gebhart/patrepeval huggingface dataset:
High-Speed and High-Resolution UPLC Separation at Zero Degrees Celsius (2008)

The conformational properties of proteins can be probed with hydrogen/deuterium exchange mass spectrometry (HXMS). In order to maintain the deuterium label during LC/MS analyses, chromatographic separation must be done rapidly (usually in under 8-10 min) and at 0 degrees C. Traditional RP-HPLC with approximately 3-mum particles has shown generally poor chromatographic performance under these conditions and thereby has been prohibitive for HXMS analyses of larger proteins and many protein complexes. Ultraperformance liquid chromatography (UPLC) employs particles smaller than 2 mum in diameter to achieve superior resolution, speed, and sensitivity as compared to HPLC. UPLC has previously been shown to be compatible with the fast separation and low temperature requirements of HXMS. Here we present construction and validation of a custom UPLC system for HXMS. The system is based on the Waters nanoACQUITY platform and contains a Peltier-cooled module that houses the injection and switching valves, online pepsin digestion column, and C-18 analytical separation column. Single proteins in excess of 95 kDa and a four-protein mixture in excess of 250 kDa have been used to validate the performance of this new system. Near-baseline resolution was achieved in 6-min separations at 0 degrees C and displayed a median chromatographic peak width of approximately 2.7 s at half-height. Deuterium recovery was similar to that obtained using a conventional HPLC and ice bath. This new system represents a significant advancement in HXMS technology that is expected to make the technique more accessible and mainstream in the near future.
Variable optical attenuator based on polymer stabilized twisted nematic liquid crystal (2004)

A variable optical attenuator (VOA) based on polymer stabilized twisted nematic (PSTN) liquid crystal (LC) is demonstrated. Comparing with the normal twisted nematic LC-based VOA, PSTN exhibits a much faster response time. Moreover, the polymer networks effectively eliminate the backflow effect which exists in the normal TNLC cell. The attenuation mechanism of the PSTN LC was studied. Both polarization rotation and light scattering effects are found to contribute to the optical attenuation. The ratio between these two mechanisms can be adjusted by changing the polymer concentration and polymer network domain size.
Intrinsic B-cell hyporesponsiveness accounts for self-tolerance in lysozyme/anti-lysozyme double-transgenic mice. (1990)

In double-transgenic mice expressing a gene construct encoding hen egg lysozyme as well as rearranged anti-lysozyme antibody genes, large numbers of anti-lysozyme B cells are present in peripheral lymphoid tissues but are profoundly tolerant. The cellular basis for this form of non-deletional self-tolerance was explored. The tolerant anti-lysozyme B cells from double-transgenic mice were found to produce much less antibody than nontransgenic controls in T-cell-dependent antigen-specific responses, in adoptive transfer in vivo, and in hanging-drop cultures in vitro, as well as in response to stimulation with the nonspecific mitogen lipopolysaccharide. The diminished responsiveness of the tolerant B cells was not due to a reduction in the number of responding B-cell precursors per se nor were suppressor cells detected in titration, depletion, or mixing experiments. Nondeletional tolerance in this model, therefore, appears to result from an intrinsic functional change in the self-reactive B cells themselves.
Health Effects of Probiotics on the Skin (2013)

Skin is the largest organ of the body and is constantly exposed to physical, chemical, bacterial, and fungal challenges. It is well known that probiotics are helpful for specific disorders and different clinical studies have indicated that probiotics have special effects in cutaneous apparatus directly or indirectly that can be considerable from versatile aspects. Probiotic bacteriotherapy can have great potential in preventing and treating the skin diseases including eczema, atopic dermatitis, acne, and allergic inflammation or in skin hypersensitivity, UV-induced skin damage, wound protection, and as a cosmetic product. The current paper comprehensively reviews the different health effects of probiotics on the skin.
Giant magnetoresistance of nanowires of multilayers (1994)

A new technique is required which enables tailoring of the morphology of a metallic nanostructured material down to the 10 nm length scale. Using nanoporous nuclear track etched membranes as templates for electrodeposition, an assembly of wires with diameters as low as 30 nm could be obtained. Alternating the electrodeposition of two metals resulted in multilayers grown perpendicular to the wire axis. Layer thicknesses as low as 2 nm could be reached. Application is demonstrated by making wires 6 μm long, 80 nm in diameter, having a succession of either Co and Cu layers or of (Ni,Fe) and Cu layers. Wires containing layers of 5–10 nm in thickness exhibited a giant magnetoresistance. The current was naturally perpendicular to the layers. At ambient temperature, a magnetoresistance of 14% for Co/Cu and of 10% for (Fe,Ni)/Cu was observed.
Pharmacology of Cloned P2X Receptors (2000)

There are seven P2X receptor cDNAs currently known. Six homomeric (P2X1, P2X2, P2X3, P2X4, P2X5, P2X7) and three heteromeric (P2X2/P2X3, P2X4/P2X6, P2X1/P2X5) P2X receptor channels have been characterized in heterologous expression systems. Homomeric P2X1 and P2X3 receptors are readily distinguishable by their rapid desensitization, the agonist action of alpha beta methyleneATP, and the block by 2',3'-O-(2,4,6-trinitrophenyl)-ATP. P2X2 receptors are unique among homomeric forms in their potentiation by low pH. Homomeric P2X4 receptors are much less sensitive to antagonism by suramin and pyridoxal 5-phosphate-6-azo-2',4'-disulfonic acid. Homomeric P2X7 receptors are the only form in which 2',3'-O-(4-benzoylbenzoyl)-ATP is more potent than ATP. The heteromeric P2X2/P2X3 receptor resembles P2X2 in slow desensitization kinetics and potentiation by low pH and is similar to P2X3 with respect to agonism by alpha beta methyleneATP and block by 2',3'-O-(2,4,6-trinitrophenyl)-ATP. Other agonists, antagonists, and ions that can be used to differentiate among the receptors are discussed.
Effects of memantine on synaptic transmission in the hippocampus in vitro. (1995)

CA1 pyramidal cell response (population spike) in the hippocampal slice preparation was monitored after electrical stimulation of the Schaffer collaterals at CA2 in the presence of different concentrations of memantine (1-amino-3,5-dimethyladamantane, Akatinol Memantine, CAS 41100-52-1) currently being prescribed for the treatment of e.g. dementia. Memantine increased the amplitude of the population spike by 100% compared to the predrug level with an EC50 of approximately 8 mumol/l. Long-term potentiation induced by a brief theta stimulus was likewise increased by a factor of 2. The concentration dependent action of D-serine, an agonist acting at the strychnine insensitive glycine-site of the NMDA (N-methyl-d-aspartic acid) receptor was enhanced in the presence of 1 mumol/l of memantine. These effects of memantine were antagonized completely by very low concentrations of the selective non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzoe (F) quinoxyline) as well as by less selective antagonists such as DNQX (6,7-dinitroquinoxaline-2,3-dione) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione). In contrast, dizocilpine tested under identical conditions and in concordance with the literature decreased long-term potentiation. Thus, memantine clearly has different effects on glutamatergic synaptic transmission compared to dizocilpine. The ability of memantine to enhance synaptic transmission in the hippocampus is in concordance with the reported positive influence on cognition deficits in humans.
Learning from hotlists and coldlists: towards a WWW information filtering and seeking agent (1995)

We describe a software agent that learns to find information on the World Wide Web (WWW), deciding what new pages might interest a user. The agent maintains a separate hotlist (for links that were interesting) and coldlist (for links that were not interesting) for each topic. By analyzing the information immediately accessible from each link, the agent learns the types of information the user is interested in. This can be used to inform the user when a new interesting page becomes available or to order the user's exploration of unseen existing links so that the more promising ones are investigated first. We compare four different learning algorithms on this task. We describe an experiment in which a simple Bayesian classifier acquires a user profile that agrees with a user's judgment over 90% of the time.
Role of Toll‐like receptors in costimulating cytotoxic T cell responses (2003)

Stimulation of Toll-like receptors (TLR) by pathogen-derived compounds leads to activation of APC, facilitating the induction of protective immunity. This phenomenon is the basis of most adjuvant formulations currently in development. Here, we tested the ability of TLR2, 3, 4, 5, 7 and 9 signaling to enhance CTL responses upon vaccination with virus-like particles. Stimulation of TLR2 and 4 failed to increase CTL responses, whereas ligands for TLR3, 5 and 7 exhibited moderate adjuvant function. In contrast, stimulation of TLR9 dramatically increased CTL responses, indicating that ligands for TLR9 are likely to be the most promising candidates for the development of novel adjuvant formulations for stimulating CTL responses.
The activin-binding protein follistatin regulates autocrine endothelial cell activity and induces angiogenesis. (1997)

Increasing evidence suggests that autocrine endothelial cell activity contributes significantly to the angiogenic cascade once the endothelial cells are initially activated by exogenous stimuli. We have employed the differential RNA-display technique to identify endothelial cell genes that are expressed under autocrine control as a result of the cells' release from growth arrest. Among the differentially expressed genes was the activin-binding and- neutralizing glycoprotein follistatin (FS), which was expressed by migrating endothelial cells and down-regulated once the cells had reached growth arrest. Cytokine exposure identified FS as a basic fibroblast growth factor (bFGF)-inducible gene. In contrast, activin-beta A, an inhibitor of endothelial cell proliferation, was constitutively expressed by migrating and resting endothelial cells. Exogenous recombinant FS induced proliferation of human umbilical vein endothelial cells and low bFGF-expressing bovine aortic endothelial cells. In vivo, FS was moderately angiogenic in the rabbit cornea. However, FS implantation in the cornea in combination with subcritical concentrations of bFGF induced a strong angiogenic response. The data demonstrate that FS by itself and particularly in synergy with bFGF induces angiogenesis. Furthermore, differential expression by endothelial cells suggests a critical role of the FS/activin-beta A system in regulating autocrine endothelial cell activity.
The Vascular Disrupting Agent, DMXAA, Directly Activates Dendritic Cells through a MyD88-Independent Mechanism and Generates Antitumor Cytotoxic T Lymphocytes (2007)

5,6-Di-methylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity. Although classified as a "vascular disrupting agent," we have recently conducted studies showing that DMXAA has remarkable efficacy in a range of tumors, working primarily as an immune modulator that activates tumor-associated macrophages and induces a subsequent CD8(+) T-cell-mediated response. To more completely analyze the effect of DMXAA on CD8(+) T-cell generation, we treated mice bearing tumors derived from EG7 thymoma cells that express the well-characterized chicken ovalbumin neotumor antigen. Treatment with DMXAA led to cytokine release, tumor cell necrosis, and ultimately reduction in tumor size that was lymphocyte dependent. Within 24 h of administration, we observed dendritic cell activation in tumor-draining lymph nodes (TDLN). This was followed by a rapid and marked increase in the number of tetramer-specific CD8(+) T cells in the spleens of treated animals. In contrast, the vascular disrupting agent combretastatin A4-phosphate, which caused a similar amount of immediate tumor necrosis, did not activate dendritic cells, nor induce an effective antitumor response. Using in vitro systems, we made the observation that DMXAA has the ability to directly activate mouse dendritic cells, as measured by increased expression of costimulatory molecules and proinflammatory cytokine release via a pathway that does not require the Toll-like receptor adaptor molecule MyD88. DMXAA thus has the ability to activate tumor-specific CD8(+) T cells through multiple pathways that include induction of tumor cell death, release of stimulatory cytokines, and direct activation of dendritic cells.
Lentiviral and Murine Retroviral Transduction of T Cells for Expression of Human CD40 Ligand (2000)

Efficient transduction of primary human T cells is an important goal toward treating a number of genetic defects. Patient T cells could be harvested by leukapheresis, transduced, and returned to the donor. A wide range of secreted or cell surface therapeutic proteins may be delivered in this way. The ability to produce antibodies is the consequence of interactions between T cells and B cells and lack of expression of CD40 ligand (CD40L) on T cells causes X-linked hyper-IgM syndrome (XHIM). We are investigating delivery of a normal CD40 ligand to treat this disorder. We tested promoters driving the expression of either reporter genes such as enhanced green fluorescent protein (eGFP) or human CDC40L. Using murine retroviruses, the best able to drive gene expression in T cells was the cytomegalovirus (CMV) promoter enhancer element; however, transduction efficiency was low. To achieve efficient, high-level gene expression we tested lentiviral gene delivery vectors. At a low multiplicity of infection (MOI) (0.5-2) a large fraction of target cells was transduced by lentiviral vectors (40-93%), and the strength of gene expression was high, as determined by flow cytometric analysis. We monitored the expression of eGFP or human CD40L on T cell lines and untransformed primary human T cells from normal and CD40L-deficient patients. We achieved efficient gene expression without an extended exposure to virus, and without the need for selection. These results are encouraging for efficient lentivirus-mediated transduction of refractory human cells to achieve therapeutic gene delivery.
Discovery of (10 R )-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations (2014)

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.
Aging-related gene signature regulated by Nlrp3 predicts glioma progression. (2015)

Aging is the strongest risk factor for glioma development, suggesting that molecular crosstalks between aging and tumorigenesis exist in many cellular pathways. Recently, Nlrp3 inflammasome have been shown to modulate several major cellular pathways such as inflammation and cell death and have been demonstrated to be an upstream target that controlled the process of brain aging. We proposed Nlrp3 inflammasome may serve as a possible molecular link between aging and glioma progression. In this study, we generated a aging-related gene signature that regulated by Nlrp3 in mouse hippocampus and demonstrated that this gene signature can distinguish subsets of glioma samples and predicts clinical outcome in radiotherapy-treated patients. In addition, using U87 and GL261 xenograft mouse glioblastoma model, we found that Nlrp3 inflammasome contributed to radiotherapy resistance in glioma. Ionizing radiation can induce Nlrp3 inflammasome expression; Nlrp3 inhibition reduced tumor growth and prolonged the survival of mouse following IR treatment; Nlrp3 inhibition reduced number of senescent cells induced by IR. These results above suggest that Nlrp3 inflammasome is an important molecular link between brain aging and glioma progression; the Nlrp3 gene signature may serve as a predictive biomarker for glioma patients.
Generation of tumor-specific T-lymphocytes by cross-priming with human dendritic cells ingesting apoptotic tumor cells. (2000)

It has been suggested that dendritic cells (DCs) are capable of ingesting apoptotic tumor cells (ATCs) and presenting tumor-associated antigens to immune cells. We evaluated the potential of human DCs, which have ingested ATCs, to serve as a source of antigenic epitopes for presentation to T cells specific for PCI-13, a squamous cell carcinoma of the head and neck cell line. Immature DCs (DCimm) generated in the presence of interleukin 4 and granulocyte machrophage colony-stimulating factor from peripheral blood monocytes of HLA-A2+ healthy donors were incubated in the presence of ATCs. Uptake of ATCs by DCs was monitored by flow cytometry and confocal microscopy after 2-18 h of coincubation. When DCs were matured (DCmat) in the presence of proinflammatory cytokines, their capacity to uptake ATCs was reduced. Responses of PCI-13-specific CD8+ T cells to unmodified PCI-13 cells and to DCimm or DCmat +/- ATCs or +/- tumor lysates were tested in gamma-IFN enzyme-linked immunospot and cytotoxicity assays. Unmodified tumor cells were found to be the best stimulators of antitumor activity of the established T-cell line, and ATCs alone were minimally stimulatory. However, DCs that ingested ATCs were able to present tumor antigens to CTLs, and DCimm and DCmat were almost equally stimulatory. When DCs plus various tumor-derived preparations were used as antigen-presenting cells with autologous HLA-A2+ T cells obtained from normal donors, DCs that had ingested ATCs were more effective in generating CD8+ CTLs than tumor cells alone or DCs pulsed with tumor lysates. The results indicate that human DCs fed with ATCs and then matured effectively generated T cell-mediated antitumor responses in vitro.
Living cationic polymerization of 4-tert-butoxystyrene and synthesis of poly(4-vinylphenol) with narrow molecular weight distribution (1989)

Cationic polymerization of 4-tert-butoxystyrene (1) initiated by hydrogen iodide/zinc iodide (HI/ZnI2) led to well-defined living polymers at temperatures up to +25°C in either toluene or methylene chloride, the latter containing a small amount of tetrabutylammonium iodide (mole ratio nBu4NI/HI = 1/100). The number-average molecular weight of the polymers increased in direct proportion to the monomer conversion, and the linear increase further continued upon addition of a second feed of 1 to the completely polymerized reaction mixture. Both before and after the monomer addition, the molecular weight distributions of the products were invariably very narrow (M̄w/M̄n ≤ 1,1). In the polymerization in salt-free methylene chloride, in contrast, the polymers showed broader molecular weight distributions, particularly at low conversions, and thus the presence of the ammonium salt proved mandatory for attaining living polymerization in this polar solvent. By treatment with hydrobromic acid the HI/ZnI2-initiated poly(1) could readily be converted into poly(4-vinylphenol) (3) that inherited the narrow molecular weight distribution and controlled molecular weight of the precursor.
Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma (2011)

Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.
Paying for health. (1991)

Health care systems, irrespective of how they are financed, present the paradox that to some observers they appear as a major component of social benefits, while to other observers they seem both excessively costly and limited in their effectiveness. These differing perceptions may be explained in part by the diversity of the determinants of health and disease, only some of which are amenable to those preventive or therapeutic measures encompassed in a health care system--the majority of determinants being genetic, societal, or else uninfluenced by those interventions at present available within a health service. The share of national resources which should be devoted to health care, and the method of raising resources, are primarily matters for political decision; but a national system has advantages both of economy and of comprehensiveness. But when it comes to allocation of resources within the established health budget, the knowledge and skills of health professionals are essential to informed decision-making. The possibilities depend critically on the 'state of the art' at a given time, as is illustrated by the radical changes over time in what could be done for patients with renal failure; and health professionals are likely to be most aware of current options, and of how to choose between them. More speculatively, they are also less likely to confuse the attitudes appropriate to providing a service with those required to run a business.