gebhart/patrepeval huggingface dataset:
Analysis of Sequences Required for the Cytotoxic Action of a Chimeric Toxin Composed of Pseudomonas Exotoxin and Transforming Growth Factor .alpha. (1994)

Chimeric toxins composed of transforming growth factor alpha fused to mutant forms of Pseudomonas exotoxin bind to the EGF receptor and kill cells bearing these receptors. In early experiments, the binding domain of Pseudomonas exotoxin was deleted and replaced with TGF alpha to make TGF alpha-PE40. This chimeric toxin required proteolytic processing within the target cell to be converted to its active form (Siegall et al. (1989) FASEB J. 3, 2647-2652). Subsequently, recombinant toxins that do not require proteolytic processing were constructed by inserting TGF alpha near the carboxyl terminus of domain III and deleting toxin residues up to the processing site at position 280. In addition, the carboxyl terminus of this toxin was converted from REDLK to KDEL to increase its activity. Recombinant toxins of this type, termed PE37/TGF alpha/KDEL, are about 100-fold more potent than TGF alpha-PE40. To determine if other sequences can be removed from such chimeric toxins to make a smaller molecule that can penetrate tissues better, we have carried out a deletion analysis of sequences present within domains II and Ib. We find that all of domain Ib and a portion of domain II can be deleted without significant loss of cytotoxic activity, but larger deletions extending further into domain II lose cytotoxic activity. We also find that inserting a small linking peptide (Gly)4Ser between residual sequences in domain II and domain III, in molecules with diminished cytotoxic activity, enhances cytotoxicity suggesting that one role of domain Ib is to prevent undesirable interactions between domains II and III.(ABSTRACT TRUNCATED AT 250 WORDS)
Spongelike Alginate Nanoparticles as a New Potential System for the Delivery of Antisense Oligonucleotides (1999)

The aim of this study was to design a new antisense oligonucleotide (ON) carrier system based on alginate nanoparticles and to investigate its ability to protect ON from degradation in the presence of serum. Pharmacokinetics and tissue distribution of ON-loaded nanoparticles have been determined after intravenous administration. An original and dynamic process for ON loading into polymeric nanoparticles has been applied. It is based on the diffusion of ON or ON/polylysine complex into the nanoparticle or the alginate gel, respectively. Indeed, the single coincubation of ON with nanoparticles led, within a few days, to an extremely efficient association. The diffusion kinetic of ON was shown to be dependent on several parameters, incubation temperature, ON concentration, presence or absence of polylysine, polylysine molecular weight, and nanoparticle preparation procedure. This new alginate-based system was found to be able to protect [33P]-radiolabeled ON from degradation in bovine serum medium and to modify their biodistribution, as an important accumulation of radioactivity was observed in the lungs, in the liver, and in the spleen after intravenous administration into mice. ON may be associated efficiently with calcium alginate in a colloidal state. Such nanosponges are promising carriers for specific delivery of ON to lungs, liver, and spleen.
Prediction of peptide affinity to HLA DRB1*0401. (1995)

A method to predict quantitatively peptide binding to HLA DRB1*0401 has been developed using a data set of the relative contributions of each of the naturally occurring amino acids in the context of a simplified peptide back-bone. The prediction assumed that the relative role of each of the peptide side chains could be treated independently and could be measured by assaying each of the 20 naturally occurring amino acids at the central 11 positions of a 13-residue peptide previously shown to contain the minimal requirements for high-affinity binding to HLA-DR proteins. The resultant database was shown to have predictive value when tested on a set of 13 unrelated peptides known to bind DRB1*0401 with a wide range of apparent affinity. The database was tested further by analyzing myelin basic protein. All 13 amino acid peptides containing a hydrophobic amino acid at the third position were synthesized and assayed for binding purified DRB1*0401. In every case, the measured affinity correlated with the predictive values within the experimental error of the assays. Finally, the ability to predict peptide binding to MHC class II molecules was shown to help in identifying T cell determinants. The specificity of DRB1*0401-restricted T cell hybridomas against human serum albumin corresponded to two peptides, predicted and shown to bind the class II protein with high affinity.
Drug release from glutaraldehyde-treated fibrin gels. (1990)

Glutaraldehyde treatment of dexamethasone-containing cylindrical fibrin gels (obtained by the thrombin-induced polymerization of fibrinogen in the presence of the drug) causes cross-linking of the gels and modification of the pore structure. The effect on the release of dexamethasone was assessed by measuring the diffusion coefficient of the drug across treated and untreated gels; diffusion across the treated gels was significantly decreased as compared with untreated gels, but was little affected by the concentration of glutaraldehyde used in the treatment. In biodegradable tests, the treated gels (all concentrations of glutaraldehyde) were resistant to digestion even in the presence of plasmin, but untreated gels were digested, and the digestion rate was accelerated by plasmin. The volume of the gels was progressively reduced as the concentration of glutaraldehyde was increased or the amount of fibrinogen was decreased, but the extent of the reduction did not correlate with the changes in the diffusion coefficient.
Endophthalmitis following intravitreal anti-vascular endothelial growth factor (VEGF) injection: a comprehensive review (2015)

The purpose of this review is to report and summarize previously reported studies and assess many of the individual steps of the intravitreal injection procedure's possible effect on the prevention of endophthalmitis. The pooled endophthalmitis rate from 20 large retrospective case series of anti-VEGF injections was 144/510,396 (0.028%; 1/3,544). Injections may be performed in an office-based location or in an operating room (OR) and low rates of endophthalmitis can be achieved in either location with careful attention to asepsis. Pre- or post-injection topical antibiotics have not been shown to be effective, and could select for more virulent microorganisms. Povidone-iodine prior to injection is accepted as the gold-standard antiseptic agent, but <i>aqueous</i> chlorhexidine may be an alternative. Antisepsis before and after gel or subconjunctival anesthetic is suggested. The preponderance of Streptococcal infections after intravitreal injection is discussed, including the possible role of aerosolization, which can be minimized by using face masks or maintaining silence. As with other invasive procedures in medicine, the use of sterile gloves, following adequate hand antisepsis, may be considered. Control of the eyelashes and lid margin is required to avoid contamination of the needle, but this can be achieved with or without a speculum. Techniques to minimize vitreous reflux have not been shown to reduce the risk of endophthalmitis. Same day bilateral injections should be performed as two separate procedures, preferably using drug from different lots, especially when using compounded drugs.
Abamectin as a pesticide for agricultural use. (1990)

The avermectins are a family of macrocyclic lactones, produced by the soil organism Streptomyces avermitilis, which were discovered in the mid-1970's as a direct result of a screening effort for natural products with anthelmintic properties. Avermectin B1 (abamectin), the major component of the fermentation, also showed potent activity against arthropods in preliminary laboratory evaluations and was subsequently selected for development to control phytophagous mites and insect pests on a variety of agricultural and horticultural crops worldwide. Major applications for which abamectin is currently registered include uses on ornamental plants, citrus, cotton, pears and vegetable crops at rates in the range of 5 to 27 grams abamectin per hectare as a foliar spray. Abamectin has shown low toxicity to non-target beneficial arthropods which has accelerated its acceptance into Integrated Pest Management (IPM) programs. Extensive studies have been conducted to support the safety of agricultural uses of abamectin to man and the environment. Abamectin is highly unstable to light and has been shown to photodegrade rapidly on plant and soil surfaces and in water following agricultural applications. Abamectin was also found to be degraded readily by soil microorganisms. Abamectin residues in or on crops are very low, typically less than 0.025 ppm, resulting in minimal exposure to man from harvesting or consumption of treated crops. In addition, abamectin does not persist or accumulate in the environment. Its instability as well as its low water solubility and tight binding to soil, limit abamectin's bioavailability in non-target organisms and, furthermore, prevent it from leaching into groundwater or entering the aquatic environment.
Study of clinical course of organ dysfunction in intensive care (2004)

Multiple organ dysfunction, does not follow a course of progressive and sequential failure. Evidence of differential daily change should further inform the use of organ failure scores as surrogate outcomes in clinical trials.
Measuring Charge Transport from Transient Photovoltage Rise Times. A New Tool To Investigate Electron Transport in Nanoparticle Films (2006)

Charge transport rate at open-circuit potential (V(oc)) is proposed as a new characterization method for dye-sensitized (DS) and other nanostructured solar cells. At V(oc), charge density is flat and measurable, which simplifies quantitative comparison of transport and charge density. Transport measured at V(oc) also allows meaningful comparison of charge transport rates between different treatments, temperatures, and types of cells. However, in typical DS cells, charge transport rates at V(oc) often cannot be measured by photocurrent transients or modulation techniques due to RC limitations and/or recombination losses. To circumvent this limitation, we show that charge transport at V(oc) can be determined directly from the transient photovoltage rise time using a simple, zero-free-parameter model. This method is not sensitive to RC limitation or recombination losses. In trap limited devices, such as DS cells, the comparison of transport rates between different devices or conditions is only valid when the Fermi level in the limiting conductor is at the same distance from the band edge. We show how to perform such comparisons, correcting for conduction band shifts using the density of states (DOS) distribution determined from the same photovoltage transients. Last we show that the relationship between measured transport rate and measured charge density is consistent with the trap limited transport model.
All-atom empirical force field for nucleic acids: I. Parameter optimization based on small molecule and condensed phase macromolecular target data (2000)

Empirical force-field calculations on biological molecules represent an effective method to obtain atomic detail information on the relationship of their structure to their function. Results from those calculations depend on the quality of the force field. In this manuscript, optimization of the CHARMM27 all-atom empirical force field for nucleic acids is presented together with the resulting parameters. The optimization procedure is based on the reproduction of small molecule target data from both experimental and quantum mechanical studies and condensed phase structural properties of DNA and RNA. Via an iterative approach, the parameters were primarily optimized to reproduce macromolecular target data while maximizing agreement with small molecule target data. This approach is expected to ensure that the different contributions from the individual moieties in the nucleic acids are properly balanced to yield condensed phase properties of DNA and RNA, which are consistent with experiment. The quality of the presented force field in reproducing both crystal and solution properties are detailed in the present and an accompanying manuscript (MacKerell and Banavali, J Comput Chem, this issue). The resultant parameters represent the latest step in the continued development of the CHARMM all-atom biomolecular force field for proteins, lipids, and nucleic acids. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 86–104, 2000
How Many Attempts Are Required to Accomplish Out‐of‐hospital Endotracheal Intubation? (2006)

Out-of-hospital rescuers often require multiple attempts to accomplish ETI. A protocol limit of three attempts offers reasonable opportunity for accomplishing ETI within the constraints of the out-of-hospital environment.
Differential Ligand Activation of Estrogen Receptors ERα and ERβ at AP1 Sites (1997)

The transactivation properties of the two estrogen receptors, ERalpha and ERbeta, were examined with different ligands in the context of an estrogen response element and an AP1 element. ERalpha and ERbeta were shown to signal in opposite ways when complexed with the natural hormone estradiol from an AP1 site: with ERalpha, 17beta-estradiol activated transcription, whereas with ERbeta, 17beta-estradiol inhibited transcription. Moreover, the antiestrogens tamoxifen, raloxifene, and Imperial Chemical Industries 164384 were potent transcriptional activators with ERbeta at an AP1 site. Thus, the two ERs signal in different ways depending on ligand and response element. This suggests that ERalpha and ERbeta may play different roles in gene regulation.
Hedgehog Signaling and Bmi-1 Regulate Self-renewal of Normal and Malignant Human Mammary Stem Cells (2006)

The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny may be targets for transformation. We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells. We show that hedgehog signaling components PTCH1, Gli1, and Gli2 are highly expressed in normal human mammary stem/progenitor cells cultured as mammospheres and that these genes are down-regulated when cells are induced to differentiate. Activation of hedgehog signaling increases mammosphere-initiating cell number and mammosphere size, whereas inhibition of the pathway results in a reduction of these effects. These effects are mediated by the polycomb gene Bmi-1. Overexpression of Gli2 in mammosphere-initiating cells results in the production of ductal hyperplasia, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. Furthermore, we show that the hedgehog signaling pathway is activated in human breast "cancer stem cells" characterized as CD44+CD24-/lowLin-. These studies support a cancer stem cell model in which the hedgehog pathway and Bmi-1 play important roles in regulating self-renewal of normal and tumorigenic human mammary stem cells.
S-Phase arrest by nucleoside analogues and abrogation of survival without cell cycle progression by 7-hydroxystaurosporine. (2001)

The mechanisms of resistance to nucleoside analogues established in preclinical models are rarely found in primary tumors resistant to therapy with these agents. We tested the hypothesis that cells sense sublethal incorporation of analogues into DNA during replication and react by arresting further DNA synthesis and cell cycle progression. After removal of drug, cells may be able to repair damaged DNA and continue proliferation, thus escaping nucleoside analogue toxicity. As a corollary, we evaluated whether dysregulation of this mechanism causes cell death. Using gemcitabine as a model of S-phase-specific nucleoside analogues in human acute myelogenous leukemia ML-1 cells, we found that DNA synthesis decreased, cells arrested in S-phase transit, and 60-70% of the population accumulated in S-phase in response to cytostatic conditions. Proliferation continued after washing the cells into drug-free medium. S-phase-arrested cells were then treated with otherwise nontoxic concentrations of UCN-01, which caused rapid onset of apoptosis without cell cycle progression specifically in cells with an S-phase DNA content. Thus, S-phase arrest by nucleoside analogues sensitizes cells to UCN-01, which appears to activate signaling for death mechanisms and/or inhibit survival pathways. These results differ from those in cells arrested at the G2 checkpoint, in which UCN-01 abrogates cell cycle arrest, permitting cells to progress in the cell cycle before apoptosis.
Identifying Strategies for Immune Intervention (1993)

In recent years the molecular basis of antigen recognition by T cells has been unraveled and the various pathways that control T cell activation and functional specialization have been defined. Consequently, it is now possible to delineate various strategies for intervention with the immune system to design protective vaccines, to induce an effective response to tumor antigens, and to control graft rejection and autoimmune diseases.
The genetics of tasting in mice: III. Quinine (1984)

SUMMARY Twenty-nine strains of mice were tested for their ability to taste a 0·8 mM solution of quinine sulphate. There were large strain differences, some strains (tasters) showing a strong aversion to the quinine and other strains (non-tasters) showing very little aversion. It was shown that the difference between strains 129/Sv and A2G is probably due to one gene. By using the CXB RI strains it was also shown that the difference between C57BL/6By and BALB/cBy is probably due to one gene. It is suggested that both differences may be due to the same gene, named Qui . In the progeny of a backcross involving both Soa and Qui there was evidence of an interaction between the genes which cannot be explained satisfactorily. Learning behaviour by the mice influenced their drinking habits, but this did not invalidate the results.
Use of the ARPE-19 cell line as a model of RPE polarity: basolateral secretion of FGF5. (1998)

ARPE-19 cells exhibit a polarized distribution of cell surface markers when examined by either confocal microscopy or surface-labeling assays. This indicates that the ARPE-19 cell line is a valid model for studies of RPE cell polarity. FGF5, a secreted protein normally produced by RPE cells, is accumulated preferentially in the basal media after only 6 hours, suggesting that it is vectorially secreted from the basolateral surface of ARPE-19 cells.
Cold atmospheric plasma modified nanocomposite cartilage scaffold (2014)

Articular cartilage connects diarthrodial joints, lubricates surface between bones, transfers and withstands repetitive load over the lifetime, which is prone to degeneration by various diseases, trauma and injuries. Once degeneration takes place, the avascular structure of human cartilage makes the self-healing extremely challenging. Therefore, the main objective of this study is to fabricate a biomimetic nanostructured cartilage scaffold by electrospinning and cold atmospheric plasma (CAP) techniques. Particularly, CAP is an ionized gas with various electrons, positive/negative ions, and excited molecules. It was utilized to create a more biomimetic and biocompatible surface of the electrospun nanocomposite cartilage scaffold. For this purpose, a polycaprolactone scaffold with randomly distributed microfibers was electrospun. Poly(lactic-co-glycolic) acid (PLGA) was employed to fabricate bovine serum albumin (BSA) loaded nanospheres using a water/oil/water double emulsion solvent extraction method and deposited into electrospun fiber mat. The nanocomposite scaffolds were further modified using CAP for 0, 1, 3, and 5 min. Scanning electron microscopy results illustrated the electrospun fibers had uniform diameter distribution and nanospheres were homogenously embedded inside the scaffold. The human bone marrow mesenchymal stem cell (MSC) experiments showed that the cartilage scaffold with BSA loaded PLGA nanospheres can sustainably improve MSC growth after 7 days. Furthermore, CAP modified nanocomposite scaffolds had enhanced cell proliferation after 5 days culture. It is ascribed to both the improvement of hydrophilicity and adhesion-mediating proteins adsorption (vitronectin) on CAP modified scaffolds. The enhanced stem cell response rendered by CAP treatment and nanospheres makes our scaffold promising for improved cartilage regeneration.
Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K) (2016)

We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).
Cognate interactions between helper T cells and B cells. V. Reconstitution of T helper cell function using purified plasma membranes from activated Th1 and Th2 T helper cells and lymphokines (1991)

Th physically interact with B cells and produce lymphokines that influence B cell growth and differentiation. The respective contribution of cell contact and lymphokines to induction of B cell growth and differentiation was addressed using purified plasma membranes (PM) from resting Th (PMrest) and anti-CD3-activated Th (PMCD3) together with lymphokines. Results show that PMCD3, but not PMrest, induce 10% of resting B cells to enter the G1 phase of the cell cycle, with few B cells entering G1b and S/G2. The inclusion of IL-4, but not IL-2, IL-5, or IFN-gamma, amplifies the B cell response to PMCD3 by increasing the total percentage of activatable B cells to greater than 40% and inducing B cell progression into G1b, S, and G2. Direct comparison between PMrest and PMCD3 purified from Th1 and Th2 indicate that both Th1 and Th2 induce similar levels of B cell proliferation in the presence of IL-4. Further, the lymphokine requirements for B cell proliferation induced by PMCD3 from Th1 and Th2 is indistinguishable. B cell differentiation to IgM, IgG1, and IgG2a synthesis by PMCD3 required IL-4 and IL-5. Using lymphokine conditions that supported B cell differentiation, PMCD3 purified from Th1 and Th2 induced similar levels of IgM, and IgG1. Given the functional data on PMCD3 from Th1 and Th2, the data indicate that there are no substantive differences between Th1- and Th2-derived PMCD3, and that the major differences in the ability of viable Th1 and Th2 to activate B cells is the lymphokines produced by the cells.