gebhart/patrepeval huggingface dataset:
Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. (1980)

The availability of compactin (ML-236B), a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, has permitted the demonstration of a hitherto unsuspected aspect of mevalonate metabolism and isoprenoid synthesis in cultured mammalian cells. 3-Hydroxy-3-methylglutaryl Coenzyme A reductase, the enzyme that synthesizes mevalonate, appears to be regulated through a multivalent feedback mechanism. Full suppression of the reductase requires the presence of at least two regulators: 1) cholesterol, which is normally derived exogenously from plasma low density lipoprotein (LDL), and 2) a nonsterol product, which is normally synthesized endogenously from mevalonate. Evidence indicates that both of these regulators of the reductase may be essential for the growth of mammalian cells in culture. The multivalent feedback regulation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, together with secondary regulatory changes in other enzymes of the sterol synthetic pathway, coordinates the branched pathway of mevalonate metabolism so as to assure a constant supply of cholesterol and nonsterol products. These new findings have important implications for the understanding of isoprenoid metabolism and its relation to cell growth.
Identification of Grass-specific Enzyme That Acylates Monolignols with p-Coumarate (2012)

Lignin is a major component of plant cell walls that is essential to their function. However, the strong bonds that bind the various subunits of lignin, and its cross-linking with other plant cell wall polymers, make it one of the most important factors in the recalcitrance of plant cell walls against polysaccharide utilization. Plants make lignin from a variety of monolignols including p-coumaryl, coniferyl, and sinapyl alcohols to produce the three primary lignin units: p-hydroxyphenyl, guaiacyl, and syringyl, respectively, when incorporated into the lignin polymer. In grasses, these monolignols can be enzymatically preacylated by p-coumarates prior to their incorporation into lignin, and these monolignol conjugates can also be "monomer" precursors of lignin. Although monolignol p-coumarate-derived units may comprise up to 40% of the lignin in some grass tissues, the p-coumarate moiety from such conjugates does not enter into the radical coupling (polymerization) reactions of lignification. With a greater understanding of monolignol p-coumarate conjugates, grass lignins could be engineered to contain fewer pendent p-coumarate groups and more monolignol conjugates that improve lignin cleavage. We have cloned and expressed an enzyme from rice that has p-coumarate monolignol transferase activity and determined its kinetic parameters.
Effects of peptide YY (PYY) on mouth to caecum intestinal transit time and on the rate of gastric emptying in healthy volunteers. (1987)

The effect of an infusion of two doses of peptide YY (PYY), a novel putative gastrointestinal hormone, has been assessed on mouth to caecum intestinal transit time and on the rate of gastric emptying after ingestion of an inert 200 ml liquid meal thought unlikely to interrupt fasting gastrointestinal motility patterns. A low dose of PYY was chosen to give plasma concentrations within the range seen postprandially in healthy subjects, while the high dose mimicked the raised levels seen in several malabsorptive conditions. During infusion of PYY at 0.18 pmol/kg/min plasma concentrations rose from a basal of 8 +/- 2 pmol/l to 38 +/- 5 pmol/l and at 0.51 pmol/kg/min to 87 +/- 10 pmol/l. Mouth to caecum transit time was delayed from 67 +/- 4 mins on the saline infusion day to 94 +/- 7 mins (p less than 0.01) on the low dose and 192 +/- 9 mins (p less than 0.001) on the high dose infusion day. Time to 50% gastric emptying was prolonged from 37 +/- 8 mins during saline infusion to 63 +/- 10 mins (p less than 0.05) during low and 130 +/- 12 mins (p less than 0.001) during high dose infusion. Thus the infusion of PYY shows a dose related inhibition of mouth to caecum intestinal transit time and of the rate of gastric emptying and suggests this novel hormonal peptide to be of importance in gastrointestinal physiology.
Genetic Variation Stimulated by Epigenetic Modification (2008)

Homologous recombination is essential for maintaining genomic integrity. A common repair mechanism, it uses a homologous or homeologous donor as a template for repair of a damaged target gene. Such repair must be regulated, both to identify appropriate donors for repair, and to avoid excess or inappropriate recombination. We show that modifications of donor chromatin structure can promote homology-directed repair. These experiments demonstrate that either the activator VP16 or the histone chaperone, HIRA, accelerated gene conversion approximately 10-fold when tethered within the donor array for Ig gene conversion in the chicken B cell line DT40. VP16 greatly increased levels of acetylated histones H3 and H4, while tethered HIRA did not affect histone acetylation, but caused an increase in local nucleosome density and levels of histone H3.3. Thus, epigenetic modification can stimulate genetic variation. The evidence that distinct activating modifications can promote similar functional outcomes suggests that a variety of chromatin changes may regulate homologous recombination, and that disregulation of epigenetic marks may have deleterious genetic consequences.
Applying TLR Synergy in Immunotherapy: Implications in Cutaneous Leishmaniasis (2010)

Therapy of intracellular pathogens can be complicated by drug toxicity, drug resistance, and the need for prolonged treatment regimens. One approach that has shown promise is immunotherapy. Leishmaniasis, a vector-borne disease ranked among the six most important tropical infectious diseases by the World Health Organization, has been treated clinically with crude or defined vaccine preparations or cytokines, such as IFN-gamma and GM-CSF, in combination with chemotherapy. We have attempted to develop an improved and defined immunotherapeutic using a mouse model of cutaneous leishmaniasis. We hypothesized that immunotherapy may be improved by using TLR synergy to enhance the parasite-specific immune response. We formulated L110f, a well-established Leishmania poly-protein vaccine candidate, in conjunction with either monophosphoryl lipid A, a TLR4 agonist, or CpG, a TLR9 agonist, or a combination of these, and evaluated anti-Leishmania immune responses in absence or presence of active disease. Only mice treated with L110f plus monophosphoryl lipid A-CpG were able to induce a strong effective T cell response during disease and subsequently cured lesions and reduced parasite burden when compared with mice treated with L110f and either single adjuvant. Our data help to define a correlate of protection during active infection and indicate TLR synergy to be a potentially valuable tool in treating intracellular infections.
Cloning and nucleotide sequence analysis of the dog insulin gene. Coded amino acid sequence of canine preproinsulin predicts an additional C-peptide fragment. (1983)

A 4.0-kilobase HindIII/EcoRI-cleaved dog genomic DNA fragment was shown to contain the dog insulin gene by restriction mapping using a human insulin cDNA probe. This fragment was subsequently cloned in a lambda vector, and the nucleotide sequence of the dog insulin gene was determined. As in several other species, the insulin gene of the dog is interrupted by two intervening sequences, one of 151 base pairs located in the 5' untranslated region and the other of 264 base pairs occurring within the codon of the 7th amino acid of the C-peptide. Translation of the nucleotide sequence in one frame revealed the primary structure of canine preproinsulin. An interesting feature of the coded amino acid sequence is that it predicts a C-peptide of 31 amino acids, 8 residues longer than that reported by Peterson et al. (Peterson, J. D., Nehrlich, S., Oyer, P. E., and Steiner, D. F. (1973) J. Biol. Chem. 247, 4866-4871). The additional octapeptide sequence, Glu-Val-Glu-Asp-Leu-Gln-Val-Arg, is located NH2-terminal to the 23-residue C-peptide sequence described in the earlier report. Its coding sequence is interrupted by the second intervening sequence. The arginine at position 8 suggests that a trypsin-like cleavage may separate the NH2-terminal octapeptide from the remainder of the C-peptide during the post-translational processing of dog proinsulin in the pancreas. The revised C-peptide sequence suggests that the proinsulin C-peptide is more highly conserved in length and overall sequence than was previously supposed.
High‐throughput gender determination using automated denaturant gel capillary electrophoresis (2005)

Sex determination of anonymous samples is a requirement before analysis of DNA variation on X or Y chromosomes. Based on this, we designed a method for screening samples on different DNA capillary sequencing instruments with a sensitivity that is able to quantify sex chromosome abnormalities. The two different amelogenin alleles sited on the X and Y chromosomes were polymerase chain reaction amplified with the same set of primers and separated by denaturant capillary electrophoresis (DCE). Sex chromosome ratios could be reproducibly determined with a relative standard deviation of 8.7%, which is sufficient to distinguish a normal XY karyotype from an XYY karyotype associated with Klinefelter syndrome. Reconstruction experiments demonstrated sensitivity down to a simulated Y:X allelic ratio of 1:127 in all three instruments, enabling the prediction of sex chromosomal aneuploidies. When tested on anonymous pooled and single samples, DCE gave a good prediction of the male to female ratio in pools of 1000 blood donors. In conclusion, DCE is a simple and robust method for sex determination that can be readily performed on commercially available CE systems.
Activation of Erythropoietin Receptor through a Novel Extracellular Binding Site (2002)

Activation of erythropoietin (EPO) receptor (EPOR) by a small peptide (ERP) was reported previously. ERP binds to a different receptor site than EPO, and binding of ERP does not change the dissociation constant and maximal binding for EPO binding to the receptor. The extracellular binding site for ERP is now characterized. The site is located in the membrane proximal, extracellular part of the receptor. ERP binds to a region on the EPOR that contains the same sequence as ERP. It is speculated that ERP binds to its identical sequence on EPOR, as ERP self-interacts. ERP is specific for EPOR and associates noncovalently with EPOR in a ratio 1:1. Peptide binding to the receptor results in receptor-mediated cellular proliferation, intracellular signaling, and erythroid colony-forming unit formation in bone marrow cells. The activity is comparable to that of EPO. Recognition of such receptor sites represents a new and important concept in receptor function.
Dimethyloxosulfonium Methylide ((CH3)2SOCH2) and Dimethylsulfonium Methylide ((CH3)2SCH2). Formation and Application to Organic Synthesis (1965)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDimethyloxosulfonium Methylide ((CH3)2SOCH2) and Dimethylsulfonium Methylide ((CH3)2SCH2). Formation and Application to Organic SynthesisE. J. Corey and Michael ChaykovskyCite this: J. Am. Chem. Soc. 1965, 87, 6, 1353–1364Publication Date (Print):March 1, 1965Publication History Published online1 May 2002Published inissue 1 March 1965https://pubs.acs.org/doi/10.1021/ja01084a034https://doi.org/10.1021/ja01084a034research-articleACS PublicationsRequest reuse permissionsArticle Views15282Altmetric-Citations1393LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Assignment of enzyme substrate specificity by principal component analysis of aligned protein sequences: An experimental test using DNA glycosylase homologs (2000)

We have studied the relationship between amino acid sequence and substrate specificity in a DNA glycosylase family by characterizing experimentally the specificity of four new members of the family. We show that principal component analysis (PCA) of the sequence family correctly predicts the substrate specificity of one of the novel homologs even though conventional sequence analysis methods fail to group this homolog with other sequences of the same specificity. PCA also suggested, correctly, that another homolog characterized previously differs in its specificity from those sequences with which it clusters by conventional criteria. These results suggest that principal component analysis of sequence families can be a useful tool in annotating genome sequences when there is ambiguity concerning which subfamily a new homolog belongs to. Published 2000 Wiley-Liss, Inc.
[Antisense oligonucleotides with antitumor activity]. (2004)

Antisense oligonucleotides (AONs) provide an efficient approach for developing target-selective anticancer drugs, because they can inhibit gene expression sequence specifically. To improve the therapeutic effenciency of AONs, two new types of the compounds have been developed. The first group of antisense oligodeoxynucleotides investigated contains base modified nucleotide units. Incorporation of 5-substituted pyrimidines into AONs increases cell membrane permeability (a), duplex stability (b), and nuclease resistance (c). These properties were studied using a large number of model oligonucleotides. The application of 5-(1-hexynyl)dU has been found to be the best modification. Application of MMP-9 collagenase inhibitor oligonucleotides (potential metastasis inhibitors) containing these nucleotide units instead of thymidines increased the collagenase inhibition potency by one order of magnitude compared to that of parental oligonucleotide including thymine bases. The second group of the compounds investigated represents a new type of antisense oligonucleotide synthesized by the antisense directed prodrug therapy (ADPT) conception. According to this principle, a telomerase inhibitor AON was conjugated with 5-fluoro-2'-deoxyuridine (FdU) and oligo-FdUs by phosphodiester bond at the 3'-terminus. The antitumor activities of conjugates in comparison with that of FdU were tested in HT1080 human fibrosarcoma and HT29 human colon adenocarcinoma cell lines. In HT29 cell culture the antiproliferative activity of prodrugs significantly increased with increasing length of the 3'-(FdU)n tail. The conjugate with one FdU unit was about 5 times, while the AON-(FdU)3 analogue was almost 19 times more active than FdU. Antitumor activity of the prodrug containing six FdU units was extremely high (relative efficiency = 26.6), therefore, in vivo testing of this analogue seems to be reasonable and promising. Antiproliferative activity of (FdU)n conjugated with a telomerase inhibitor increased by 5-13 times in HT1080 cells as compared to FdU administered in nucleoside form.
Improving Vaccine Performance with Adjuvants (2000)

New vaccines are presently under development and in testing for the control of infectious diseases, including human immunodeficiency virus (HIV) and tuberculosis. Several of these vaccines are composed of synthetic, recombinant, or highly purified subunit antigens. Subunit vaccines are designed to include only the antigens required for protective immunization and to be safer than whole-inactivated or live-attenuated vaccines. However, the purity of the subunit antigens and the absence of the self-adjuvanting immunomodulatory components associated with attenuated or killed vaccines often result in weaker immunogenicity. Immunologic adjuvants are agents that enhance specific immune responses to vaccines. Formulation of vaccines with potent adjuvants is an attractive approach for improving the performance of vaccines composed of subunit antigens. Adjuvants have diverse mechanisms of action and should be selected for use on the basis of the route of administration and the type of immune response (antibody, cell-mediated, or mucosal immunity) that is desired for a particular vaccine.
Phase I trial of the trifunctional anti-HER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer (2005)

2530 Background: Ertumaxomab is an intact bispecific monoclonal antibody targeting HER2 and CD3. The heavy chain is composed of murine IgG2a and rat IgG2b subclasses with strong binding to activatory Fcγ-RI/III-receptors of accessory immune cells. The formation of a tri-cell complex between tumor cell, T-cell and accessory cell results in tumor cell killing by various immunological mechanisms. Methods: Seventeen patients with metastatic breast cancer were enrolled into a multi-center phase I dose-escalating trial. Three ascending doses (10–200μg) were administered intravenously on day 1, 7±1 and 13±1. Patients were followed up for 69 days. Safety and tolerability were primary Objectives: Secondary variables were anti-tumor activity and measurement of different immunological parameters (cytokines, hematological markers). Results: Sixteen out of 17 enrolled patients with a median age of 60,5 years and a HER2-expression score of 1+ (25%), 2+ (12.5%), and 3+ (62,5%) have completed the study up to date. 100μg was identified as maximal tolerable single dose. Most adverse events were mild and transient including fever (75%), chills (50%), nausea (44%), vomiting (25%), pain (38%). Grade 3/4 (CTC) were lymphocytopenia (69%) and elevation of liver enzymes (38%). One patient (200μg dose) developed severe hypotension and respiratory distress syndrome, one patient (150μg dose) developed a systemic inflammatory response syndrome and acute renal failure. All adverse events were fully reversible. Aggravation of congestive heart-failure was seen in a patient (200μg dose) with pre-existing ventricular dysfunction. Antitumor response was seen in 4 out of 15 evaluable patients (1CR, 2 PR, 1 SD) at dose levels of ≥100μg. Measurement of cytokines (IL-6, IL-2, TNF-α, IFN-γ) suggests a strong Th1-associated immune response. Induction of human-anti-mouse/rat-antibodies (HAMA/HARA) was detected in 3 patients (19%) only. Conclusions: Treatment with triple infusions of ertumaxomab yields a strong immunological response. Doses up to 100 μg can be safely infused with close monitoring of patients. Tumor response in some patients is encouraging suggesting anti-tumor efficacy. No significant financial relationships to disclose.
Histologic Alterations in Dermal Repair after Thermal Injury Effects of Topical Angiotensin II (1997)

Previously, we determined that quantitative assessment of epithelialization of the burn site could be performed using quantitative immunohistochemistry with an antibody to the protein cyclin. In this study, the effect of administration of angiotensin II (AII) on two histologic parameters of healing-the number of vascular channels at the burn site and the number of cells proliferating in hair follicles at the edge of the burn and within the burn-were evaluated. Beginning on day 4, vascular channels were noted within the burn site. Significantly more channels were noted in the burns treated with AII than those treated with placebo. With the exception of 3 postinjury days, this increase continued through day 17. Thereafter, the number of vascular channels peaked, and no differences were noted between control and treated burns. The number of cells proliferating in the hair follicle was also evaluated. At the edge of the burn, on average, 126 cells per microscope field (10x) were undergoing proliferation in the AII-treated burn on days 1 through 16 after burn injury. This is approximately a 50% increase over the number of cells proliferating in the placebo-treated burns. On day 12 (approximately 5 days before that observed in control burns), this AII-dependent proliferative response began to increase and peaked on day 19 at a level comparable to control. Thereafter, the proliferative response remained at this level through day 28. Within the area of the burn on days 1 through 15, 21 cells per medium power field on average (approximately 50% more than control) were undergoing proliferation. As on the edge of the burn, an AII-dependent increase in the number of cells proliferating in the hair follicles was observed during the latter phase of healing (on day 16 after the initiation of injury). However, unlike the edge of the burn, administration of AII led to a continued increase (approximately 50%) in the number of cells per field undergoing proliferation. AII increased neovascularization and cellular proliferation after burn injury. Through an increase in these two cellular events, AII may in turn accelerate healing of tissues after thermal injury.
Lower-Defect Graphene Oxide Nanoribbons from Multiwalled Carbon Nanotubes (2010)

An improved method is described for the production of graphene oxide nanoribbons (GONRs) via longitudinal unzipping of multiwalled carbon nanotubes. The method produces GONRs with fewer defects and/or holes on the basal plane, maintains narrow ribbons <100 nm wide, and maximizes the high aspect ratio. Changes in the reaction conditions such as acid content, time, and temperature were investigated. The new, optimized method which introduces a second, weaker acid into the system, improves the selectivity of the oxidative unzipping presumably by in situ protection of the vicinal diols formed on the basal plane of graphene during the oxidation, and thereby prevents their overoxidation and subsequent hole generation. The optimized GONRs exhibit increased electrical conductivity over those chemically reduced nanoribbons produced by previously reported procedures.