gebhart/patrepeval huggingface dataset:
Estrogen receptor transcription and transactivation Estrogen receptor knockout mice: what their phenotypes reveal about mechanisms of estrogen action (2000)

Natural, synthetic and environmental estrogens have numerous effects on the development and physiology of mammals. Estrogen is primarily known for its role in the development and functioning of the female reproductive system. However, roles for estrogen in male fertility, bone, the circulatory system and immune system have been established by clinical observations regarding sex differences in pathologies, as well as observations following menopause or castration. The primary mechanism of estrogen action is via binding and modulation of activity of the estrogen receptors (ERs), which are ligand-dependent nuclear transcription factors. ERs are found in highest levels in female tissues critical to reproduction, including the ovaries, uterus, cervix, mammary glands and pituitary gland. Since other affected tissues have extremely low levels of ER, indirect effects of estrogen, for example induction of pituitary hormones that affect the bone, have been proposed. The development of transgenic mouse models that lack either estrogen or ER have proven to be valuable tools in defining the mechanisms by which estrogen exerts its effects in various systems. The aim of this article is to review the mouse models with disrupted estrogen signaling and describe the associated phenotypes.
Malonyl-Coenzyme A:Acyl Carrier Protein Acyltransferase of Streptomyces glaucescens: A Possible Link between Fatty Acid and Polyketide Biosynthesis (1995)

Streptomyces glaucescens, a Gram-positive soil bacterium, produces the polyketide antibiotic tetracenomycin (Tcm) C. To study possible biochemical connections between the biosynthesis of bacterial fatty acids and polyketides, the abundant acyl carrier protein (ACP) detected throughout the growth of the tetracenomycin (Tcm) C-producing S. glaucescens was purified to homogeneity and found to behave like many other ACPs from bacteria and plants (apparent M(r) of 20,000 on gel filtration chromatography, apparent M(r) of 3400-4800 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, and pI approximately 3.8). By using an oligodeoxynucleotide synthesized in accordance with the sequence of residues 25-36 of the ACP, the fabC gene encoding this protein was cloned, and expression of this gene in Escherichia coli yielded the ACP entirely as the active holoenzyme. Sequence analysis of 4.3 kilobases (kb) of DNA flanking fabC revealed the presence of three other genes oriented in the same transcriptional direction in the order fabD, fabH, fabC, and fabB. Each of the four genes is predicted to encode proteins with high sequence similarity to the following components of the E. coli fatty acid synthase (FAS): the FabD malonyl-coenzyme A:ACP acyltransferase (MAT), FabH 3-oxoacyl:ACP synthase III, AcpP ACP, and FabB 3-oxoacyl:ACP synthase I. Expression of the S. glaucescens fabD gene in E. coli produced active MAT able to catalyze in vitro the transfer of radioactive malonate from malonyl-coenzyme A to the E. coli AcpP and S. glaucescens FabC ACPs, as well as to the TcmM ACP component of the Tcm type II polyketide synthase [Shen, B., et al. (1992) J. Bacteriol 174, 3818-3821]. Expression of fabD also restored the high-temperature growth of the E. coli fabD89 mutant that bears a temperature-sensitive MAT. The latter finding and the close similarity between the organization of the S. glaucescens fabDHCB and E. coli FAS-encoding genes (fabH/fabD/fabG/acpP/fabF) suggest that the S. glaucescens genes encode FAS enzymes. Moreover, on the basis of its in vitro activity, it is possible that the S. glaucescens FabD MAT is responsible for charging the TcmM ACP with malonate in vivo, a key step in the synthesis of the deca(polyketide) precursor of Tcm C. This implies the existence of a functional connection between fatty acid and polyketide metabolism in this bacterium.
Synthesis of 1,2,3-triazoles by reaction of azide ion with αβ-unsaturated nitro-compounds and nitriles (1971)

N. S. Zefirov, N. K. Chapovskaya and V. V. Kolesnikov, J. Chem. Soc. D, 1971, 1001 DOI: 10.1039/C29710001001
Natural Substrates and Inhibitors of Mannan-Binding Lectin-Associated Serine Protease-1 and -2: A Study on Recombinant Catalytic Fragments (2003)

Mannan-binding lectin-associated serine protease (SP) (MASP)-1 and MASP-2 are modular SP and form complexes with mannan-binding lectin, the recognition molecule of the lectin pathway of the complement system. To characterize the enzymatic properties of these proteases we expressed their catalytic region, the C-terminal three domains, in Escherichia coli. Both enzymes autoactivated and cleaved synthetic oligopeptide substrates. In a competing oligopeptide substrate library assay, MASP-1 showed extreme Arg selectivity, whereas MASP-2 exhibited a less restricted, trypsin-like specificity. The enzymatic assays with complement components showed that cleavage of intact C3 by MASP-1 and MASP-2 was detectable, but was only approximately 0.1% of the previously reported efficiency of C3bBb, the alternative pathway C3-convertase. Both enzymes cleaved C3i 10- to 20-fold faster, but still at only approximately 1% of the efficiency of MASP-2 cleavage of C2. We believe that C3 is not the natural substrate of either enzyme. MASP-2 cleaved C2 and C4 at high rates. To determine the role of the individual domains in the catalytic region of MASP-2, the second complement control protein module together with the SP module and the SP module were also expressed and characterized. We demonstrated that the SP domain alone can autoactivate and cleave C2 as efficiently as the entire catalytic region, while the second complement control protein module is necessary for efficient C4 cleavage. This behavior strongly resembles C1s. Each MASP-1 and MASP-2 fragment reacted with C1-inhibitor, which completely blocked the enzymatic action of the enzymes. Nevertheless, relative rates of reaction with alpha-2-macroglobulin and C1-inhibitor suggest that alpha-2-macroglobulin may be a significant physiological inhibitor of MASP-1.
Drug Synergism and Dose-Effect Data Analysis (2000)

Not since this author's bestselling Manual of Pharmacologic Calculation-long out of print-has there been a reference available for drug data analysis, and even that work did not deal with drug combinations. Although pharmacologists and most other scientists know what synergism is, mainstream textbooks tend to neglect it as a quantitative topic. Few
Challenges with Intestine and Multivisceral Re-Transplantation: Importance of Timing of Re-Transplantation and Optimal Immunosuppression (2018)

BACKGROUND Patients undergoing re-transplantation often receive high doses of immunosuppression, which may lead to an immunocompromised status of the recipient. This study investigates the outcomes after intestine/multivisceral re-transplantation. MATERIAL AND METHODS Clinical outcomes of 23 patients undergoing 24 re-transplantations at a single intestine transplant center were reviewed. Bone marrow suppression was used as a surrogate marker of immunocompromised status, and was defined as platelet count <50 k/mm3 and absolute lymphocyte count <200/mm³. RESULTS All re-transplants except one were liver inclusive. Fifteen of 23 patients died at a median time of 12 months (range 0.2-75) after re-transplantation. Of the 15 deaths, nine (60%) resulted from complications associated with a compromised host immune status: graft versus host disease (GVHD) affecting bone marrow (three cases), persistent viral infection (three cases), post-transplant lymphoproliferative disorder (PTLD (one case), metastatic cancer (one case), multi-drug resistant polymicrobial sepsis (one case). Four deaths (27%) resulted from severe rejection. Non-survivors were more likely to have received alemtuzumab, and had higher incidence of bone marrow suppression. In addition to immunocompromised status and rejection, the use of alemtuzumab was associated with mortality after intestinal/multivisceral re-transplantation. CONCLUSIONS High mortality was associated with intestine/multivisceral re-transplantation. To improve clinical outcomes of intestine and multivisceral transplantation, it is important to allow reconstitution of host immunity. Longer interval between the two transplantations, and strategies such as allograft specific immunosuppression, may spare the host from the devastating effects of potent immunosuppression currently used.
Crossover from 3D Ising to Isotropic Lifshitz Critical Behavior in a Mixture of a Homopolymer Blend and Diblock Copolymer (1999)

Thermal composition fluctuations and the associated crossover from the 3D Ising to the isotropic Lifshitz universality class have been studied in a three component mixture made of a critical polymer blend and the corresponding diblock copolymer. The critical exponents were found to be appreciably larger than those of the 3D Ising, in agreement with expectations from the larger upper critical dimension. Very near the critical temperature a crossover to a renormalized Lifshitz critical behavior was observed possibly caused by fluctuation induced rearrangements of the diblock copolymers.
Antisense-Mediated Exon Skipping to Reframe Transcripts (2012)

Numerous genetic disorders are caused by loss-of-function mutations that disrupt the open reading frame of the gene either by nonsense or by frameshift (insertion, deletion, indel, or splicing) mutations. Most of the time, the result is the absence of functional protein synthesis due to mRNA degradation by nonsense-mediated mRNA decay, or rapid degradation of a truncated protein. Antisense-based splicing modulation is a powerful tool that has the potential to treat genetic disorders by restoring the open reading frame through selective removal of the mutated exon, or by restoring correct splicing.We have developed this approach for a severe genetic skin disorder, recessive dystrophic epidermolysis bullosa, caused by mutations in the COL7A1 gene encoding type VII collagen. This gene is particularly suited for exon-skipping approaches due to its unique genomic structure. It is composed of 118 exons, 83 of which are in frame. Moreover, these exons encode a single repetitive collagenous domain.Using this gene as an example, we describe general methods that demonstrate the feasibility and efficacy of the antisense-mediated exon-skipping strategy to reframe transcripts.
A Brief Historical Review of the Waterfall/Cascade of Blood Coagulation (2003)

This article explores some of the events and people involved in unraveling the basic mechanisms leading to the clotting of blood. It also brings to focus the important role that my teachers and colleagues had on my career in research. When I entered college majoring in chemistry I had little idea that I would have an opportunity to become a professor of biochemistry at a major university. This was clearly the result of the excellent advice and encouragement that I received, particularly from my teachers early in my career.
Surface Tension Forces in Sleep Apnea: The Role of a Soft Tissue Lubricant: A Randomized Double-blind, Placebo-controlled Trial (1998)

Upper airway obstruction in patients with sleep apnea may occur in the absence of a negative intraluminal upper airway pressure. We hypothesized that surface tension forces may play a role in the pathogenesis of obstructive sleep apnea (OSA), and that a topical soft tissue lubricant might reduce the severity of OSA. Ten male patients (age 49 +/- 10 yr [mean +/- SD]; body mass index [BMI] 31 +/- 5 kg/m2) with OSA (apnea-hypopnea index [AHI] 17 +/- 9) were studied. The arousal index was lower with the lubricant treatment than with placebo (mean difference 8; 95% CI 4 to 11 arousals/h; p = 0.001). The AHI was lower, in each of the 10 patients, on the lubricant treatment than the placebo (mean change 10, 95% CI 6 to 13; p = 0.0003). The lower AHI with lubricant as compared with placebo was present in both supine (mean difference 13; 95% CI 5 to 20; p = 0.006) and nonsupine (mean difference 6; 95% CI 0 to 12; p = 0.05) positions. There was no significant difference in sleep architecture between the lubricant and placebo treatments. Application of a topical lubricant consistently reduced the severity of OSA. This implies a pathogenetic role for surface tension forces in OSA, and a potential role for surface tension-reducing agents in the treatment of OSA.
Sarcolipin Regulates the Activity of SERCA1, the Fast-twitch Skeletal Muscle Sarcoplasmic Reticulum Ca2+-ATPase (1998)

The 31-amino acid proteolipid, sarcolipin (SLN), is associated with the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+-ATPase (SERCA1). Constructs of human and rabbit SLN and of rabbit SLN with the FLAG epitope at its N terminus (NF-SLN) or its C terminus (SLN-FC) were coexpressed with SERCA1 in HEK-293 T-cells. Immunohistochemistry was used to demonstrate colocalization of NF-SLN and SERCA1 in the endoplasmic reticulum membrane and to demonstrate the cytosolic orientation of the N terminus of SLN. Coexpression of native rabbit SLN or NF-SLN with SERCA1 decreased the apparent affinity of SERCA1 for Ca2+ but stimulated maximal Ca2+ uptake rates (Vmax). The N terminus of SLN is not well conserved among species, and the addition of an N-terminal FLAG epitope did not alter SLN function. Anti-FLAG antibody reversed both the inhibition of Ca2+ uptake by NF-SLN at low Ca2+ concentrations and the stimulatory effect of NF-SLN on Vmax. Addition of the FLAG epitope to the highly conserved C terminus decreased the apparent affinity of SERCA1 for Ca2+ relative to native SLN and decreased Vmax significantly. Mutations in the C-terminal domain showed that this sequence is critical for SLN function. Mutational analysis of the transmembrane helix, together with the additive regulatory effects of coexpression of both SLN and phospholamban (PLN) with SERCA1, provided evidence for different mechanisms of interaction of SLN and PLN with SERCA molecules. Ca2+ uptake rates in sarcoplasmic reticulum vesicles, isolated from rabbit fast-twitch muscle (tibialis anterior) subjected to chronic low frequency stimulation, were reduced by approximately 40% in 3- and 4-day stimulated muscle, with a marginal increase in apparent affinity of SERCA1 for Ca2+. SERCA1 mRNA and protein levels were unaltered after stimulation. In contrast, SLN mRNA was decreased by 15%, and SLN protein was reduced by 40%. Reduced SLN expression could explain the decrease in SERCA1 activity observed in these muscles and might represent an early functional adaptation to chronic low frequency stimulation.
Evaluation of Nucleoside Phosphonates and Their Analogs and Prodrugs for Inhibition of Orthopoxvirus Replication (2003)

In the event of a bioterrorism attack using smallpox virus, there currently is no approved drug for the treatment of infections with this virus. We have reported previously that (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC) (also known as cidofovir [CDV]) has good activity against poxvirus infections; however, a major limitation is the requirement for intravenous administration. Two related acyclic nucleoside phosphonates (ANPs), adefovir (PMEA) and tenofovir (PMPA), are active against human immunodeficiency virus or hepatitis B virus but do not have activity against the orthopoxviruses. Therefore, we have evaluated a number of analogs and potential oral prodrugs of these three compounds for their ability to inhibit the replication of vaccinia virus or cowpox virus in tissue culture cells. The most-active compounds within the CDV series were (S)-HPMPA and (butyl L-alaninyl) cyclic HPMPC, with 50% effective concentrations (EC(50)s) from 4 to 8 microM, compared with 33 to 43 microM for CDV. Although PMEA itself was not active, adefovir dipivoxil [bis[(pivaloyl)oxymethyl] PMEA] and bis(butyl L-alaninyl) PMEA were active against both viruses, and bis(butyl L-alaninyl) PME-N6-(cyclopropyl)DAP and (isopropyl L-alaninyl)phenyl PME-N6-(cyclopropyl)DAP were the most active compounds tested, with EC(50)s of 0.1 to 2.6 microM. In the PMPA series, none of the analogs tested had significantly better activity than PMPA itself. These data indicate that a number of these ANP derivatives have activity against vaccinia virus and cowpox virus in vitro and should be evaluated for their efficacies in animal models.
Transplantation of glial cell line‐derived neurotrophic factor‐expressing cells into the striatum and nucleus accumbens attenuates acquisition of cocaine self‐administration in rats (2003)

Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), may play a role in drug-induced biochemical and behavioural adaptations that characterize addiction. We found that GDNF mRNA levels are lower in the striatum of rats that chronically self-administered cocaine. Therefore, we examined the effect of transplanted cells used as a biodelivery system for GDNF on cocaine self-administration in rats. A human astrocyte-like cell line, which produces and excretes GDNF, was transplanted into the striatum and nucleus accumbens of rats. These rats showed a significantly lower number of active lever presses in the cocaine self-administration paradigm compared with control rats. Moreover, rats that received a chronic infusion of GDNF via a micro-osmotic pump also exhibited weak cocaine self-administration. Therefore, we conclude that exogenous augmentation of GDNF repositories may be useful in suppressing cocaine self-administration.
Persistence of Th17/Tc17 Cell Expression upon Smoking Cessation in Mice with Cigarette Smoke-Induced Emphysema (2013)

Th17 and Tc17 cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), a disease caused predominantly by cigarette smoking. Smoking cessation is the only intervention in the management of COPD. However, even after cessation, the airway inflammation may be present. In the current study, mice were exposed to room air or cigarette smoke for 24 weeks or 24 weeks followed by 12 weeks of cessation. Morphological changes were evaluated by mean linear intercepts (Lm) and destructive index (DI). The frequencies of CD8(+)IL-17(+)(Tc17) and CD4(+)IL-17(+)(Th17) cells, the mRNA levels of ROR gamma and IL-17, and the levels of IL-8, TNF-alpha, and IFN-gamma in lungs or bronchoalveolar lavage fluid of mice were assayed. Here we demonstrated that alveolar enlargement and destruction induced by cigarette smoke exposure were irreversible and that cigarette smokeenhanced these T-cell subsets, and related cytokines were not significantly reduced after smoking cessation. In addition, the frequencies of Th17 and Tc17 cells in lungs of smoke-exposed mice and cessation mice were positively correlated with emphysematous lesions. More important, the frequencies of Tc17 cells were much higher than Th17 cells, and there was a significantly positive correlation between Th17 and Tc17. These results suggested that Th17/Tc17 infiltration in lungs may play a critical role in sustaining lung inflammation in emphysema. Blocking the abnormally increased numbers of Tc17 and Th17 cells may be a reasonable therapeutic strategy for emphysema.
Complexity Reduction of Polymorphic Sequences (CRoPS™): A Novel Approach for Large-Scale Polymorphism Discovery in Complex Genomes (2007)

Application of single nucleotide polymorphisms (SNPs) is revolutionizing human bio-medical research. However, discovery of polymorphisms in low polymorphic species is still a challenging and costly endeavor, despite widespread availability of Sanger sequencing technology. We present CRoPS as a novel approach for polymorphism discovery by combining the power of reproducible genome complexity reduction of AFLP with Genome Sequencer (GS) 20/GS FLX next-generation sequencing technology. With CRoPS, hundreds-of-thousands of sequence reads derived from complexity-reduced genome sequences of two or more samples are processed and mined for SNPs using a fully-automated bioinformatics pipeline. We show that over 75% of putative maize SNPs discovered using CRoPS are successfully converted to SNPWave assays, confirming them to be true SNPs derived from unique (single-copy) genome sequences. By using CRoPS, polymorphism discovery will become affordable in organisms with high levels of repetitive DNA in the genome and/or low levels of polymorphism in the (breeding) germplasm without the need for prior sequence information.
Role of pathogenic natural antibodies and complement in a murine model of spinal cord injury (P4051) (2013)

Abstract Traumatic spinal cord injury (SCI) results in complement activation and inflammation, which are implicated in a secondary injury that determines the extent of functional recovery. SCI has similar pathophysiological characteristics to ischemia reperfusion injury (IRI), and IRI in some organs is initiated by the binding of "natural" self-reactive IgM to post-ischemic neoepitopes, with the subsequent activation of complement. We demonstrated that Ab deficient Rag1-/- mice are protected from SCI, and that injury can be restored by reconstitution with a self-reactive natural IgM mAb specific for annexin A4. Following SCI, IgM bound to the spinal cord in wt mice, and anti-annexin A4 mAb bound to the spinal cord in Rag1-/- mice. Furthermore, IgM and C3d (complement activation product) co-localized after injury. We constructed a single chain antibody (scFv) derived from the anti-annexin A4 hybridoma and investigated: 1. Its ability to block the binding of pathogenic self-reactive IgM after SCI and, 2. Its utility as a targeting vehicle for delivery of a complement inhibitor after SCI (by linking the scFv to the complement inhibitor, Crry). The scFv-Crry construct, and to a lesser degree scFv alone, were protective against SCI, as measured by improved functional recovery, tissue sparing and demyelination. Data indicate an important role for self-reactive IgM in initiating complement activation after SCI, and that post-SCI neoepitopes represent therapeutic targets.
High-resolution medical imaging system for 3D imaging of radioactive sources with 1-mm FWHM spatial resolution (2003)

This paper describes a modification of a new imaging system developed at Argonne National Laboratory that has the potential of achieving a spatial resolution of 1 mm FWHM. The imaging system uses a crystal diffraction lens to focus gamma rays from the radioactive source. The medical imaging application of this system would be to detect small amounts of radioactivity in the human body that would be associated with cancer. The best spatial resolution obtained with the present lens at the time of the presentation made at the Medical Imaging Symposium 2001, was 6.7 mm FWHM for a 1-mm-diameter source. Since then it has been possible to improve the spacial resolution of the lens system to 3 mm FWHM. Experiments with the original lens system have led to a new design for a lens system that could have a spacial resolution of 1 mm FWHM. This is accomplished by: one, reducing the radial dimension of the crystals, and two, by replacing the small individual crystals with bent strips of single-crystalline material. Experiments are under way to test this approach.