gebhart/patrepeval huggingface dataset:
Binding of hsp90 to the Glucocorticoid Receptor Requires a Specific 7-Amino Acid Sequence at the Amino Terminus of the Hormone-binding Domain (1998)

The glucocorticoid receptor (GR) HBD must be bound to the protein chaperone hsp90 in order to acquire the high affinity steroid binding conformation. Despite this crucial role of hsp90, its binding site in GR remains poorly defined. Large portions of the GR HBD have been implicated and no similarity has been established between steroid receptor HBDs and the catalytic domains of the protein kinases (e.g. pp60(src), Raf) that also form stable heterocomplexes with hsp90. Thus, it has been thought that some general property of the proteins, such as exposure of hydrophobic residues in partially denatured regions, determines the assembly of stable hsp90 heterocomplexes. In this work, we have studied fusion proteins containing glutathione S-transferase (GST) and very short amino-terminal truncations just before and at the beginning of the rat GR HBD that are otherwise intact to the carboxyl terminus. Overexpression in COS cells of the chimeras GST537C and GST547C was found to yield receptors that were bound to hsp90 and had wild-type steroid binding affinity. However, removal of 7 more amino acids to form GST554C resulted in a fusion protein that did not bind either hsp90 or steroid. Additional mutations revealed that the role of these 7 amino acids was neither to provide a spacer between protein domains nor to expose a protein surface by introducing a bend in the conserved alpha-helix. Instead, these observations support a model in which the sequence of the 7 amino acids directly or indirectly affects hsp90 binding to the GR HBD. Thus, a region of GR that has not been thought to be relevant for hsp90 binding is now seen to be of critical importance, and these data argue strongly against the commonly accepted model of receptor-hsp90 heterocomplex assembly in which the chaperone initially interacts nonspecifically with hydrophobic regions of the partially denatured HBD and subsequently assists its folding to the steroid binding confirmation.
Reliability of Nested PCR for Detection of <i>Chlamydia pneumoniae</i> DNA in Atheromas: Results from a Multicenter Study Applying Standardized Protocols (2002)

The present multicenter study was designed to find explanations for the discrepancies in the reported rates of detection of Chlamydia pneumoniae DNA in endarterectomy specimens. Coded identical sets of (i) a C. pneumoniae DNA dilution series (panel 1; n = 10), (ii) spiked control tissue specimens (panel 2; n = 10 specimens, including 5 negative controls), and (iii) endarterectomy specimens (panel 3; 15 atheromas, 5 negative controls) were analyzed at four laboratories by three standardized DNA extraction methods in each laboratory and a nested touchdown PCR protocol targeting the ompA gene of C. pneumoniae. Panel 1 samples were correctly identified as positive to levels of 0.3 inclusion-forming units (IFU)/PCR mixture (100%) and 0.03 IFU/PCR mixture (50%). All negative controls were correctly reported as negative. Panel 2 samples were identified as C. pneumoniae positive to levels of 0.01 IFU/PCR mixture (100%) and 0.005 IFU/PCR mixture (91%), independent of the DNA extraction method used, and only one false-positive result was reported. For panel 3 samples, 5 of 240 (2%) analyses (in which DNA extractions and PCR were performed at the same laboratory) were positive; the positive specimens were from three endarterectomy specimens and two negative controls. After exchange of DNA extracts between laboratories, 13 of 15 atheroma samples were C. pneumoniae DNA positive in at least 1 of a series of 48 analyses per atheroma sample; however, the overall positivity rate did not exceed 5% (33 of 720 analyses) and therefore was lower than that for the negative controls (8%; 19 of 240 analyses). Not a single positive result could be achieved when all panel 3 extracts (n = 240 analyses) were reamplified by a 16S rRNA PCR followed by hybridization with a C. pneumoniae-specific probe. Statistical analyses demonstrated that positive results did not occur in an independent and random fashion and could most likely be explained by amplicon carryover at the nested PCR level as well as amplicon introduction during DNA extraction, but not by the patterns of distribution of very low target levels or a certain DNA extraction protocol. The results of studies by nested PCR for detection of the prevalence of C. pneumoniae will always be questionable.
Immunologic Aspects of Neurological and Neuromuscular Diseases (1992)

THE NERVOUS system traditionally has been considered an "immunologically privileged" site that is shielded by functional or anatomic barriers from systemic immune responses.<sup>1</sup>However, several lines of experimental and clinical evidence suggest that immune responses can affect and even take place within the nervous system. The nature of the antigen-presenting cells in the central nervous system (CNS) is controversial. Fontana et al<sup>2</sup>reported that astrocytes can present antigen-to-antigen reactive T cells in culture in a major histocompatibility complex (MHC)-restricted fashion. Furthermore, the astrocyte can be induced to express MHC class II antigens after exposure to interferon gamma or viruses. However, others have not been able to reproduce all of these findings and have marshaled evidence for microglia of bone marrow origin as the important antigen-presenting cells in the CNS. There also is increasing interest in the role of various cytokines in the pathogenesis of neurological diseases. Astrocytes secrete
Application of Electroactive Films in Corrosion Protection: II . Metal Hexacyanometalate Films on Surfaces (1991)

The metal hexacyanometalate films, Prussian blue (PB), Ni hexacyanoferrate (NiHCF), and Cu hexacyanoferrate (CuHCF), were studied for their ability to poise the potential of an oxide‐covered metal in a stable, passive region of voltage. This requires the films to catalyze oxygen reduction, and oxygen reduction on PB films was found to be as large as 0.14 mA/cm2. However, no net oxygen reduction was observed on NiHCF and CuHCF films. When PB films were galvanically coupled to Ti electrodes, the open‐circuit potential was stabilized at 0.38–0.52 V vs. SCE even at area ratios (Ti/PB) as high as 10. PB films directly deposited onto Ti electrodes were also studied. The films could only be reduced at a negative potential (−0.18 V vs. SCE) near the flatband potential for , and electrochemical oxidation did not occur under dark, deaerated conditions. Upon exposure of reduced PB on to dissolved , or to illumination, the PB film was oxidized and the coupled system adopted a stable potential between +0.2 and 0.3 V.
94 GHz FMCW radar for low visibility aircraft landing system (2002)

The authors describe a 94 GHz bistatic FMCW (frequency-modulation continuous-wave) radar under development for an aircraft landing system. Using a narrow vertical fan beam antenna, the system scans the runaway rapidly in azimuth, processes the radar returns, and obtains a realistic real-time runway image with sufficient information and resolution to enable a pilot to operate in and out of the airport in conditions with visibility as low as zero, without dependence on today's auto-land systems. This system may use an airport's glide slope indicator to approach the landing area. The range performance requirements of the landing system are illustrated.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">></ETX>
Analysis of Temporal Shear Stress Gradients During the Onset Phase of Flow Over a Backward-Facing Step (2001)

Endothelial cells in blood vessels are exposed to bloodflow and thus fluid shear stress. In arterial bifurcations and stenoses, disturbed flow causes zones of recirculation and stagnation, which are associated with both spatial and temporal gradients of shear stress. Such gradients have been linked to the generation of atherosclerotic plaques. For in-vitro studies of endothelial cell responses, the sudden-expansion flow chamber has been widely used and described. A two-dimensional numerical simulation of the onset phase of flow through the chamber was performed. The wall shear stress action on the bottom plate was computed as a function of time and distance from the sudden expansion. The results showed that depending on the time for the flow to be established, significant temporal gradients occurred close to the second stagnation point of flow. Slowly ramping the flow over 15 s instead of 200 ms reduces the temporal gradients by a factor of 300, while spatial gradients are reduced by 23 percent. Thus, the effects of spatial and temporal gradients can be observed separately. In experiments on endothelial cells, disturbed flow stimulated cell proliferation only when flow onset was sudden. The spatial patterns of proliferation rate match the exposure to temporal gradients. This study provides information on the dynamics of spatial and temporal gradients to which the cells are exposed in a sudden-expansion flow chamber and relates them to changes in the onset phase of flow.
Neurotrophic Effect of a Novel TrkB Agonist on Retinal Ganglion Cells (2010)

Together, these findings demonstrate the potential for antibody-mediated TrkB agonism as a potential therapeutic approach to enhance RGC survival after optic nerve injury. Further studies are needed to elucidate the mechanistic differences between this TrkB agonist and BDNF.
Design and evaluation of a vibrotactile seat to improve spatial awareness while driving (2010)

In this paper, we describe the design and evaluation of a vibrotactile driver's seat that is used to display spatial information during two driving tasks. Many studies have recently shown the effectiveness of haptic and vibrotactile feedback to augment collision warning systems in automobiles. Simultaneously, driver distraction and situational awareness have been identified as significant safety issues in all areas of transportation. We hypothesize that vibrotactile feedback may be used to enhance and improve spatial awareness while driving if it is used continuously and naturally so that it is part of the normal operation of the automobile. We designed a tactile feedback seat from low cost pager motors and characterized the spatial resolution of the seat. We then developed a driving simulation in which the location of vehicles behind and next to the driver's vehicle is communicated through vibrotactile feedback from the seat back. The effectiveness of the seat was evaluated in two driving tasks designated commuting and racing. In the commuting exercise, the test subjects (N=12) maintained a target speed while simultaneously avoiding other vehicles and performing a secondary task. A "near-miss" blind spot recording method was used to evaluate the effect of the feedback in reducing hazard exposure. In the racing exercise, the test subjects (N=10) raced other virtual competitors while using the feedback to maintain awareness of other vehicles in close proximity. Effectiveness was measured by comparing the accumulated time that cars were blocked behind the driver's car. Three feedback conditions were tested: only vibrotactile feedback, rear view mirror and vibrotactile feedback, rear view mirror only. Our preliminary results showed that vibrotactile feedback used in conjunction with the rear view mirror improved performance over using just the rear view mirror. We discuss some of the challenges of creating driving simulations and evaluation metrics that are both realistic and repeatable.
A Jitter Estimation Method for Cascaded, Programmable Phase- Locked Loops (2008)

In a phase-locked loop (PLL), it is critical to understand how reference clock noise affects the output quality, particularly in applications where PLLs are cascaded. That is, where the output of one PLL serves as the reference clock for another PLL. Traditionally, this problem is solved by qualitative analyses, rules of thumb, and simulation, all of which require confirmation with measurements. We present a characterization technique that quantifies and predicts the transfer of reference clock noise to the PLL output, without requiring a circuit model. We will present theory, data, and measurement correlations, as well as application examples. Author Biographies Dr. Daniel Chow is a senior member of technical staff in the characterization group at Altera Corporation. His responsibilities include testing and validation of high-speed components. Specifically, he is responsible for developing Altera’s knowledge base on jitter measurement issues. Dr. Chow received his Ph.D. from the University of California, Davis.
Ultra-high-order self-oscillating mixers based on multiple-element technique (2009)

Novel design approaches for ultra-high-order subharmonic self-oscillating mixers (SOMs) based on a multiple-element technique are presented. They are of high impact for high-end millimetre-wave systems as subharmonic operation reduces local oscillator frequency requirements. An outline of the basic theory and a design procedure for arbitrary high mixing orders are presented, and a sixth-order SOM is fabricated for the first time. The prototype exhibits a conversion gain of +2.8 dB at an RF input frequency of 7.4 GHz.
[Characteristics and influencing factors of ammonia contamination from production of monosodium glutamate]. (2005)

Fluxes of ammonia contamination from production of monosodium glutamate (MSG) were quantitatively observed and relationships with some important influencing factors were statistically analyzed. The study indicates that there is a big difference in the release of ammonia at each step of MSG production including sewage treatment, depending on technical processes. The flux of ammonia released in the process of fermentation was highest, up to 880 mg x (L x min)(-1), and that in the process of refining sugar was lowest, only 0.07 mg x (L x min)(-1). Fluxes of NH3 emission during the whole process of MSG production are significantly related with the concentration of ammonium-nitrogen (NH4+ -N) in discharged solution linearly, and with concentrations of nitrate-nitrogen (NO3- -N) including nitrite-nitrogen (NO2- -N) in discharged solution exponentially. Although there is no linear relationship between fluxes of NH3 emission during the whole process of MSG production and pH values in discharged solution, it is significantly related with fluxes of NH3 emission during the process of sewage treatment.
Analysis of nonuniform nonlinear distributed feedback structures: generalized transfer matrix method (1995)

A new method for the analysis of almost-periodic, nonuniform, nonlinear distributed feedback (NLDFB) structures is presented. A grating segmentation technique used for linear DFB devices is combined with the analytic solutions corresponding to a strictly periodic, uniform NLDFB device. The method is demonstrated for tapered, chirped, and phase-shifted structures. New results describing the operation of single- and multiple-phase shifted NLDFB are reported. NLDFB structures with a axially-varying effective Kerr index are also considered.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">></ETX>
Bush encroachment under three contrasting land‐use practices in a mesic South African savanna (2009)

Abstract This study determined the effects of land‐use practice had on the rate and extent of bush encroachment in a mesic savanna in KwaZulu‐Natal, South Africa. Changes in woody cover were measured for 1 km 2 sites in areas under communal, commercial and conservation land‐use systems for the period between 1937 and 2000. Land users from each area were interviewed to gain the histories of each area and to determine how the changes in woody cover had impacted them and whether anything was being done to counteract the spread of trees and shrubs on their land. Bush encroachment occurred across all three of the land‐use types in the 67‐year period between 1937 and 2000. The results showed that land‐use practice had enormous impacts on the process of bush encroachment. The communal site showed a decrease in grass (21%) and tree (5%) cover and an increase in shrub cover (13%). At the commercial site, there was a considerable decrease in grass cover (46%) and moderate increase in shrub cover (10%) and a massive increase in tree cover (36%). The area under conservation showed a substantial decrease in grass cover (47%), a slight decrease in shrub cover (19%) and a massive increase in tree cover (66%). The perceived causes of these changes were fairly similar amongst the different land users. The changes were mostly not perceived to be a problem for the communal land users. The main advantages mentioned were increased woody resources for building and firewood and increased browse availability. The commercial and conservation land users perceived the changes to have significant negative connotations including the loss of grazing land and biodiversity and secondary invasion of encroached areas by alien plant species. Despite these perceptions, very little has been done to combat bush encroachment in the commercial and conservation land use systems.
IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia (2011)

IL-10-deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to a brain hemorrhage if they are unable to clear peak bacteremia. In this study, we investigated the protective role of IL-10 during relapsing-remitting bacteremia and explored the molecular events involved in the protection of brain endothelium by IL-10. Brain endothelial injury was measured with cytotoxicity and diverse apoptotic assays, whereas the signaling pathway analysis was done by quantitative PCR array. The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL-10-deficient mice during relapsing-remitting infection. Human brain microvascular endothelial cells (HBMEC) produced abundant proinflammatory mediators upon exposure to whole bacteria or purified bacterial lipoprotein but did not produce any detectable IL-10. Whole bacteria and purified outer membrane lipoprotein rapidly killed HBMEC by apoptosis in a time- and concentration-dependent manner. Exogenous IL-10 protected HBMEC from apoptosis. HBMEC apoptosis during exposure to a low number of bacteria was associated with downregulation of TNF and TNFAIP3 and upregulation of BAX. In contrast, HBMEC apoptosis during exposure to high concentrations of purified outer membrane lipoprotein was associated with marked upregulation of FAS, FAS ligand, and the adaptor molecules RIPK1 and CFLAR. Exogenous IL-10 reversed all the apoptotic signaling changes induced by whole bacteria or its purified lipoprotein. The results indicate that prominent brain endothelial cell apoptosis occurs during relapsing-remitting bacteremia in the absence of IL-10 and point to a prominent role for bacterial lipoprotein-mediated activation of FAS and caspase-3 in this process.
FDA Approval Summary: Tagraxofusp-erzs For Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (2019)

Tagraxofusp-erzs (Elzonris, Stemline) is a cytotoxin that targets CD123-expressing cells. On December 21, 2018, FDA approved tagraxofusp-erzs for the treatment of blastic plasmacytoid dendritic cell neoplasms (BPDCN) in adult and pediatric patients 2 years and older. Approval was based on the response rate in a single-arm trial, Study STML-401-0114; the pivotal cohort included 13 patients with treatment-naïve BPDCN who received tagraxofusp-erzs monotherapy. The complete response or clinical complete response (CR/CRc) rate in the pivotal cohort was 54% (95% CI: 25%-81%), and the median duration of CR/CRc was not reached with a median follow-up of 11.5 months (range: 0.2-12.7). In a separate exploratory cohort, a CR/CRc was achieved by 2 (13%) patients with R/R BPDCN. Safety was assessed in 94 patients with myeloid neoplasms treated with tagraxofusp-erzs at the approved dose and schedule. The major toxicity was capillary leak syndrome (CLS), which occurred in 55% of patients and was fatal in 2%. Hepatotoxicity and hypersensitivity reactions were reported in 88% and 46% of patients, respectively. Other common (≥30%) adverse reactions were nausea, fatigue, peripheral edema, pyrexia, and weight increase. A high proportion of patients (85%) developed neutralizing antidrug antibodies. Tagraxofusp-erzs is the first FDA-approved treatment for BPDCN.
Blockade of TGF-β Signaling by the TGFβR-I Kinase Inhibitor LY2109761 Enhances Radiation Response and Prolongs Survival in Glioblastoma (2011)

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-β is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-β receptor (TGFβR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFβR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem-like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFβR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma.
Characteristics of the Inhibition of NADPH Oxidase Activation in Neutrophils by Apocynin, a Methoxy-Substituted Catechol (1994)

Phagocytes are able to generate reactive oxygen species by an activatable NADPH oxidase system. We investigated the inhibition of NADPH oxidase activation by a methoxy-substituted catechol, apocynin. Oxygen uptake by neutrophils incubated with 300 microM apocynin was completely inhibited at 7 min after addition of serum-treated zymosan (STZ), with a lagtime of inhibition of 2 to 3 min. The lagtime of effect of apocynin in neutrophils relatively deficient of myeloperoxidase was about 50% longer when compared with normal cells. Inhibition of the STZ-induced respiratory burst by apocynin was also observed in human eosinophils but not in human alveolar macrophages. Immunoblots of neutrophil membranes, isolated at 2 and 7 min after STZ stimulation of neutrophils, demonstrated translocation of the cytosolic oxidase components p47-phox and p67-phox to the membrane fraction. Translocation at 7 min after STZ stimulation was markedly reduced when the neutrophils had been incubated with 300 microM apocynin, but translocation was normal after 2 min of stimulation. These properties suggest that apocynin is an intracellular inhibitor of the assembly of NADPH oxidase in neutrophils and eosinophils and that apocynin requires conversion by peroxidases to exert its inhibitory effect. The capacity of neutrophils for intracellular killing of Staphylococcus aureus was not affected by apocynin. The potential therapeutic value of apocynin was demonstrated in vitro by its ability to protect secretory leukocyte proteinase inhibitor from oxidative inactivation by neutrophils.