gebhart/patrepeval huggingface dataset:
Infusion pharmacokinetics of Lipocurc™ (liposomal curcumin) and its metabolite tetrahydrocurcumin in Beagle dogs. (2012)

Curcumin's instability and its metabolite, tetrahydrocurcumin (THC) pose a major issue for the establishment of dependable pharmacokinetics and excretion profiles. Additional pharmacokinetic variances are associated with durations of intravenous infusions. We found that stabilizing curcumin with phosphoric acid allows accurate quantitative determinations of curcuminoids in the plasma and bile, by preventing degradation during the analytical processes. Two male and two females dogs were infused with Lipocurc™ 10 mg/kg over two hours, and another four dogs (two males and two females) were infused with Lipocurc™ 10 mg/kg over eight hours. Plasma levels of curcumin and THC were determined during the infusions and at necropsy. THC levels were 6.3-9.6-fold higher than curcumin during both infusion rates, suggesting a combination of a high-rate of enzymatic curcumin metabolism and a comparatively slower rate of blood THC clearance. When levels of curcumin and THC were compared during infusion durations, the two-hour infusion levels were significantly higher than the eight-hour infusion. The plasma half-lives of both compounds following the two-hour infusion ranged from 0.4-0.7 hours, and was a consequence of both hepatic and renal clearance However, at higher plasma concentrations renal excretion predominated, particularly with THC. Enhanced clearance rates were noted during eight-hour infusions, which prevented achieving a steady state. These observations suggest that for leukemias and lymphomas, the two-hour infusion may be advantageous based upon higher concentration profiles, and unstimulated clearance rates, however data on curcumin penetration into circulating hematopoietic cancer cells and efficacy data are required in order to confirm these suggestions.
Similar pattern of MCP‐1 expression in spinal cords and eyes of Lewis rats with experimental autoimmune encephalomyelitis associated anterior uveitis (1997)

Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine family responsible for the recruitment of T cells that have been found during inflammation of the spinal cord in experimental autoimmune encephalomyelitis (EAE) in Lewis rats immunized with myelin basic protein (MBP). Lewis rats injected with MBP also developed anterior uveitis (AU), which coincided with the onset of EAE. In the present studies, we examined the expression and distribution of MCP-1 in the eye and spinal cord during disease and compared it to the expression of Th1 cell type cytokines. Initially, MCP-1 expression was detected at the preclinical phase in the iris/ciliary body and lumbar spinal cord and increased during the course of EAE/AU. Mononuclear infiltrating cells and endothelial cells and astrocytes of the CNS could be identified as a source of MCP-1 by in situ hybridization. Kinetics of expression of Th1 characteristic cytokines such as IL-2 and IFNγ was in agreement with the expression of MCP-1 chemokine. Moreover, induction of the gene expression of MCP-1 seemed to occur earlier than that of MIP-2, and it correlated with increasing disease severity. MCP-1 seems to contribute to the initial recruitment of inflammatory cells into both the tissues of the eye and CNS over the course of disease. J. Neurosci. Res. 50:531–538, 1997. © 1997 Wiley-Liss, Inc.
Endothelin‐1 modulates vascular smooth muscle structure and vasomotion: Implications in cardiovascular pathology (1993)

Abstract Endothelin‐1 modulates vascular smooth muscle tone by exerting potent vasoconstrictor actions through the ET A receptor subtype located on the membranes of vascular smooth muscle cells. This receptor subtype also mediates the growth‐promoting actions of this peptide in vascular smooth muscle cells. The ET A receptor is distinct, however, from the endothelin receptor subtype located on the endothelium; the anatomically and functionally distinct ET B receptor mediates the release of the endothelium‐derived factor nitric oxide, a labile substance which not only produces potent vasodilation but also possesses anti‐mitogenic activity. This report describes the interaction between these two vasoactive factors in the control of cardiovascular function. Under normal conditions the endothelium serves to modulate the contractile and proliferative actions of endothelin‐1. However, many cardiovascular disorders (e.g., hypertension, atherosclerosis, vascular restenosis, subarachnoid hemorrhage, etc.) are associated with both abnormal endothelial cell function, resulting in an inability to synthesize and/or release nitric oxide, and elevated circulating levels of endothelin‐1. Since the resultant loss/inhibition of nitric oxide will augment both the contractile and proliferative actions of endothelin‐1, this has the potential to promote vasoconstriction and smooth muscle hyperplasia/hypertrophy at the site of any such lesion. Since evidence is accumulating that both endothelin‐1 and nitric oxide play pivotal roles in the control of both vascular smooth muscle tone and growth, any imbalance between these two counter‐regulatory systems is likely to have profound pathological consequences within the cardiovascular system. © 1993 Wiley‐Liss, Inc.
Genetic Patterns in Head and Neck Cancers That Contain or Lack Transcriptionally Active Human Papillomavirus (2004)

HNSCCs with transcriptionally active HPV16 DNA are characterized by occasional chromosomal loss, whereas HNSCCs lacking HPV DNA are characterized by gross deletions that involve whole or large parts of chromosomal arms and that already occur early in HNSCC development. These distinct patterns of genetic alterations suggest that HPV16 infection is an early event in HNSCC development.
Lipidic Supramolecular Assemblies for Gene Transfer (1996)

Intensive work in the last 6 years has demonstrated that first generation non-viral vectors (cationic liposomes and polylysine conjugates) are effective in gene transfer. However, these vectors are not suitable for intravenous administration; only poorly reproducible results were obtained. We discuss here all identified problems with these vectors and show that at least some of the problems can be solved by using polycation condensed DNA together with lipids. These novel supramolecular assemblies, LPD's, are about 50–100 fold more active in gene transfection than the first generation vectors. The structure and mode of action of the LPD's are also discussed.
DEB025 (Alisporivir) Inhibits Hepatitis C Virus Replication by Preventing a Cyclophilin A Induced Cis-Trans Isomerisation in Domain II of NS5A (2010)

DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. It is currently being evaluated in phase II clinical trials. DEB025 binds to CypA, a peptidyl-prolyl cis-trans isomerase which is a crucial cofactor for HCV replication. Here we report that it was very difficult to select resistant replicons (genotype 1b) to DEB025, requiring an average of 20 weeks (four independent experiments), compared to the typically <2 weeks with protease or polymerase inhibitors. This indicates a high genetic barrier to resistance for DEB025. Mutation D320E in NS5A was the only mutation consistently selected in the replicon genome. This mutation alone conferred a low-level (3.9-fold) resistance. Replacing the NS5A gene (but not the NS5B gene) from the wild type (WT) genome with the corresponding sequence from the DEB025(res) replicon resulted in transfer of resistance. Cross-resistance with cyclosporine A (CsA) was observed, whereas NS3 protease and NS5B polymerase inhibitors retained WT-activity against DEB025(res) replicons. Unlike WT, DEB025(res) replicon replicated efficiently in CypA knock down cells. However, DEB025 disrupted the interaction between CypA and NS5A regardless of whether the NS5A protein was derived from WT or DEB025(res) replicon. NMR titration experiments with peptides derived from the WT or the DEB025(res) domain II of NS5A corroborated this observation in a quantitative manner. Interestingly, comparative NMR studies on two 20-mer NS5A peptides that contain D320 or E320 revealed a shift in population between the major and minor conformers. These data suggest that D320E conferred low-level resistance to DEB025 probably by reducing the need for CypA-dependent isomerisation of NS5A. Prolonged DEB025 treatment and multiple genotypic changes may be necessary to generate significant resistance to DEB025, underlying the high barrier to resistance.
Multi-process constrained estimation (1991)

A method that maximizes the information flow through a constrained communications channel when it is desired to estimate the state of multiple nonstationary processes is described. The concept of a constrained channel is introduced as a channel that is not capable of transferring all of the information required. A measure of information is developed based on the estimation entropy utilizing the Kalman filter state estimator. It is shown that this measure of information can be used to determine which process to observe in order to maximize a measure of global information flow. For stationary processes, the sampling sequence can be computed a priori, but nonstationary processes require real-time sequence computation.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
The human preproinsulin gene: synthesis, cloning, gene modification, and expression studies (1984)

A 355 base pair (bp) DNA sequence coding for human preproinsulin has been assembled by joining a synthetic DNA leader sequence coding for 24 preregion amino acids to the previously synthesized DNA duplex of 277 bp constituting the sequence of BCA chain. It was next cloned in M13 mp8 single-stranded bacteriophage and subjected to site-specific mutagenesis and phase shifting to allow its inducible expression under lac operator control. An affinity leader sequence of 25 bp has been added in an attempt to facilitate purification of the preproinsulin.
Translation initiation in GB viruses A and C: evidence for internal ribosome entry and implications for genome organization (1996)

GB viruses A and C (GBV-A and GBV-C) are two recently described RNA viruses which appear to be members of the Flaviviridae. Although both viruses appear to contain long 5' nontranslated regions, the sites of polyprotein initiation and the presence of core-like proteins remain to be determined. Translation studies were undertaken to determine the mechanism and sites of polyprotein initiation in GBV-A and GBV-C. Rabbit reticulocyte lysates programmed with monocistronic RNAs containing 5' ends of GBV-A or GBV-C fused in-frame with the chloramphenicol acetyltransferase (CAT) open reading frame generated GBV-CAT fusion proteins in vitro. Site-specific mutagenesis and N-terminal sequencing located the sites of translation initiation immediately upstream of the putative signal sequence for the GBV E1 envelope glycoproteins. Efficient translation of the monocistronic GBV-CAT RNAs required the inclusion of GBV coding sequences. This, coupled with the presence of at least 523 nucleotides of 5' nontranslated RNA containing multiple AUG codons, suggests that translation initiation of these RNAs did not utilize a ribosome scanning mechanism. Translation of bicistronic RNAs containing 5' nontranslated sequences within the intercistronic space was consistent with the presence of a weakly active internal ribosome entry site in both GBV-A and GBV-C. Secondary structure predictions indicate that the 5' ends of these viruses assume similar complex structures distinct from those identified in the internal ribosome entry site-containing picornaviruses, pestiviruses, and hepatitis C viruses. The data indicate that GBV-A and GBV-C are unique members of the Flaviviridae that do not contain core-like proteins at the N termini of their putative polyproteins.
Characterization of rat CD80 and CD86 by molecular cloning and mAb (1997)

The CD28/B7 pathway provides a critical co-stimulatory signal for T cell activation. In the present study, we cloned rat CD80 and CD86 cDNA from a HTLV-1-transformed rat T cell line, Lewis-S1, expressing a high level of CTLA-4-Ig binding proteins. The predicted CD80 and CD86 polypeptides were composed of 321 and 313 amino acids respectively, and exhibited features common to human and mouse B7 family proteins. Both CD80 and CD86 mRNAs were abundantly detected in HTLV-1-transformed rat T cell lines but not in a thymic lymphoma cell line. To further explore the function of rat CD80 and CD86, we generated cDNA transfectants and anti-rat CD80 (3H5) and anti-rat CD86 (24F) mAb. Rat CD80 or CD86 transfectants exhibited a potent co-stimulatory activity for rat T cell proliferation, which was blocked by 3H5 and 24F mAb respectively. 3H5 or 24F immunoprecipitated a 80-90 or 90-100 kDa surface protein from Lewis-S1 cells. HTLV-1-transformed rat T cell lines expressed high levels of both CD80 and CD86 as estimated by staining with 3H5 and 24F, which acted co-stimulatory for allogeneic T cell activation as estimated by blocking with 3H5 and 24F. These mAb will be useful for investigating the pathophysiological functions of CD80 and CD86 in transplantation, autoimmune diseases and HTLV-1-associated pathologies in the rat system.
Stereoselective Synthesis and Antiviral Activity of d-2‘,3‘-Didehydro-2‘,3‘-dideoxy-2‘-fluoro-4‘-thionucleosides (2002)

As 2',3'-didehydro-2',3'-dideoxy-2'-fluoronucleosides have exhibited interesting antiviral effects against HIV-1 as well as HBV, it is of interest to synthesize the isosterically substituted 4'-thionucleosides in which 4'-oxygen is replaced by a sulfur atom. To study structure-activity relationships, various pyrimidine and purine nucleosides were synthesized from the key intermediate (2R,4S)-1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-beta-D-ribofuranoside 8, which was prepared from the 2,3-O-isopropylidene-D-glyceraldehyde 1 in 13 steps. The antiviral activity of the synthesized compounds were evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which cytidine 17, 5-fluorocytidine 18, adenosine 24, and 2-fluoroadenosine 32 showed moderate to potent anti-HIV activities (EC(50) 1.3, 11.6, 8.1, and 1.2 microM, respectively). It is noteworthy that 2-fluoroadenosine analogue 32 showed antiviral potency as well as high cytotoxicity (IC(50) 1.5, 1.1, and 7.6 microM for PBM, CEM, and Vero, respectively) whereas no other compound showed cytotoxicity up to 100 microM. The cytidine 17 and 5-fluorocytidine 18 analogues showed significantly decreased antiviral activity against the clinically important lamivudine-resistant variants (HIV-1(M184V)), whereas the corresponding D-2'-Fd4 nucleosides showed limited cross-resistance. Molecular modeling studies demonstrated that the larger van der Waals radius as well as the close proximity to Met184 of the 4'-sulfur atom of D-2'-F-4'-Sd4C (17) may be the reasons for the decreased antiviral potency of synthesized 4'-thio nucleosides against the lamivudine-resistant variants (HIV-1(M184V)).
Metal‐Chelate Affinity Chromatography (1996)

Recombinant proteins engineered to have six consecutive histidine residues on either the amino or carboxyl terminus can be purified using a resin containing nickel ions (Ni(2+)) that have been immobilized by covalently attached nitrilotriacetic acid (NTA). This technique, known as metal-chelate affinity chromatography (MCAC), can readily be performed with either native or denatured protein. This unit discusses techniques for creating a fusion protein consisting of the protein of interest with a histidine tail attached. A procedure for expression of histidine-tail fusion proteins and their purification in native form by MCAC is described, and two alternate protocols describe purification of histidine-tail fusion proteins by MCAC under denaturing conditions and their renaturation by either dialysis or solid-phase renaturation. Support protocols are provided for analysis of the purified product and regeneration of the NTA resin. All of these protocols are easily adaptable to any protein expression system.
The interface of atherosclerosis and thrombosis: basic mechanisms (1998)

Occlusive vascular disease most often results from thrombosis superimposed on atherosclerotic plaque. Disruption of plaque exposes thrombogenic substances within the plaque to blood and may result in thrombotic occlusion of the affected vessel. Mural thrombi may be incorporated into plaque, enhancing the evolution of atherosclerotic lesions. Inflammation plays a key role in the formation and complication of atherosclerosis. Inflammatory mediators regulate processes that determine the composition of the plaque's fibrous cap, a structure that separates blood from the thrombogenic lipid core. Several inflammatory mediators control the release of metalloproteinases (enzymes that break down cap constituents) from smooth muscle cells, macrophages and other cells within plaque. Inflammatory mediators also control the production of connective tissue matrix by cells in the plaque. Factors involved in coagulation, such as thrombin, can regulate non-thrombotic functions of vascular wall cells such as smooth muscle proliferation or cytokine release. The many mechanisms involved in arterial occlusive disease present numerous points at which intervention with pharmacologic agents may prove effective in lowering the risk of acute arterial thrombotic complications.
Sacral neuromodulation outcomes for the treatment of refractory idiopathic detrusor overactivity stratified by indication – lack of anticholinergic efficacy versus intolerability (2013)

Introduction: Patients may fail oral overactive bladder therapies due to either poor drug efficacy or intolerability. We determined if the success of sacral neuromodulation varies if performed secondary to lack of anticholinergic efficacy versus drug intolerability.Methods: A retrospective review was performed on 152 patients undergoing staged sacral neuromodulation from 2004 to 2010 for refractory idiopathic detrusor overactivity with or without urge incontinence. Outcomes following sacral neuromodulation trials were compared based on the primary indication for anticholinergic failure: lack of drug efficacy versus intolerable side effects.Results: Overall, successful sacral neuromodulation trials were reported in 70% (106/152) of patients. Successful outcomes were noted in 70% (89/128) and 71% (17/24) of patients with poor anticholinergic efficacy and drug intolerability, respectively (p = NS).Conclusions: We found no significant difference in outcome success in patients undergoing sacral neuromodulation trials for refractory detrusor overactivity due to lack of anticholinergic efficacy versus intolerability.
Functional Roles of the E3 Ubiquitin Ligase UBR5 in Cancer (2015)

The Ubiquitin-Proteasome System (UPS) is an important regulator of cell signaling and proteostasis, which are essential to a variety of cellular processes. The UPS is disrupted in many diseases including cancer, and targeting the UPS for cancer therapy is gaining wide interest. E3 ubiquitin ligases occupy a key position in the hierarchical UPS enzymatic cascade, largely responsible for determining substrate specificity and ubiquitin (Ub) chain topology. The E3 ligase UBR5 (aka EDD1) is emerging as a key regulator of the UPS in cancer and development. UBR5 expression is deregulated in many cancer types and UBR5 is frequently mutated in mantle cell lymphoma. UBR5 is highly conserved in metazoans, has unique structural features, and has been implicated in regulation of DNA damage response, metabolism, transcription, and apoptosis. Hence, UBR5 is a key regulator of cell signaling relevant to broad areas of cancer biology. However, the mechanism by which UBR5 may contribute to tumor initiation and progression remains poorly defined. This review synthesizes emerging insights from genetics, biochemistry, and cell biology to inform our understanding of UBR5 in cancer. These molecular insights indicate a role for UBR5 in integrating/coordinating various cellular signaling pathways. Finally, we discuss outstanding questions in UBR5 biology and highlight the need to systematically characterize substrates, and address limitations in current animal models, to better define the role of UBR5 in cancer.
Thermoelectric figure of merit of metal–semiconductor barrier structure based on energy relaxation length (1998)

The thermoelectric figure of merit is calculated for a compound material comprising thin semiconductor and wider metallic layers. The layers are perpendicular to the direction of current. The semiconductor barriers exclude electrons with energies ε&amp;lt;μ from the current. This exclusion increases thermopower. One may obtain a material with a very high ZT if the distance between the barriers is on the order of the energy relaxation length. This material should have the resistivity characteristic of a metal and the thermopower characteristic of a semiconductor. An additional significant rise in ZT can be achieved by increasing the contact area at the metal–semiconductor interface.
Characterization of Murine Sarcoma Virus Transformation of Guinea Pig Cells and Activation of an RNA Tumor-like Virus from Nonproducer Guinea Pig Cells (2015)

Guinea pig embryo (GEP) cells were transformed in vitro by the Kirsten strain of mouse sarcoma virus (Ki-MSV). The transformed cells were found to release infectious virus continuously and produced high titers of group-specific (gs) complement-fixing (CF) antigen characteristics of the murine sarcoma-leukemia virus complex. Foci of transformed cells were similar in appearance to those obtained with Ki-MSV in mouse and rat cells. The transformed cells produced RNA dependent DNA polymerase and type C virus particles with a density of approximately 1.15 g/ml in sucrose gradients by 3H-uridine labeling. The transformed cells produced tumors when transplanted into newborn guinea pigs. A number of focus-derived clonal lines from Ki-MSV transformed cells were isolated and characterized. All the focus-derived lines were found to be either producers or nonproducers (NP). The NP guinea pig cells produced neither infectious virus nor viral antigens of the murine sarcoma-leukemia virus complex although they were morphologically indistinguishable from virus-releasing MSV transformed GPE lines and produced tumors when transplanted into newborn guinea pigs. However, the sarcoma virus genome could be rescued in these NP cells by cocultivation with "helper" murine leukemia virus (MuLV) releasing GPE cells. Particles resembling guinea pig leukemia virus were activated from guinea pig NP cells or cultured normal guinea pig cells following chemical treatment. These particles were approximately 100 nm in the mature form and had a density of 1.16-1.17 g/ml. They contained RNA dependent DNA polymerase activity.
Regulatory B cells (2009)

B cells positively regulate immune responses through antibody production and optimal CD4(+) T cell activation. However, a specific and functionally important subset of B cells can also negatively regulate immune responses in mouse autoimmunity and inflammation models. The lack or loss of regulatory B cells has been demonstrated by exacerbated symptoms in experimental autoimmune encephalitis, chronic colitis, contact hypersensitivity, collagen-induced arthritis, and non-obese diabetic mouse models. We have recently found that IL-10-producing regulatory B cells predominantly localize within a rare CD1d(hi)CD5(+) B cell subset that shares cell surface markers with both B-1 and marginal zone B cells. We have labeled this specific subset of regulatory B cells as B10 cells to highlight that these rare CD1d(hi)CD5(+) B cells only produce IL-10 and are responsible for most IL-10 production by B cells, and to distinguish them from other regulatory B cell subsets that may also exist. This review focuses on the recent progress in this field and the exciting opportunities for understanding how this unique B cell subset influences diverse immune functions.