gebhart/patrepeval huggingface dataset:
Induction of micronuclei in mouse bone marrow cells: An evaluation of nucleoside analogues used in the treatment of AIDS (1991)

Various nucleoside analogues are being used or are being considered for use as therapeutic drugs to inhibit replication of the HTLV-III/LAV virus in infected human cells. Here, the ability of seven nucleoside analogues, a combination of two analogues, and two other therapeutic compounds to induce genotoxic and cytotoxic damage in vivo was evaluated in the mouse bone marrow micronucleus test. Using a 3-consecutive-day oral treatment protocol, almost all of the test chemicals induced a significant increase in the frequency of micronucleated polychromatic erythrocytes (MN-PCE) in male B6C3F1 mice, ranked in decreasing potency as 6-thioguanine greater than Cytarabine HCl greater than 3'-azido-3'-deoxythymidine (AZT)/2',3'-dideoxycytidine combination = AZT greater than Ribavirin = 2',3'-didehydro-3'-deoxythymidine greater than 2',3'-dideoxyadenosine = 2',3'-dideoxycytidine. The frequency of MN-PCE was not increased significantly by treatment with 2',3-dideoxyinosine (DDI) or pentamidine isethionate (PI). The differential ability of AZT and DDI to induce MN in mouse bone marrow was verified from peripheral blood smears prepared from subchronic (90 day) oral studies. The lack of genotoxic activity by DDI was route-specific since, when tested by intraperitoneal injection, a small but significant increase in MN-PCE was observed. A number of these chemicals induced a significant depression in erythropoiesis. However, there was not a significant correlation between the increase in MN-PCE and the depression in the percentage of PCE. This lack of a correlation suggests that factors other than DNA damage may contribute to the inhibition in the rate of erythropoiesis. The presence of increased levels of micronuclei in bone marrow PCE following treatment with various nucleoside analogues suggests that intrinsic genotoxic activity in mammalian cells should be one factor considered during drug selection for AIDS therapy.
Survival dependency of intramuscular ICC on vagal afferent nerves in the cat esophagus (2007)

Interstitial cells of Cajal (ICC) have been proposed as stretch receptors for vagal afferent nerves in the stomach based on immunohistochemical studies. The aim of the present study was to use electron microscopy and the anterograde degeneration technique to investigate ultrastructural features and survival dependency of ICC associated with vagal afferent innervation of the cat esophagus. This is the first report on the ultrastructural characteristics of ICC in the cat esophagus. Intramuscular ICC (ICC-IM) were identified throughout the musculature, whereas ICC in the myenteric plexus were rare. ICC-IM were particularly numerous in septa aligned with smooth muscle bundles. They were in synapse-like contact with nerve varicosities and in gap junction contact with smooth muscle cells. Smooth muscle cells also made contact with ICC through peg and socket junctions. Precision damage through small-volume injection of saline in the center of the nodose ganglion from the lateral side, known to selectively affect sensory nerves, was followed within 24 h by degeneration of a subset of nerve varicosities associated with ICC-IM, as well as degeneration of the associated ICC-IM. Smooth muscle cells were not affected. Nerves of Auerbachs plexus and associated ICC were not affected. In summary, ICC-IM aligning the esophageal muscle bundles form specialized synapse-like contacts with vagal afferent nerves as well as gap junction and peg-and-socket contacts with smooth muscle cells. This is consistent with a role of ICC-IM as stretch receptors associated with vagal afferent nerves; the ICC-vagal nerve interaction appears essential for the survival of the ICC.
The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones (1991)

1. The interaction of the intravenous general anaesthetic propofol (2,6-diisopropylphenol) with the GABAA receptor has been investigated in voltage-clamped bovine chromaffin cells and rat cortical neurones in cell culture. Additionally, the effects of propofol on the glycine and GABAA receptors of murine spinal neurones were determined. 2. Propofol (1.7-16.8 microM) reversibly and dose-dependently potentiated the amplitude of membrane currents elicited by GABA (100 microM) applied locally to bovine chromaffin cells. Intracellular application of propofol (16.8 microM) was ineffective. In rat cortical neurones and murine spinal neurones, extracellular application of 8.4 microM and 1.7-16.8 microM propofol respectively produced a potentiation of GABA-evoked currents qualitatively similar to that seen in the bovine chromaffin cell. 3. The potentiation by propofol (1.7 microM) was not associated with a change in the reversal potential of the GABA-evoked whole cell current. On outside-out membrane patches isolated from bovine chromaffin cells, propofol (1.7 microM) had little or no effect on the GABA single channel conductances, but greatly increased the probability of the GABA-gated channel being in the conducting state. 4. The potentiation of GABA-evoked whole cell currents by propofol (1.7 microM) was not influenced by the benzodiazepine antagonist flumazenil (0.3 microM). A concentration of propofol (1.7 microM) that substantially potentiated GABA currents had little effect on currents induced by the activation of the GABAA receptor by pentobarbitone (1 mM). 5. Bath application of propofol (8.4-252 microM), to bovine chromaffin cells voltage clamped at -60 mV, induced an inward current associated with an increase in membrane current noise on all cells sensitive to GABA. Intracellular application of propofol (16.8 microM) was ineffective in this respect. Local application of propofol (600 microM) induced whole cell currents with a reversal potential dependent upon the Cl- gradient across the cell membrane. 6. On outside-out membrane patches formed from bovine chromaffin cells, propofol (30 microM) induced single channels with mean chord conductances of 29 and 12 pS. The frequency of propofol channels was greatly reduced by coapplication of 1 microM bicuculline. Under identical ionic conditions, GABA (1 microM) activated single channels with mean chord conductances of 33, 16 and 10pS. 7. Bath applied propofol (0.84-16.8 microM) dose-dependently potentiated strychnine-sensitive currents evoked by glycine (100 microM) in murine spinal neurones. 8. The relevance of the present results to the general anaesthetic action of propofol is discussed.
Current Advances in Retroviral Gene Therapy (2011)

There have been major changes since the incidents of leukemia development in X-SCID patients after the treatments using retroviral gene therapy. Due to the risk of oncogenesis caused by retroviral insertional activation of host genes, most of the efforts focused on the lentiviral therapies. However, a relative clonal dominance was detected in a patient with β-thalassemia Major, two years after the subject received genetically modified hematopoietic stem cells using lentiviral vectors. This disappointing result of the recent clinical trial using lentiviral vector tells us that the current and most advanced vector systems does not have enough safety. In this review, various safety features that have been tried for the retroviral gene therapy are introduced and the possible new ways of improvements are discussed. Additional feature of chromatin insulators, co-transduction of a suicidal gene under the control of an inducible promoter, conditional expression of the transgene only in appropriate target cells, targeted transduction, cell type-specific expression, targeted local administration, splitting of the viral genome, and site specific insertion of retroviral vector are discussed here.
Binaphthol-Titanium Complex-Catalyzed Fluoral-Ene Reaction with Vinyl Sulfides for Asymmetric Synthesis of Diastereomeric α-Trifluoromethyl-β-methyl Carbinols: Diastereomer Switch of Antiferroelectric or Ferroelectric Properties of Diastereomeric Liquid-Crystalline Systems1 (1996)

We synthesized a new type of antiferroelectric and ferroelectric liquid-crystalline molecules with double stereogenic centers based on the binaphthol-titanium complex-catalyzed fluoral-ene reaction with vinyl sulfides. Furthermore, we experimentally showed the importance of the diastereomer effect for the appearance of the antiferroelectric SmCA* phase.
Influence of Fatty Acid Profile of Total Parenteral Nutrition Emulsions on the Fatty Acid Composition of Different Tissues of Piglets (2008)

Total parenteral nutrition (TPN) studies in human babies of very-low-birth-weight suggest that the lipid emulsions currently available are not optimum for neonatal nutrition. Since fatty acid metabolism in human and pigs is very similar, the present study examines how lipid emulsions used in clinical TPN (i.e. ClinOleic, Intralipid, Lipofundin or Omegaven), with different fatty acid compositions, administered to neonatal piglets for 7 days, influenced their tissue fatty acid composition as compared to those enterally fed with a sow milk replacer. A positive linear relationship was found between the proportion of all individual fatty acids in the lipid emulsions or in the milk replacer versus those in plasma, skeletal muscle, subcutaneous fat, liver, heart, pancreas, stomach or intestine total lipids or in brain phospholipids, the latter showing the lowest correlation coefficient. With the exception of brain, the proportion of either oleic acid or alpha-linolenic acid in the individual tissues was correlated with those present in the corresponding lipid emulsion or milk replacer, whereas the proportion of linoleic acid correlated significantly with all the tissues studied. With the exception of brain phospholipids, both eicosapentaenoic and docosahexaenoic acids were higher in the tissues of piglets receiving Omegaven than in all other groups. In conclusion, with the exception of the brain, fatty acid composition of plasma and different tissues in piglets are strongly influenced by the fatty acid profile of TPN emulsions. Fatty acid composition of brain phospholipids are, however, much less influenced by dietary composition, indicating an active and efficient metabolism that ensures its appropriate composition at this key stage of development.
The Honduran human immunodeficiency virus type 1 (HIV-1) epidemic is dominated by HIV-1 subtype B as determined by V3 domain sero- and genotyping (1997)

The distribution of subtypes A through F of human immunodeficiency virus type 1 (HIV-1) in Honduras was analyzed in 120 HIV-1 positive serum samples by V3 peptide serotyping and HIV-1 cDNA sequencing. In the Honduran HIV-1 epidemic, subtype B was detected in 98 of 99 subtyped samples.
Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment (2015)

We identified plasma biomarkers that presaged outcomes in patients with gastrointestinal graft-versus-host disease (GVHD) by measuring 23 biomarkers in samples collected before initiation of treatment. Six analytes with the greatest accuracy in predicting grade 3-4 GVHD in the first cohort (74 patients) were then tested in a second cohort (76 patients). The same 6 analytes were also tested in samples collected at day 14 ± 3 from 167 patients free of GVHD at the time. Logistic regression and calculation of an area under a receiver-operating characteristic (ROC) curve for each analyte were used to determine associations with outcome. Best models in the GVHD onset and landmark analyses were determined by forward selection. In samples from the second cohort, collected a median of 4 days before start of treatment, levels of TIM3, IL6, and sTNFR1 had utility in predicting development of peak grade 3-4 GVHD (area under ROC curve, 0.88). Plasma ST2 and sTNFR1 predicted nonrelapse mortality within 1 year after transplantation (area under ROC curve, 0.90). In the landmark analysis, plasma TIM3 predicted subsequent grade 3-4 GVHD (area under ROC curve, 0.76). We conclude that plasma levels of TIM3, sTNFR1, ST2, and IL6 are informative in predicting more severe GVHD and nonrelapse mortality.
The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death (2020)

The spliceosome assembles on pre-mRNA in a stepwise manner through five successive pre-spliceosome complexes. The spliceosome functions to remove introns from pre-mRNAs to generate mature mRNAs that encode functional proteins. Many small molecule inhibitors of the spliceosome have been identified and they are cytotoxic. However, little is known about genetic determinants of cell sensitivity. Activating transcription factor 3 (ATF3) is a transcription factor that can stimulate apoptotic cell death in response to a variety of cellular stresses. Here, we used a genetic approach to determine if ATF3 was important in determining the sensitivity of mouse embryonic fibroblasts (MEFs) to two splicing inhibitors: pladienolide B (PB) and isoginkgetin (IGG), that target different pre-spliceosome complexes. Both compounds led to increased ATF3 expression and apoptosis in control MEFs while ATF3 null cells were significantly protected from the cytotoxic effects of these drugs. Similarly, ATF3 was induced in response to IGG and PB in the two human tumour cell lines tested while knockdown of ATF3 protected cells from both drugs. Taken together, ATF3 appears to contribute to the cytotoxicity elicited by these spliceosome inhibitors in both murine and human cells.
Preparation of colloidal silver dispersions by the polyol process. Part 1—Synthesis and characterization (1996)

Modification of the polyol process has enabled the synthesis of nanometre-sized silver particles with a narrow size distribution. Dispersions of colloidal silver have been prepared by the reduction of silver nitrate in ethylene glycol in the presence of a polymeric protective agent, namely polyvinylpyrrolidone (PVP). Ageing these dispersions at 120 °C for 1 h yields systems with average particle sizes ranging from 15 to 36 nm. The amount of both precursor and protective agent was found to control the final particle size and size distribution of the colloidal silver, which exhibits a well crystallized structure.
Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi (2008)

Huntington's disease (HD) is a fatal, dominant neurodegenerative disease caused by a polyglutamine repeat expansion in exon 1 of the HD gene, which encodes the huntingtin protein. We and others have shown that RNAi is a candidate therapy for HD because expression of inhibitory RNAs targeting mutant human HD transgenes improved neuropathology and behavioral deficits in HD mouse models. Here, we developed shRNAs targeting conserved sequences in human HD and mouse HD homolog (HDh) mRNAs to initiate preclinical testing in a knockin mouse model of HD. We screened 35 shRNAs in vitro and subsequently narrowed our focus to three candidates for in vivo testing. Unexpectedly, two active shRNAs induced significant neurotoxicity in mouse striatum, although HDh mRNA expression was reduced to similar levels by all three. Additionally, a control shRNA containing mismatches also induced toxicity, although it did not reduce HDh mRNA expression. Interestingly, the toxic shRNAs generated higher antisense RNA levels, compared with the nontoxic shRNA. These results demonstrate that the robust levels of antisense RNAs emerging from shRNA expression systems can be problematic in the mouse brain. Importantly, when sequences that were toxic in the context of shRNAs were placed into artificial microRNA (miRNA) expression systems, molecular and neuropathological readouts of neurotoxicity were significantly attenuated without compromising mouse HDh silencing efficacy. Thus, miRNA-based approaches may provide more appropriate biological tools for expressing inhibitory RNAs in the brain, the implications of which are crucial to the development of RNAi for both basic biological and therapeutic applications.
Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge (2005)

A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.
Urovirulence Determinants inEscherichia coliStrains Causing Prostatitis (1997)

To define the urovirulence properties of Escherichia coli strains producing prostatitis, E. coli strains isolated from men with acute (7 strains) or chronic (23) prostatitis were compared with E. coli isolates from women with pyelonephritis (30), acute cystitis (60), or complicated urinary tract infection (UTI; 30). Strains from prostatitis patients were significantly more likely to express hemolysin than were strains causing complicated UTI (73% vs. 43%; P = .02) and more often demonstrated hybridization with the cytotoxic necrotizing factor-1 (CNF-1) probe (63%) than did strains from women (44%-48%). P fimbrial expression was highest among pyelonephritis (73%) and prostatitis strains (53%) and lowest among E. coli from women with complicated UTI (23%) and cystitis (30%; P < .05, prostatitis strains vs. either of the latter 2 groups). Results suggest that E. coli strains producing prostatitis generally possess urovirulence profiles similar to those of strains from women with acute uncomplicated pyelonephritis and that hemolysin and CNF-1 are especially prevalent in prostatitis strains.
Therapeutic androgen receptor ligands (2003)

In the past several years, the concept of tissue-selective nuclear receptor ligands has emerged. This concept has come to fruition with estrogens, with the successful marketing of drugs such as raloxifene. The discovery of raloxifene and other selective estrogen receptor modulators (SERMs) has raised the possibility of generating selective compounds for other pathways, including androgens (that is, selective androgen receptor modulators, or SARMs).
CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches (2013)

The stem cell niche provides a regulatory microenvironment for cells as diverse as totipotent embryonic stem cells to cancer stem cells (CSCs) which exhibit stem cell-like characteristics and have the capability of regenerating the bulk of tumor cells while maintaining self-renewal potential. The transmembrane glycoprotein CD44 is a common component of the stem cell niche and exists as a standard isoform (CD44s) and a range of variant isoforms (CD44v) generated though alternative splicing. CD44 modulates signal transduction through post-translational modifications as well as interactions with hyaluronan, extracellular matrix molecules and growth factors and their cognate receptor tyrosine kinases. While the function of CD44 in hematopoietic stem cells has been studied in considerable detail, our knowledge of CD44 function in tissue-derived stem cell niches remains limited. Here we review CD44s and CD44v in both hematopoietic and tissue-derived stem cell niches, focusing on their roles in regulating stem cell behavior including self-renewal and differentiation in addition to cell-matrix interactions and signal transduction during cell migration and tumor progression. Determining the role of CD44 and CD44v in normal stem cell, CSC and (pre)metastatic niches and elucidating their unique functions could provide tools and therapeutic strategies for treating diseases as diverse as fibrosis during injury repair to cancer progression.
Actions of intrathecal diphtheria toxin-substance P fusion protein on models of persistent pain (1999)

Substance P (SP) plays a central role in the transduction of second messenger signals from primary afferent nociceptive terminals to second-order neurons in the spinal cord. We have tested a recombinant engineered diphtheria toxin/SP fusion protein (DAB389SP) in acute and chronic pain models in the rat. DAB389SP binds to the SP receptor (SPR) and is internalized and kills SPR-expressing cells by blocking cellular protein synthesis. DAB389SP delivery was by intrathecal infusion, of varying duration, at the lumbar level. In the chronic constriction injury model of neuropathic pain a significant reduction in mechanically induced hyperalgesia was obtained. This effect was less marked in an acute carageenan inflammation model. Although other pain characteristics (mechano-allodynia, cold-allodynia, and heat-hyperalgesia) showed some improvement, these were less pronounced. Immunocytochemistry revealed a toxin-induced reduction in lamina I, of SPR and of NMDA NR1 subunit receptor expressing neurons, and of c-Fos, an inducible molecular marker of persistent nociceptive activity. The use of cytotoxic fusion proteins to target specific cell types may be of considerable benefit in the study of nociception and the treatment of chronic pain.
Epigenetic Modification Is Central to Genome Reprogramming in Somatic Cell Nuclear Transfer (2005)

The recent high-profile reports of the derivation of human embryonic stem cells (ESCs) from human blastocysts produced by somatic cell nuclear transfer (SCNT) have highlighted the possibility of making autologous cell lines specific to individual patients. Cell replacement therapies have much potential for the treatment of diverse conditions, and differentiation of ESCs is highly desirable as a means of producing the ranges of cell types required. However, given the range of immunophenotypes of ESC lines currently available, rejection of the differentiated cells by the host is a potentially serious problem. SCNT offers a means of circumventing this by producing ESCs of the same genotype as the donor. However, this technique is not without problems because it requires resetting of the gene expression program of a somatic cell to a state consistent with embryonic development. Some remodeling of parental DNA does occur within the fertilized oocyte, but the somatic genome presented in a radically different format to those of the gametes. Hence, it is perhaps unsurprising that many genes are expressed aberrantly within "cloned" embryos and the ESCs derived from them. Epigenetic modification of the genome through DNA methylation and covalent modification of the histones that form the nucleosome is the key to the maintenance of the differentiated state of the cell, and it is this that must be reset during SCNT. This review focuses on the mechanisms by which this is achieved and how this may account for its partial failure in the "cloning" process. We also highlight the potential dangers this may introduce into ESCs produced by this technology.