gebhart/patrepeval huggingface dataset:
Selective Expansion of Cross-Reactive Cd8+ Memory T Cells by Viral Variants (1999)

The role of memory T cells during the immune response against random antigenic variants has not been resolved. Here, we show by simultaneous staining with two tetrameric major histocompatibility complex (MHC)-peptide molecules, that the polyclonal CD8(+) T cell response against a series of natural variants of the influenza A nucleoprotein epitope is completely dominated by infrequent cross-reactive T cells that expand from an original memory population. Based on both biochemical and functional criteria, these cross-reactive cytotoxic T cells productively recognize both the parental and the mutant epitope in vitro and in vivo. These results provide direct evidence that the repertoire of antigen-specific T cells used during an infection critically depends on prior antigen encounters, and indicate that polyclonal memory T cell populations can provide protection against a range of antigenic variants.
Atrial fibrillation ablation. (2005)

Radiofrequency catheter ablation is currently used widely and successfully to treat a variety of arrhythmias, and ablation for atrial fibrillation represents the frontier of arrhythmia research. Development in many areas will offer to the electrophysiologic community a more rational and effective background upon which select patients for ablation and identify the optimal ablative strategy. Among mechanisms recognized for having a role in atrial fibrillation stay pulmonary vein focal triggers, rotor at the pulmonary vein-left atrial junction, a critical mass to sustain fibrillatory conduction and vagal ganglia. The latter represents the frontier of research as with new technologies based on magnetic resonance imaging they could be easily and specifically identified and targeted for ablation. It is fundamental that both CARTO and NavX systems are currently investigating integration with magnetic resonance imaging to reconstruct the left atrium. Furthermore a learning curve effect can be abated with the use of new systems for the remote control of the catheter such as stereotaxis. In the last decade, we empirically devised a technique that is both safe and effective for curing atrial fibrillation. Briefly, using a three-dimensional mapping system, either CARTO or NavX system, we reconstruct the left atrium and the pulmonary ostia; thereafter circumferential ablation lines are normally created starting at the lateral mitral annulus and withdrawing posterior then anterior to the left-sided pulmonary veins, passing between the left superior pulmonary vein and the left atrial appendage before completing the circumferential line on the posterior wall of the left atrium. The right pulmonary veins are isolated in a similar fashion, and then a posterior line connecting the two circumferential lines on the roof is performed to reduce the risk of macroreentrant atrial tachycardias. The endpoint for circumferential ablation is a > 70-90% reduction in voltage within the isolated regions. In this article we sought to describe critical methodological aspects of our techniques along with future implementation with new technologies and to summarize our published clinical experience on the most prestigious journals.
Estimation of Action Potential Changes from Field Potential Recordings in Multicellular Mouse Cardiac Myocyte Cultures (2003)

The characterization of the FP allows us for the first time to estimate AP changes and the contribution of individual current components to the AP by the help of non-invasive recording within a multicellular cardiac preparation during long-term culture.
Inactivation of suppressor T-cell activity by nontoxic monophosphoryl lipid A (1988)

Treatment with nontoxic monophosphoryl lipid A (MPL), which was derived from a polysaccharide-deficient, heptoseless Re mutant of Salmonella typhimurium, was found to inactivate suppressor T-cell activity, as evidenced by a decrease in the degree of low-dose immunological paralysis expressed and an increase in the magnitude of the antibody response to type III pneumococcal polysaccharide. The effects produced, which could not be attributed to the polyclonal activation of immune B cells by MPL, were dependent upon the dose of MPL used, as well as the time when MPL was given relative to low-dose priming or immunization with type III pneumococcal polysaccharide. Neither amplifier nor helper T-cell activity was decreased by treatment with the same, or larger, doses of MPL. The significance of these findings to the use of MPL as an immunological adjuvant or an immunomodulating agent is discussed.
New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis (2012)

Metabolic bone disorders arise as primary diseases or may be secondary due to a multitude of organ malfunctions. Animal models are required to understand the molecular mechanisms responsible for the imbalances of bone metabolism in disturbed bone mineralization diseases. Here we present the isolation of mutant mouse models for metabolic bone diseases by phenotyping blood parameters that target bone turnover within the large-scale genome-wide Munich ENU Mutagenesis Project. A screening panel of three clinical parameters, also commonly used as biochemical markers in patients with metabolic bone diseases, was chosen. Total alkaline phosphatase activity and total calcium and inorganic phosphate levels in plasma samples of F1 offspring produced from ENU-mutagenized C3HeB/FeJ male mice were measured. Screening of 9,540 mice led to the identification of 257 phenodeviants of which 190 were tested by genetic confirmation crosses. Seventy-one new dominant mutant lines showing alterations of at least one of the biochemical parameters of interest were confirmed. Fifteen mutations among three genes (Phex, Casr, and Alpl) have been identified by positional-candidate gene approaches and one mutation of the Asgr1 gene, which was identified by next-generation sequencing. All new mutant mouse lines are offered as a resource for the scientific community.
Microwave tomography: theoretical and experimental investigation of the iteration reconstruction algorithm (1998)

Results of experiments on the two-dimensional (2-D) quasi real-time microwave tomographic system have been reported. Various reconstruction possibilities of this system have been demonstrated on phantoms and canine hearts. The early utilized Rytov approximation is appropriate for low-contrast inverse problems. A new iterative reconstruction algorithm is proposed in this paper. The iterations converge to an accurate solution of the scalar Helmholtz-equation inverse problem in the case of higher contrasts. The goal of the reported study is an experimental and theoretical investigation of the proposed iteration algorithm. The influence on the quality of the reconstructed images and on the spatial resolution of such factors as the number of receivers, the accuracy of the scattered field measurements, and the dielectric contrast have been investigated.
Invariant Chain and the MHC Class II Cytoplasmic Domains Regulate Localization of MHC Class II Molecules to Lipid Rafts in Tumor Cell-Based Vaccines (2004)

Cell-based tumor vaccines, consisting of MHC class I+ tumor cells engineered to express MHC class II molecules, stimulate tumor-specific CD4+ T cells to mediate rejection of established, poorly immunogenic tumors. Previous experiments have demonstrated that these vaccines induce immunity by functioning as APCs for endogenously synthesized, tumor-encoded Ags. However, coexpression of the MHC class II accessory molecule invariant chain (Ii), or deletion of the MHC class II cytoplasmic domain abrogates vaccine immunogenicity. Recent reports have highlighted the role of lipid microdomains in Ag presentation. To determine whether Ii expression and/or truncation of MHC class II molecules impact vaccine efficacy by altering MHC class II localization to lipid microdomains, we examined the lipid raft affinity of MHC class II molecules in mouse M12.C3 B cell lymphomas and SaI/A(k) sarcoma vaccine cells. Functional MHC class II heterodimers were detected in lipid rafts of both cell types. Interestingly, expression of Ii in M12.C3 cells or SaI/A(k) cells blocked the MHC class II interactions with cell surface lipid rafts. In both cell types, truncation of either the alpha- or beta-chain decreased the affinity of class II molecules for lipid rafts. Simultaneous deletion of both cytoplasmic domains further reduced localization of class II molecules to lipid rafts. Collectively, these data suggest that coexpression of Ii or deletion of the cytoplasmic domains of MHC class II molecules may reduce vaccine efficacy by blocking the constitutive association of MHC class II molecules with plasma membrane lipid rafts.
Adverse effects and other safety aspects of the hepatitis C antivirals (2000)

The preferred treatment for patients with chronic hepatitis C, either treatment-naive, relapsers or nonresponders to IFN monotherapy, is now IFN-ribavirin combination treatment. The adverse effects of IFN are well established and familiar to hepatologists all over the world. More than 25,000 patients worldwide have been treated with combination therapy. Patients re-treated with a combination regimen are more likely to tolerate IFN better than treatment-naive patients, probably due to better case selection. The safety profile of regimens containing IFN-alpha plus ribavirin is generally consistent with the safety profile of each agent when employed in monotherapy; there is little or no synergistic toxicity. Anorexia, dyspnoea, cough, pruritus and rash are the only adverse events reported at a consistently higher frequency with combination treatment, and are usually mild to moderate in severity and rarely result in dose reductions or discontinuation. The primary cause of dose reduction for combination therapy is haemolytic anaemia, which can be managed effectively. The most common reason for discontinuation of therapy for either type of therapy is psychiatric problems, especially depression, which seems to be closely related to the duration of treatment. In patients receiving combination therapy, anaemia and depression need close monitoring, and dose modification in some cases. Strict guidelines for dose reduction and discontinuation are essential to prevent serious adverse events. Because of the teratogenic risk from ribavirin, pregnancy is contraindicated in patients or their partners during and 6 months after treatment.
Observation of a single-beam gradient-force optical trap for dielectric particles in air (1997)

A single-beam gradient-force optical trap for dielectric particles, which relies solely on the radiation pressure force of a TEM(00)-mode laser light, is demonstrated in air for what is believed to be the first time. It was observed that micrometer-sized glass spheres with a refractive index of n=1.45 remained trapped in the focus region for more than 30 min, and we could transfer them three dimensionally by moving the beam focus and the microscope stage. A laser power of ~40 mW was sufficient to trap a 5- microm -diameter glass sphere. The present method has several distinct advantages over the conventional optical levitation method.
Memory effect in filled nematic liquid crystals (1997)

Abstract The irreversible electro-optical response (memory effect) of 'liquid crystal-aerosil' suspensions under the influence of an electric field is investigated. Thereby, the influence of the aerosil concentration on the efficiency of the memory effect is studied. The experimental results are discussed in the frame of a model where the filled nematic is considered as a system of aerosil agglomerates in a liquid crystal matrix stabilized by the forces of liquid crystal orientational elasticity.
MICA/NKG2D-mediated immunogene therapy of experimental gliomas. (2003)

The failure of conventional cancer therapy renders glioblastoma an attractive target for immunotherapy. Tumor cells expressing ligands of the activating immunoreceptor NKG2D stimulate tumor immunity mediated by natural killer (NK), gammadelta T, and CD8(+) T cells. We report that human glioma cells express the NKG2D ligands MICA, MICB, and members of the UL16-binding protein family constitutively. However, glioma cells resist NK cell cytolysis because of high MHC class I antigen expression. Plasmid-mediated or adenovirus-mediated overexpression of MICA in glioma cells enhances their sensitivity to NK and T-cell responses in vitro and markedly delays the growth of s.c. and intracerebral LN-229 human glioma cell xenografts in nude mice and of SMA-560 gliomas in syngeneic VMDk mice. Glioma cells forming progressive tumors after implantation of stably MICA-transfected human LN-229 cells lost MICA expression, indicating a strong selection against MICA expression in vivo. Rejection of MICA-expressing SMA-560 cells in VMDk mice resulted in protective immunity to a subsequent challenge with wild-type tumor cells. Finally, the growth of syngeneic intracerebral SMA-560 tumors is inhibited by peripheral vaccination with adenovirus-mediated, MICA-infected irradiated tumor cells, and vaccination results in immune cell activation in the NK and T-cell compartments in vivo. These data commend MICA immunogene therapy as a novel experimental treatment for human malignant gliomas.
PII-60Pharmacokinetics ABS pharmacodynamics of BIWH 3 in healthy Duffy antigen positive and Duffy antigen negative male volunteers (2006)

BACKGROUND/AIMS BIWH 3 is a recombinant pyro-glu monocyte chemotactic protein-1 (MCP-1). Based on arteriogenic effects of MCP-1 in animals, MCP-1 was developed for critical limb ischemia. This study investigated safety, tolerability, and PK of BIWH 3 after single 1-hr iv infusions of 20 ng/kg −; 2 μg/kg in healthy males. Since the Duffy Antigen Receptor of Chemokines might be an important scavenger of MCP-1, BIWH 3 PK was assessed in Duffy positive and negative subjects. METHODS This was a randomized double-blind dose escalation study. 3 Duffy positive subjects each were enrolled at 20 and 60 ng/kg doses (2:1 active:placebo). At higher doses, 5 Duffy positive and 5 Duffy negative subjects were enrolled at each dose (4:1 active:placebo). Safety and tolerance were assessed for each dose. Plasma samples were collected for PK analysis and for PD of markers of leukocyte, coagulation, platelet and endothelial activation. RESULTS MCP-1 concentrations increased in a dose-proportional manner, and were rapidly cleared with a half-life of 0.4–0.5 h. There were no PK differences between Duffy negative and positive subjects. There was no consistent relationship of any PD markers to the PK of BIWH 3, except for the PD of MCP-1 induced monocytosis. CONCLUSIONS BIWH 3 was well tolerated by the study subjects in single iv infusions up to 20 μg/kg. Exposure was dose proportional, and didn't change with Duffy antigen status. PK-PD data were in line with the chemoattracting actions of BIWH 3 on monocytes in vitro and in animal studies. Clinical Pharmacology & Therapeutics (2005) 79, P52–P52; doi: 10.1016/j.clpt.2005.12.185
Modeling of the wideband indoor radio channel for geolocation applications in residential areas (2003)

The wideband indoor radio channel has been characterized at a variety of center frequencies and building architectures for the purpose of evaluating the performance of communications systems. Emerging position location applications, both civilian and military, require information relevant to evaluate the performance of geolocation receivers that is significantly different from the information used for communications applications. In this paper, the differences in radio channel modeling for communications and geolocation applications are elaborated. Characterization of the radio channel for geolocation purposes is examined. The results of modeling for geolocation undertaken at four different radio frequencies in a residential area based on enhancements to the JTC model using radio channel measurements are presented.
DVD authoring (2003)

Got ideas for TV-based information design, games and Easter eggs? Make them work on DVDs you create with this versatile software.
Identification of Immune Factors Regulating Antitumor Immunity Using Polymeric Vaccines with Multiple Adjuvants (2014)

The innate cellular and molecular components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. In this study, we used polymeric cancer vaccines incorporating different classes of adjuvants to induce tumor protection, to identify dendritic cell (DC) subsets and cytokines critical to this efficacy. Three-dimensional, porous polymer matrices loaded with tumor lysates and presenting distinct combinations of granulocyte macrophage colony-stimulating factor (GM-CSF) and various Toll-like receptor (TLR) agonists affected 70% to 90% prophylactic tumor protection in B16-F10 melanoma models. In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I:C) or CpG-ODN induced the complete regression of solid tumors (≤40 mm(2)), resulting in 33% long-term survival. Regression analysis revealed that the numbers of vaccine-resident CD8(+) DCs, plasmacytoid DCs (pDC), along with local interleukin (IL)-12, and granulocyte colony-stimulating factor (G-CSF) concentrations correlated strongly to vaccine efficacy regardless of adjuvant type. Furthermore, vaccine studies in Batf3(-/-) mice revealed that CD8(+) DCs are required to affect tumor protection, as vaccines in these mice were deficient in cytotoxic T lymphocytes priming and IL-12 induction in comparison with wild-type. These studies broadly demonstrate that three-dimensional polymeric vaccines provide a potent platform for prophylactic and therapeutic protection, and can be used as a tool to identify critical components of a desired immune response. Specifically, these results suggest that CD8(+) DCs, pDCs, IL-12, and G-CSF play important roles in priming effective antitumor responses with these vaccines.
Controlling an "irrational system" (1989)

As a pediatrician caring for children from low-income families, am delighted that the AAP has designated access to health care for all children and pregnant women as its top priority. However, Iam dismayed that the AAP9s president, Donald Schiff, M.D., appears to reject the possibility of a universal, comprehensive solution to the access problem for our country. In his call for the removal of barriers to child health care (February 1989 AAP News), Dr. Schiff states: I don9t mean establishing a mandated, monolithic, Washington-directed health plan for our children such as National Health Insurance. As our escalating health care crisis has shown us, nothing short of a comprehensive solution is likely to solve either the access problem or to effectively control costs.
Direct Vpr-Vpr Interaction in Cells monitored by two Photon Fluorescence Correlation Spectroscopy and Fluorescence Lifetime Imaging (2008)

We report that Vpr oligomerization in HeLa cells relies on the hydrophobic core formed by the three alpha helices. This oligomerization is required for Vpr localization at the nuclear envelope but not for Vpr-mediated apoptosis.
Hydrogen-Bonding: An update (2003)

This article focusses on the crystallographic research aimed at a better understanding of hydrogen bonds which has been published since January 1990. In the interest of continuity, earlier work is quoted when it relates to that published during this period.
PRECLINICAL EVALUATION AND INTRAOPERATIVE HUMAN RETINAL IMAGING WITH A HIGH-RESOLUTION MICROSCOPE-INTEGRATED SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY DEVICE (2013)

This report describes high-resolution MIOCT imaging using the prototype device in human eyes during vitreoretinal surgery, with successful achievement of predefined end points for imaging. Further refinements and investigations will be directed toward fully integrating MIOCT with vitreoretinal and other ocular surgery to image surgical maneuvers in real time.
The transcriptional co-activator LEDGF/p75 displays a dynamic scan-and-lock mechanism for chromatin tethering (2010)

Nearly all cellular and disease related functions of the transcriptional co-activator lens epithelium-derived growth factor (LEDGF/p75) involve tethering of interaction partners to chromatin via its conserved integrase binding domain (IBD), but little is known about the mechanism of in vivo chromatin binding and tethering. In this work we studied LEDGF/p75 in real-time in living HeLa cells combining different quantitative fluorescence techniques: spot fluorescence recovery after photobleaching (sFRAP) and half-nucleus fluorescence recovery after photobleaching (hnFRAP), continuous photobleaching, fluorescence correlation spectroscopy (FCS) and an improved FCS method to study diffusion dependence of chromatin binding, tunable focus FCS. LEDGF/p75 moves about in nuclei of living cells in a chromatin hopping/scanning mode typical for transcription factors. The PWWP domain of LEDGF/p75 is necessary, but not sufficient for in vivo chromatin binding. After interaction with HIV-1 integrase via its IBD, a general protein-protein interaction motif, kinetics of LEDGF/p75 shift to 75-fold larger affinity for chromatin. The PWWP is crucial for locking the complex on chromatin. We propose a scan-and-lock model for LEDGF/p75, unifying paradoxical notions of transcriptional co-activation and lentiviral integration targeting.
Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor (2016)

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
Molecular approaches to parasitology (1995)

PART ONE: Systematics: Questions and Approaches for the Molecular Parasitologist Antigenic Variation in Giardia Lamblia Biological Functions of Nematode Surfaces PART TWO: Metabolism and Drug Action Ivermectin The Replication of Kinetoblast DNA PART THREE: Gene Expression and Genetics Toxoplasma as a Paradigm for the Use of Genetics in the Study of Protozoan Parasites Trans-Splicing in Flatworms PART FOUR: Cell Biology Cell Biology of Trichomonads: Protein Targetting to the Hydrogenosome Cytokine Control of Macrophage Parasites The Immunology of Schistosomiasis.