gebhart/patrepeval huggingface dataset:
Induction of Th17 Cells in the Tumor Microenvironment Improves Survival in a Murine Model of Pancreatic Cancer (2010)

Abstract An important mechanism by which pancreatic cancer avoids antitumor immunity is by recruiting regulatory T cells (Tregs) to the tumor microenvironment. Recent studies suggest that suppressor Tregs and effector Th17 cells share a common lineage and differentiate based on the presence of certain cytokines in the microenvironment. Because IL-6 in the presence of TGF-β has been shown to inhibit Treg development and induce Th17 cells, we hypothesized that altering the tumor cytokine environment could induce Th17 and reverse tumor-associated immune suppression. Pan02 murine pancreatic tumor cells that secrete TGF-β were transduced with the gene encoding IL-6. C57BL/6 mice were injected s.c. with wild-type (WT), empty vector (EV), or IL-6–transduced Pan02 cells (IL-6 Pan02) to investigate the impact of IL-6 secretion in the tumor microenvironment. Mice bearing IL-6 Pan02 tumors demonstrated significant delay in tumor growth and better overall median survival compared with mice bearing WT or EV Pan02 tumors. Immunohistochemical analysis demonstrated an increase in Th17 cells (CD4+IL-23R+ cells and CD4+IL-17+ cells) in tumors of the IL-6 Pan02 group compared with WT or EV Pan02 tumors. The upregulation of IL-17–secreting CD4+ tumor-infiltrating lymphocytes was substantiated at the cellular level by flow cytometry and ELISPOT assay and mRNA level for retinoic acid-related orphan receptor γt and IL-23R by RT-PCR. Thus, the addition of IL-6 to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer. The delayed tumor growth and improved survival suggests that induction of Th17 in the tumor microenvironment produces an antitumor effect.
Clinical Progress in Gene Therapy: Sustained Partial Correction of the Bleeding Disorder in Patients Suffering from Severe Hemophilia B (2011)

SCOPUS: no.j
What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? (2014)

The author considers hypothetical comparisons between oral conjugated equine estrogens and transdermal estradiol and between oral medroxyprogesterone acetate and oral micronized progesterone for their effects on four primary outcomes of the Women's Health Initiative (WHI): cardiovascular disease risk, cerebrovascular disease risk, venous thromboembolism risk, and breast cancer risk. Although the discussion in this article focuses on transdermal estradiol delivered through patches, gels, or lotions, it could be broadened to include all forms of nonoral estrogen administration. After a brief review of the WHI and a survey of the relevant literature in which the safety of these various hormone therapies is assessed or compared, the author uses statistical methods to ascertain the attributable risk of venous thromboembolism for transdermal estradiol versus oral hormone therapy and imputes those risks into the WHI primary outcomes.
A Gateway Cloning Vector Set for High-Throughput Functional Analysis of Genes in Planta (2003)

The current challenge, now that two plant genomes have been sequenced, is to assign a function to the increasing number of predicted genes. In Arabidopsis, approximately 55% of genes can be assigned a putative function, however, less than 8% of these have been assigned a function by direct experimental evidence. To identify these functions, many genes will have to undergo comprehensive analyses, which will include the production of chimeric transgenes for constitutive or inducible ectopic expression, for antisense or dominant negative expression, for subcellular localization studies, for promoter analysis, and for gene complementation studies. The production of such transgenes is often hampered by laborious conventional cloning technology that relies on restriction digestion and ligation. With the aim of providing tools for high throughput gene analysis, we have produced a Gateway-compatible Agrobacterium sp. binary vector system that facilitates fast and reliable DNA cloning. This collection of vectors is freely available, for noncommercial purposes, and can be used for the ectopic expression of genes either constitutively or inducibly. The vectors can be used for the expression of protein fusions to the Aequorea victoria green fluorescent protein and to the beta-glucuronidase protein so that the subcellular localization of a protein can be identified. They can also be used to generate promoter-reporter constructs and to facilitate efficient cloning of genomic DNA fragments for complementation experiments. All vectors were derived from pCambia T-DNA cloning vectors, with the exception of a chemically inducible vector, for Agrobacterium sp.-mediated transformation of a wide range of plant species.
Apomixis: Molecular Strategies for the Generation of Genetically Identical Seeds without Fertilization (1995)

Sexual reproduction in flowering plants (angiosperms) generates genetically diverse progeny because of the recombination and independent assortment of genes derived from both parents. For commercial agriculture, plants have been selected from the plethora of evolved flowering plant species, and wild species continue to be used as sources of genes in breeding and molecular crop improvement programs. Although we seek and value the diversity in the plant kingdom for use in agricultural breeding programs, once a suitable plant is bred, modern agriculture is dependent on uniformity of seed and vegetable and fruit quality. This demand for product consistency in plantations of often nongenetically uniform populations is clearly at odds with the sexual reproductive mechanisms that have evolved to maximize genetic diversity. Our reliance on sexual reproduction in agricultural systems also presents vulnerabilities associated with fertilization mechanisms. If agricultural production is pollination dependent, anthers can be sensitive to environmental conditions such as temperature and crop sprays that may inhibit either pollen formation or pollination, thus preventing development of fruit and seed. Fertilization is problematic if flowers are self-incompatible or if plants have single-sex flowers, since there is a dependence on the simultaneous flowering of a compatible variety and on pollinator behavior mechanisms that are in turn influenced by environmental conditions and farm design. Thus, if crops could be produced independent of pollination and fertilization, these problems could be avoided, leading to more control in the consistency of crop yield. Clonal reproduction through seed, independent of fertilization, is not fanciful in plants. Some angiosperms commonly reproduce in this manner by a process called apomixis. The purpose of this review is to briefly describe apomictic development, argue for the use of apomixis in agricultural production, consider the genetic basis of apomixis, and discuss molecular approaches that may lead to the isolation of genes controlling apomixis to lock this process into elite production lines of agriculturally important crops.
Bactericidal activity of human lysozymes carrying various lengths of polyproline chain at the C‐terminus (1997)

The amphiphilic polypeptide polyproline having different chain lengths was connected to the C-terminus of human lysozyme by the recombinant DNA technique. The hydrophobicity of human lysozyme increased with increasing length of the polyproline chain. Although the bactericidal activity of wild-type lysozyme is limited to gram-positive bacteria and the hydrolytic activity of the mutant lysozyme decreased with increasing chain length of polyproline, the mutant lysozymes showed bactericidal activity to gram-negative bacteria and the activity increased with increasing hydrophobicity of the mutant enzyme. Experiments with Escherichia coli phospholipid liposomes revealed that the mutant human lysozymes dissipated the valinomycin-induced transmembrane electrochemical potential, and the dissipation increased with increasing hydrophobicity. The increased hydrophobicity of the mutant enzyme may induce interaction of lysozyme with the outer membrane and subsequent penetration into the inner membrane of E. coli, resulting in an increase of bactericidal activity.
The Elastase-PK101 Structure: Mechanism of an Ultrasensitive Activity-based Probe Revealed (2015)

Human neutrophil elastase (HNE) plays a central role in neutrophil host defense, but its broad specificity makes HNE a difficult target for both inhibitor and probe development. Recently, we identified the unnatural amino acid containing activity-based probe PK101, which exhibits astounding sensitivity and selectivity for HNE, yet completely lacks mechanistic explanation for its unique characteristics. Here, we present the crystal structure of the HNE-PK101 complex which not only reveals the basis for PK101 ultrasensitivity but also uncovers so far unrecognized HNE features. Strikingly, the Nle(O-Bzl) function in the P4 position of PK101 reveals and leverages an "exo-pocket" on HNE as a critical factor for selectivity. Furthermore, the PK101 P3 position harbors a methionine dioxide function, which mimics a post-translationally oxidized methionine residue and forms a critical hydrogen bond to the backbone amide of Gly219 of HNE. Gly219 resides in a Gly-Gly motif that is unique to HNE, yet compulsory for this interaction. Consequently, this feature enables HNE to accommodate substrates that have undergone methionine oxidation, which constitutes a hallmark post-translational modification of neutrophil signaling.
MicroRNA Expression Patterns to Differentiate Pancreatic Adenocarcinoma From Normal Pancreas and Chronic Pancreatitis (2007)

Pancreatic cancer may have a distinct miRNA expression pattern that may differentiate it from normal pancreas and chronic pancreatitis. miRNA expression patterns may be able to distinguish between long- and short-term survivors, but these findings need to be validated in other study populations.
Towards a new “stromal-based” classification system for human breast cancer prognosis and therapy (2009)

Here, we discuss recent evidence that an absence of stromal Cav-1 expression in human breast cancers is a powerful single independent predictor of early disease recurrence, metastasis and poor clinical outcome. These findings have now been validated in two independent patient populations. Importantly, the predictive value of stromal Cav-1 is independent of epithelial marker status, making stromal Cav-1 a new "universal" or "widely-applicable" breast cancer prognostic marker. We propose based on the expression of stromal Cav-1, that breast cancer patients could be stratified into high-risk and low-risk groups. High-risk patients showing an absence of stromal Cav-1 should be offered more aggressive therapies, such as anti-angiogenic approaches, in addition to the standard therapy regimens. Mechanistically, loss of stromal Cav-1 is a surrogate biomarker for increased cell cycle progression, growth factor secretion, "stemness", and angiogenic potential in the tumor microenvironment. Since almost all cancers develop within the context of a stromal microenvironment, this new stromal classification system may be broadly applicable to other epithelial and non-epithelial cancer subtypes, as well as "pre-malignant" lesions (carcinoma in situ).
Sequence-specific recognition of double helical nucleic acids by proteins. (1976)

The base pairs in double helical nucleic acids have been compared to see how they can be recognized by proteins. We conclude that a single hydrogen bond is inadequate for uniquely identifying any particular base pair, as this leads to numerous degeneracies. However, using two hydrogen bonds, fidelity of base pair recognition may be achieved. We propose specific amino-acid side chain interactions involving two hydrogen bonds as a component of the recognition system for base pairs. In the major groove we suggest that asparagine or glutamine binds to adenine of the base pair or arginine binds to guanine. In the minor groove, we suggest an interaction between asparagine or glutamine with guanine of the base pair. We also discuss the role that ions and other amino-acid side chains may play in recognition interactions.
Analysis of national pay-as-you-drive insurance systems and other variable driving charges (1995)

Under Pay as You Drive insurance (PAYD), drivers would pay part of their automobile insurance premium as a per-gallon surcharge every time they filled their gas tank. By transfering a portion of the cost of owning a vehicle from a fixed cost to a variable cost, PAYD would discourage driving. PAYD has been proposed recently in California as a means of reforming how auto insurance is provided. PAYD proponents claim that, by forcing drivers to purchase at least part of their insurance every time they refuel their car, PAYD would reduce or eliminate the need for uninsured motorist coverage. Some versions of PAYD proposed in California have been combined with a no-fault insurance system, with the intention of further reducing premiums for the average driver. Other states have proposed PAYD systems that would base insurance premiums on annual miles driven. In this report we discuss some of the qualitative issues surrounding adoption of PAYD and other policies that would convert other fixed costs of driving (vehicle registration, safety/emission control system inspection, and driver license renewal) to variable costs. We examine the effects of these policies on two sets of objectives: objectives related to auto insurance reform, and those related to reducing fuel consumption, CO{sub 2} emissions, and vehicle miles traveled. We pay particular attention to the first objective, insurance reform, since this has generated the most interest in PAYD to date, at least at the state level.
Ajulemic Acid, a Synthetic Nonpsychoactive Cannabinoid Acid, Bound to the Ligand Binding Domain of the Human Peroxisome Proliferator-activated Receptor γ (2007)

Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype gamma of the peroxisome proliferator-activated receptor (PPARgamma) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-A resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.
In vivo bioluminescence: A cellular reporter for research and industry (1990)

The detection of specific bacterial pathogens, indicator microorganisms and antimicrobial substances, and the recovery of microorganisms from sub-lethal injury, are all aspects of importance to industry which are currently being targeted using in vivo bioluminescence. In all instances, a key requirement for the application of bioluminescence is the establishment of a strict correlation between in vivo bioluminescence and cell viability, as determined by colony counting on agar plates. Comparative studies for biocides (phenol, chlorhexidine diacetate, phenol thioether), for a virucide (hypochlorite) and for cellular recovery of S. typhimurium from sub-lethal injury, all indicate that such a correlation is valid. Furthermore, real-time measurements of in vivo bioluminescence reveal a major population of bacterial cells that retain functional intracellular biochemistry, but are defective in their ability to replicate post of freeze injury.
Effect of Vinylene Carbonate Additive in Li-Ion Batteries: Comparison of LiCoO[sub 2]∕C, LiFePO[sub 4]∕C, and LiCoO[sub 2]∕Li[sub 4]Ti[sub 5]O[sub 12] Systems (2009)

International audience
Inhibition of Matrix Metalloproteinases Prevents Allergen-Induced Airway Inflammation in a Murine Model of Asthma (1999)

Although matrix metalloproteinases (MMPs) have been reported to play crucial roles in the migration of inflammatory cells through basement membrane components in vitro, the role of MMPs in the in vivo accumulation of the cells to the site of inflammation in bronchial asthma is still obscure. In this study, we investigated the role of MMPs in the pathogenesis of bronchial asthma, using a murine model of allergic asthma. In this model, we observed the increase of the release of MMP-2 and MMP-9 in bronchoalveolar lavage fluids after Ag inhalation in the mice sensitized with OVA, which was accompanied by the infiltration of lymphocytes and eosinophils. Administration of tissue inhibitor of metalloproteinase-2 to airways inhibited the Ag-induced infiltration of lymphocytes and eosinophils to airway wall and lumen, reduced Ag-induced airway hyperresponsiveness, and increased the numbers of eosinophils and lymphocytes in peripheral blood. The inhibition of cellular infiltration to airway lumen was observed also with tissue inhibitor of metalloproteinase-1 and a synthetic matrix metalloproteinase inhibitor. These data suggest that MMPs, especially MMP-2 and MMP-9, are crucial for the infiltration of inflammatory cells and the induction of airway hyperresponsiveness, which are pathophysiologic features of bronchial asthma, and further raise the possibility of the inhibition of MMPs as a therapeutic strategy of bronchial asthma.
Identification of B-cell lymphoma subsets by plasma protein profiling using recombinant antibody microarrays (2014)

B-cell lymphoma (BCL) heterogeneity represents a key issue, often making the classification and clinical management of these patients challenging. In this pilot study, we outlined the first resolved view of BCL disease heterogeneity on the protein level by deciphering disease-associated plasma biomarkers, specific for chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, using recombinant antibody microarrays targeting mainly immunoregulatory proteins. The results showed the BCLs to be heterogeneous, and revealed potential novel subgroups of each BCL. In the case of diffuse large B-cell lymphoma, we also indicated a link between the novel subgroups and survival.
Novel NFAT Sites That Mediate Activation of the Interleukin-2 Promoter in Response to T-Cell Receptor Stimulation (1995)

The transcription factors NFAT and AP-1 have been shown to be essential for inducible interleukin-2 (IL-2) expression in activated T cells. NFAT has been previously reported to bind to two sites in the IL-2 promoter: in association with AP-1 at the distal antigen response element at -280 and at -135. On the basis of DNase I footprinting with recombinant NFAT and AP-1 proteins, gel shift assays, and transfection experiments, we have identified three additional NFAT sites in the IL-2 promoter. Strikingly, all five NFAT sites are essential for the full induction of promoter activity in response to T-cell receptor stimulation. Four of the five NFAT sites are part of composite elements able to bind AP-1 in association with NFAT. These sites display a diverse range of cooperativity and interdependency on NFAT and AP-1 proteins for binding. One of the NFAT sites directly overlaps the CD28-responsive element. We present evidence that CD28 inducibility is conferred by the AP-1 component in NFAT-AP-1 composite elements. These findings provide further insight into the mechanisms involved in the regulation of the IL-2 promoter.
Monitoring the pH-Dependent Oximation of Methyl Ethyl Ketone and Benzaldehyde by in situ Fourier Transform IR Spectroscopy in a Heterogeneous Liquid–Liquid Two-Phase System (2009)

ABSTRACT In situ Fourier transform IR spectroscopy was a useful tool in monitoring the pH-dependent and two-step oximation of methyl ethyl ketone and benzaldehyde in a liquid–liquid two-phase system, one phase of which was water. Carrying out the oximations at pH 8, the oximation was complete within 45 min and the corresponding carbonyl compound–hydroxylamine adduct (2) could be detected as an intermediate, but at pH 10, the corresponding oxime (3) was formed faster, practically without the appearance of the intermediate. At pH ∼ 2.5 using methyl ethyl ketone, the protonated form of the corresponding oxime (3'a) developed gradually without the transient appearance of the intermediate (2). pH dependence of the 3a → 3'a and 3'a → 3a interconversions were studied in separate experiments.
Selenite is a substrate for calf thymus thioredoxin reductase and thioredoxin and elicits a large non‐stoichiometric oxidation of NADPH in the presence of oxygen (1992)

The thioredoxin system, comprising NADPH, thioredoxin reductase and thioredoxin reduces protein disulfides via redox-active dithiols. We have discovered that sodium selenite is a substrate for the thioredoxin system; 10 microM selenite plus 0.05 microM calf thymus thioredoxin reductase at pH 7.5 caused a non-stoichiometric oxidation of NADPH (100 microM after 30 min). In contrast, thioredoxin reductase from Escherichia coli showed no direct reaction with selenite, but addition of 3 microM E. coli thioredoxin also resulted in non-stoichiometric oxidation of NADPH, consistent with oxidation of the two active-site thiol groups in thioredoxin to a disulfide. Kinetically, the reaction was complex with a lag phase at low selenite concentrations. Under anaerobic conditions the reaction stopped after 1 mol selenite had oxidized 3 mol NADPH; the admission of air then resulted in continued consumption of NADPH consistent with autooxidation of selenium intermediate(s). Ferricytochrome c was effectively reduced by calf thymus thioredoxin reductase and selenite in the presence of oxygen. Selenite caused a strong dose-dependent inhibition of the formation of thiol groups from insulin disulfides with either the E. coli or calf-thymus thioredoxin system. Thus, under aerobic conditions selenite catalyzed, NADPH-dependent redox cycling with oxygen, a large oxygen-dependent consumption of NADPH and oxidation of reduced thioredoxin inhibiting its disulfide-reductase activity.