMMA beads permit antibiotic leaching at a controlled rate compatible with possible clinical application.
Mild preconditioning and low-level engraftment confer methotrexate resistance in mice transplanted with marrow expressing drug-resistant dihydrofolate reductase activity (2000)

Abstract Effective engraftment of hematopoietic cells targeted for gene transfer is facilitated by cytoreductive preconditioning such as high-dose total body irradiation (TBI). To minimize the adverse side effects associated with TBI, experiments were conducted to determine whether sublethal doses of TBI would allow sufficient engraftment of MTX-resistant hematopoietic cells to confer survival on recipient mice administered MTX. FVB/N animals were administered 1, 2, or 4 Gy TBI (lethal dose, 8.5 Gy), transplanted with 107 FVB/N transgenic marrow cells expressing an MTX-resistant dihydrofolate reductase (DHFR) transgene, and then administered MTX daily for 60 days. Control mice administered 1 Gy with or without subsequent transplantation of normal marrow cells succumbed to MTX toxicity by day 45. In contrast, nearly all animals transplanted with transgenic marrow survived MTX administration, regardless of the TBI dose used for preconditioning. The donor DHFR transgenic marrow engraftment level was proportional to the preconditioning dose of TBI but was surprisingly reduced in animals given 2 or 4 Gy TBI and subsequently administered MTX when compared with control animals administered phosphate-buffered saline. Animals preconditioned with 1 Gy were also protected from MTX toxicity when transplanted with reduced amounts (5 × 106 and 1 × 106 cells) of DHFR transgenic donor marrow, resulting in low-level (approximately 1%) engraftment. In conclusion, very mild preconditioning allows sufficient low-level engraftment of genetically modified stem cells for in vivo manifestation of the modified phenotype, suggesting the usefulness of mild preconditioning regimens in human gene therapy trials targeting hematopoietic stem cells.
Analysis of the Fecal Microflora of Human Subjects Consuming a Probiotic Product Containing Lactobacillus rhamnosus DR20 (2000)

The composition of the fecal microflora of 10 healthy subjects was monitored before (6-month control period), during (6-month test period), and after (3-month posttest period) the administration of a milk product containing Lactobacillus rhamnosus DR20 (daily dose, 1.6 x 10(9) lactobacilli). Monthly fecal samples were examined by a variety of methods, including bacteriological culture analysis, fluorescent in situ hybridization with group-specific DNA probes, denaturing gradient gel electrophoresis of the V2-V3 region of 16S rRNA genes amplified by PCR, gas-liquid chromatography, and bacterial enzyme activity analysis. The composition of the Lactobacillus population of each subject was analyzed by pulsed-field gel electrophoresis of bacterial DNA digests in order to differentiate between DR20 and other strains present in the samples. Representative isolates of lactobacilli were identified to the species level by sequencing the V2-V3 region of their 16S rRNA genes and comparing the sequences obtained (BLAST search) to sequences in the GenBank database. DR20 was detected in the feces of all of the subjects during the test period, but at different frequencies. The presence of DR20 among the numerically predominant strains was related to the presence or absence of a stable indigenous population of lactobacilli during the control period. Strain DR20 did not persist at levels of >10(2) cells per g in the feces of most of the subjects after consumption of the product ceased; the only exception was one subject in which this strain was detected for 2 months during the posttest period. We concluded that consumption of the DR20-containing milk product transiently altered the Lactobacillus and enterococcal contents of the feces of the majority of consumers without markedly affecting biochemical or other bacteriological factors.
Transcranial Brain Stimulation (2012)

Since the discovery of transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), these non-invasive brain stimulation (NIBS) techniques have been used to investigate the state of cortical excitability, and the excitability of the cortico-cortical and corticospinal pathways. In addition, these techniques have been found
Condensed heteroaromatic ring systmes. XVI. Synthesis of pyrrolo[2,3-d]pyrimidine derivatives. (1989)

The synthesis of pyrrolo[2, 3-d]pyrimidine derivatives was accomplished by the following two methods. One is the palladium-catalyzed reaction terminal acetylenes with N-(5-halo-4-pyrimidinyl)methanesulfonamides prepared by the nucleophilic substitution of 4-chloro-5-halopyrimidines with methanesulfonamide. The other is the photocyclization of 4-azidopyrimidines containing an olefinic function at the 5-position. The synthesis of 4-azidopyrimidine derivatives is also described.
Expression of Heparan Sulfate d-Glucosaminyl 3-O-Sulfotransferase Isoforms Reveals Novel Substrate Specificities (1999)

The 3-O-sulfation of glucosamine residues is an important modification during the biosynthesis of heparan sulfate (HS). Our previous studies have led us to purify and molecularly clone the heparan sulfate D-glucosaminyl 3-O-sulfotransferase (3-OST-1), which is the key enzyme converting nonanticoagulant heparan sulfate (HSinact) to anticoagulant heparan sulfate (HSact). In this study, we expressed and characterized the full-length cDNAs of 3-OST-1 homologous genes, designated as 3-OST-2, 3-OST-3A, and 3-OST-3B as described in the accompanying paper (Shworak, N. W., Liu, J., Petros, L. M., Zhang, L., Kobayashi, M., Copeland, N. G., Jenkins, N. A., and Rosenberg, R. D. (1999) J. Biol. Chem. 274, 5170-5184). All these cDNAs were successfully expressed in COS-7 cells, and heparan sulfate sulfotransferase activities were found in the cell extracts. We demonstrated that 3-OST-2, 3-OST-3A, and 3-OST-3B are heparan sulfate D-glucosaminyl 3-O-sulfotransferases because the enzymes transfer sulfate from adenosine 3'-phosphophate 5'-phospho-[35S]sulfate ([35S]PAPS) to the 3-OH position of glucosamine. 3-OST-3A and 3-OST-3B sulfate an identical disaccharide. HSact conversion activity in the cell extract transfected by 3-OST-1 was shown to be 300-fold greater than that in the cell extracts transfected by 3-OST-2 and 3-OST-3A, suggesting that 3-OST-2 and 3-OST-3A do not make HSact. The results of the disaccharide analysis of the nitrous acid-degraded [35S]HS suggested that 3-OST-2 transfers sulfate to GlcA2S-GlcNS and IdoA2S-GlcNS; 3-OST-3A transfers sulfate to IdoA2S-GlcNS. Our results demonstrate that the 3-O-sulfation of glucosamine is generated by different isoforms depending on the saccharide structures around the modified glucosamine residue. This discovery has provided evidence for a new cellular mechanism for generating a defined saccharide sequence in structurally complex HS polysaccharide.
Mechanical behavior of robocast alumina (1998)

Direct fabrication of alumina parts by robocasting was completed. This method is based on three-dimensional deposition of binderless aqueous alumina slurries. Parts were made with different deposition paths and mechanical testing performed to determine the effects of bead alignment. Properties were also compared to alumina processed more traditionally.
Peptide-mediated Interference of TIR Domain Dimerization in MyD88 Inhibits Interleukin-1-dependent Activation of NF-κB (2005)

Myeloid differentiation factor 88 (MyD88) plays a crucial role in the signaling pathways triggered by interleukin (IL)-1 and Toll-like receptors in several steps of innate host defense. A crucial event in this signaling pathway is represented by dimerization of MyD88, which allows the recruitment of downstream kinases like IRAK-1 and IRAK-4. Herein, we have investigated the function of the Toll/IL-1 receptor (TIR) domain in MyD88 homodimerization in cell-free and in vitro experimental settings by using epta-peptides that mimic the BB-loop region of the conserved TIR domain of different proteins. By using a pull-down assay with purified glutathione S-transferase-MyD88 TIR or co-immunoprecipitation experiments, we found that epta-peptides derived from the TIR domain of MyD88 and IL-18R are the most effective in inhibiting homodimerization with either the isolated TIR or full-length MyD88. Moreover, we demonstrated that a cell permeable analog of MyD88 epta-peptide inhibits homodimerization of MyD88 TIR domains in an in vitro cell system and significantly reduces IL-1 signaling, as assayed by activation of the downstream transcription factor NF-kappaB. Our results indicate that the BB-loop in TIR domain of MyD88 is a good target for specific inhibition of MyD88-mediated signaling in vivo.
Wnt pathway activation in mesothelioma: evidence of Dishevelled overexpression and transcriptional activity of beta-catenin. (2003)

Malignant pleural mesothelioma is a relatively uncommon and yet incurable tumor. The pathogenesis of mesothelioma remains poorly understood. This study evaluated the role of Wnt signaling in mesothelioma. Western blot analysis was conducted to confirm the expression of Dishevelled (Dvl) and cytosolic beta-catenin in matched autologous tissue samples (tumor and normal pleura), malignant pleural effusions, and in established mesothelioma cell lines LRK1A, REN and H513. Thirteen of 15 mesotheliomas examined showed consistent overexpression of Dvl and increased cytosolic beta-catenin levels as compared with controls. To evaluate T-cell factor (Tcf)-dependent transcriptional activity of beta-catenin, luciferase assays were conducted. Fresh mesothelioma cells (effusion derived), as well as LRK1A, REN, and H513 cell lines showed a significant fold increase (1.5-2.4-fold, P < 0.01) in Tcf-dependent transcriptional activity of beta-catenin. To evaluate the biological significance of Dvl function in mesothelioma, a PDZ domain deletion mutant (DeltaPDZ-Dvl) was created and stably transfected into LRK1A, REN, and H513. The effect of DeltaPDZ-Dvl on mesothelioma growth was assayed in vitro (colony formation assay in soft agar) and in vivo (s.c. implantation in athymic mice NCRNU-M). In mesothelioma cells tested, DeltaPDZ-Dvl-mediated inhibition of Dvl decreased cytosolic beta-catenin levels, diminished Tcf-mediated transcription, and suppressed tumorigenesis of LRK1A and REN in vitro and in vivo. DeltaPDZ-Dvl also down-regulated expression of c-myc in REN and COX-2 in H513. Our data suggest that in malignant pleural mesothelioma, Wnt signaling is activated through Dvl overexpression and downstream signaling through beta-catenin. Inhibition of this signaling leads to significant antitumor effects. These results demonstrate Dvl overexpression in human cancer and, specifically, that Wnt signaling plays a role in mesothelioma pathogenesis. These data offer possible new avenues for therapeutic intervention.
Chromatin remodeling and initiation of DNA replication (2001)

While much has been learned in recent years about the process of chromatin remodeling and its role in activation of transcription, relatively little has been reported on the role of chromatin remodeling in DNA replication. However, it is well established that transcription factors and chromatin structure play an important role in replication origin usage. Recent work has begun to indicate that chromatin remodeling factors are likely to play an important role in the regulation of replication origin usage. The results to date are most consistent with the role for chromatin remodeling factors in DNA replication as being indirect, and very similar to their role in transcription. The current evidence suggests that transcription factors bind to auxiliary sequences adjacent to replication origins and recruit chromatin remodeling factors to create either nucleosome-free regions or regions of specifically spaced nucleosomes. This results in activation of the nearby origin, presumably by making the origin region more accessible to replication factors. Until recently, there has been very little evidence of direct interactions between chromatin remodeling factors and the DNA replication machinery. Recent studies have provided data indicating that direct interactions may exist between chromatin remodeling factors and two cellular replication factors, the Origin Recognition Complex and Proliferating Cell Nuclear Antigen. However, since these replication factors are also involved in other nuclear processes, such as transcriptional silencing and DNA repair, respectively, further study is necessary to establish whether these direct interactions are also important for DNA replication.
bFGF as an autocrine growth factor for human melanomas. (1988)

Normal human melanocytes in culture require specific additives such as basic fibroblast growth factor (bFGF) and dibutyryl cyclic adenosine monophosphate (dbcAMP) in order to proliferate in defined or serum-containing medium (Halaban et al., 1987). This stringent requirement is absent in cells derived from metastatic melanomas which not only proliferate in regular culture medium, but also produce a substance immunologically related to bFGF (Halaban et al., 1987). We show here that the mitogenic activity necessary for normal human melanocytes is constitutively present in several lines of human metastatic melanomas and that this activity is inactivated by anti-bFGF antibodies. Melanoma cells, but not normal melanocytes, express bFGF gene transcripts. Although the molecular mechanism underlying the abnormal expression of bFGF in melanomas is not known, the results suggest that bFGF acts as an autocrine growth factor in melanomas.
Cyclosporine promotes glomerular endothelin binding in vivo. (1991)

It has previously been shown that administration of cyclosporine causes a prompt (within 15 min after infusion) increase in circulating level of endothelin 1 and a pattern of glomerular hypoperfusion and hypofiltration which can be ameliorated with antiendothelin antibody. We now show that 60 min after cyclosporine, serum endothelin 1 level falls to less than 2.55 +/- 0.31 pg/mL (N = 6), a value comparable to that found in normal animals (less than 2 pg/mL). The study presented here also examines whether sustained cyclosporine-induced glomerular dysfunction is associated with altered endothelin receptor characteristics. Saturation and competitive inhibition binding studies in isolated glomerular membranes showed two binding sites. Of these, the density of the low-affinity site was affected by cyclosporine treatment (851 +/- 117 versus 425 +/- 61 fmol/mg of protein; P less than 0.05; N = 6) without a change in equilibrium dissociation constant, KD. The high-affinity site was not affected. The receptor characteristics of another vasoconstrictor, angiotensin II, were not affected by cyclosporine. In addition, there was no difference in endothelin binding sites in hepatic tissue between cyclosporine and control rats. These results raise the intriguing possibility that cyclosporine-induced glomerular dysfunction involves upregulation of endothelin binding sites and that altered endothelin receptors appear specific to the kidney.