gebhart/patrepeval huggingface dataset:
Selective Inhibition of Trigeminovascular Neurons by Fremanezumab: A Humanized Monoclonal Anti-CGRP Antibody (2017)

A large body of evidence supports an important role for calcitonin gene-related peptide (CGRP) in migraine pathophysiology. This evidence gave rise to a global effort to develop a new generation of therapeutics that inhibit the interaction of CGRP with its receptor in migraineurs. Recently, a new class of such drugs, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs), were found to be effective in reducing the frequency of migraine. The purpose of this study was to better understand how the CGRP-mAb fremanezumab (TEV-48125) modulates meningeal sensory pathways. To answer this question, we used single-unit recording to determine the effects of fremanezumab (30 mg/kg, IV) and its isotype control Ab on spontaneous and evoked activity in naive and cortical spreading depression (CSD)-sensitized trigeminovascular neurons in the spinal trigeminal nucleus of anesthetized male and female rats. The study demonstrates that, in both sexes, fremanezumab inhibited naive high-threshold (HT) neurons, but not wide-dynamic range trigeminovascular neurons, and that the inhibitory effects on the neurons were limited to their activation from the intracranial dura but not facial skin or cornea. In addition, when given sufficient time, fremanezumab prevents the activation and sensitization of HT neurons by CSD. Mechanistically, these findings suggest that HT neurons play a critical role in the initiation of the perception of headache and the development of cutaneous allodynia and central sensitization. Clinically, the findings may help to explain the therapeutic benefit of CGRP-mAb in reducing headaches of intracranial origin such as migraine with aura and why this therapeutic approach may not be effective for every migraine patient.<b>SIGNIFICANCE STATEMENT</b> Calcitonin gene-related peptide (CGRP) monoclonal antibodies (CGRP-mAbs) are capable of preventing migraine. However, their mechanism of action is unknown. In the current study, we show that, if given enough time, a CGRP-mAb can prevent the activation and sensitization of high-threshold (central) trigeminovascular neurons by cortical spreading depression, but not their activation from the skin or cornea, suggesting a potential explanation for selectivity to migraine headache, but not other pains, and a predominantly peripheral site of action.
CCL1-CCR8 Interactions: An Axis Mediating the Recruitment of T Cells and Langerhans-Type Dendritic Cells to Sites of Atopic Skin Inflammation (2005)

Atopic dermatitis represents a chronically relapsing skin disease with a steadily increasing prevalence of 10-20% in children. Skin-infiltrating T cells, dendritic cells (DC), and mast cells are thought to play a crucial role in its pathogenesis. We report that the expression of the CC chemokine CCL1 (I-309) is significantly and selectively up-regulated in atopic dermatitis in comparison to psoriasis, cutaneous lupus erythematosus, or normal skin. CCL1 serum levels of atopic dermatitis patients are significantly higher than levels in healthy individuals. DC, mast cells, and dermal endothelial cells are abundant sources of CCL1 during atopic skin inflammation and allergen challenge, and Staphylococcus aureus-derived products induce its production. In vitro, binding and cross-linking of IgE on mast cells resulted in a significant up-regulation of this inflammatory chemokine. Its specific receptor, CCR8, is expressed on a small subset of circulating T cells and is abundantly expressed on interstitial DC, Langerhans cells generated in vitro, and their monocytic precursors. Although DC maintain their CCR8+ status during maturation, brief activation of circulating T cells recruits CCR8 from intracytoplamic stores to the cell surface. Moreover, the inflammatory and atopy-associated chemokine CCL1 synergizes with the homeostatic chemokine CXCL12 (SDF-1alpha) resulting in the recruitment of T cell and Langerhans cell-like DC. Taken together, these findings suggest that the axis CCL1-CCR8 links adaptive and innate immune functions that play a role in the initiation and amplification of atopic skin inflammation.
Bone Morphogenetic Protein 4 Contributes to the Maintenance of Primitive Cord Blood Hematopoietic Progenitors in an Ex Vivo Stroma-Noncontact Co-Culture System (2006)

Establishment of conditions supporting hematopoietic stem cell (HSC) maintenance and expansion ex vivo is critical for wider clinical application of cord blood (CB) transplantation. AFT024 is a murine fetal liver cell line that expands primitive hematopoietic cells via a process that is not understood. Here we show that bone morphogenic protein 4 (BMP4) is produced by AFT024 and contributes significantly to the maintenance of co-cultured CB-derived primitive cells. Significant amounts of BMP4 mRNA are produced by the supportive AFT024 stromal cell line, and secreted BMP4 protein accumulates in AFT024 conditioned medium. Blockade of BMP4 activity in this coculture model using neutralizing BMP4 monoclonal antibody reduced expansion of primitive CB cells on the basis of phenotypic (CD34(+)CD38(-)) and functional criteria [long-term culture initiating cells (LTC-IC)] and significantly reduced the capacity of the cultured CB stem cells to support repopulation in the nonobese diabetic-severe combined immunodeficiency (NOD-SCID) xenograft model. Therefore, BMP4 is a key growth factor for maintenance of HSC and contributes to the unique properties of the AFT024 stromal noncontact culture.
Pipeline synthesis and optimization of FPGA-based video processing applications with CAL (2011)

This article describes a pipeline synthesis and optimization technique that increases data throughput of FPGA-based system using minimum pipeline resources. The technique is applied on CAL dataflow language, and designed based on relations, matrices, and graphs. First, the initial as-soon-as-possible (ASAP) and as-late-as-possible (ALAP) schedules, and the corresponding mobility of operators are generated. From this, operator coloring technique is used on conflict and nonconflict directed graphs using recursive functions and explicit stack mechanisms. For each feasible number of pipeline stages, a pipeline schedule with minimum total register width is taken as an optimal coloring, which is then automatically transformed to a description in CAL. The generated pipelined CAL descriptions are finally synthesized to hardware description languages for FPGA implementation. Experimental results of three video processing applications demonstrate up to 3.9× higher throughput for pipelined compared to non-pipelined implementations, and average total pipeline register width reduction of up to 39.6 and 49.9% between the optimal, and ASAP and ALAP pipeline schedules, respectively.
Gene expression and viral prodution in latently infected, resting CD4 + T cells in viremic versus aviremic HIV-infected individuals (2003)

The presence of HIV-1 in latently infected, resting CD4(+) T cells has been clearly demonstrated in infected individuals; however, the extent of viral expression and the underlying mechanisms of the persistence of HIV-1 in this viral reservoir have not been fully delineated. Here, we show that resting CD4(+) T cells from the majority of viremic patients are capable of producing cell-free HIV-1 spontaneously ex vivo. The levels of HIV-1 released by resting CD4(+) T cells were not significantly reduced in the presence of inhibitors of cellular proliferation and viral replication. However, resting CD4(+) T cells from the majority of aviremic patients failed to produce virions, despite levels of HIV-1 proviral DNA and cell-associated HIV-1 RNA comparable to viremic patients. The DNA microarray analysis demonstrated that a number of genes involving transcription regulation, RNA processing and modification, and protein trafficking and vesicle transport were significantly upregulated in resting CD4(+) T cells of viremic patients compared to those of aviremic patients. These results suggest that active viral replication has a significant impact on the physiologic state of resting CD4(+) T cells in infected viremic patients and, in turn, allows release of HIV-1 without exogenous activation stimuli. In addition, given that no quantifiable virions were produced by the latent viral reservoir in the majority of aviremic patients despite the presence of cell-associated HIV-1 RNA, evidence for transcription of HIV-1 RNA in resting CD4(+) T cells of aviremic patients should not necessarily be taken as direct evidence for ongoing viral replication during effective therapy.
Polymers for 3D Printing and Customized Additive Manufacturing (2017)

Additive manufacturing (AM) alias 3D printing translates computer-aided design (CAD) virtual 3D models into physical objects. By digital slicing of CAD, 3D scan, or tomography data, AM builds objects layer by layer without the need for molds or machining. AM enables decentralized fabrication of customized objects on demand by exploiting digital information storage and retrieval via the Internet. The ongoing transition from rapid prototyping to rapid manufacturing prompts new challenges for mechanical engineers and materials scientists alike. Because polymers are by far the most utilized class of materials for AM, this Review focuses on polymer processing and the development of polymers and advanced polymer systems specifically for AM. AM techniques covered include vat photopolymerization (stereolithography), powder bed fusion (SLS), material and binder jetting (inkjet and aerosol 3D printing), sheet lamination (LOM), extrusion (FDM, 3D dispensing, 3D fiber deposition, and 3D plotting), and 3D bioprinting. The range of polymers used in AM encompasses thermoplastics, thermosets, elastomers, hydrogels, functional polymers, polymer blends, composites, and biological systems. Aspects of polymer design, additives, and processing parameters as they relate to enhancing build speed and improving accuracy, functionality, surface finish, stability, mechanical properties, and porosity are addressed. Selected applications demonstrate how polymer-based AM is being exploited in lightweight engineering, architecture, food processing, optics, energy technology, dentistry, drug delivery, and personalized medicine. Unparalleled by metals and ceramics, polymer-based AM plays a key role in the emerging AM of advanced multifunctional and multimaterial systems including living biological systems as well as life-like synthetic systems.
Polarization-Induced Hole Doping in Wide–Band-Gap Uniaxial Semiconductor Heterostructures (2009)

Impurity-based p-type doping in wide-band-gap semiconductors is inefficient at room temperature for applications such as lasers because the positive-charge carriers (holes) have a large thermal activation energy. We demonstrate high-efficiency p-type doping by ionizing acceptor dopants using the built-in electronic polarization in bulk uniaxial semiconductor crystals. Because the mobile hole gases are field-ionized, they are robust to thermal freezeout effects and lead to major improvements in p-type electrical conductivity. The new doping technique results in improved optical emission efficiency in prototype ultraviolet light-emitting-diode structures. Polarization-induced doping provides an attractive solution to both p- and n-type doping problems in wide-band-gap semiconductors and offers an unconventional path for the development of solid-state deep-ultraviolet optoelectronic devices and wide-band-gap bipolar electronic devices of the future.
Generating model transformation rules from examples using an evolutionary algorithm (2012)

We propose an evolutionary approach to automatically generate model transformation rules from a set of examples. To this end, genetic programming is adapted to the problem of model transformation in the presence of complex input/output relationships (i.e., models conforming to meta-models) by generating declarative programs (i.e., transformation rules in this case). Our approach does not rely on prior transformation traces for the model-example pairs, and directly generates executable, many-to-many rules with complex conditions. The applicability of the approach is illustrated with the well-known problem of transforming UML class diagrams into relational schemas, using examples collected from the literature.
Effect of Perhexiline and Oxfenicine on Myocardial Function and Metabolism During Low-Flow Ischemia/Reperfusion in the Isolated Rat Heart (2000)

Perhexiline is a potent prophylactic anti-anginal agent that has been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1. We compared the hemodynamic and biochemical effects of perhexiline (0.5 and 2.0 microM) and of another CPT-1 inhibitor, oxfenicine (0.5 mM), in Langendorff-perfused rat hearts subjected to 60 min of low-flow ischemia (95% flow reduction) followed by 30 min of reperfusion. Both perhexiline (2 microM only) and oxfenicine attenuated (p < 0.003, p < 0.0002, respectively) increases in diastolic tension during ischemia, without significant effects on developed tension, or on cardiac function during reperfusion. Myocardial concentrations of long-chain acylcarnitines (LCAC), products of CPT-1 action, were decreased (p < 0.05) by oxfenicine, unaffected by 2 microM perhexiline, and increased slightly by 0.5 microM perhexiline. Perhexiline, but not the active metabolite of oxfenicine, also inhibited cardiac CPT-2 with similar IC50 and Emax, although lower Hill slope, compared with CPT-1. Oxfenicine, but not perhexiline, reduced concentrations of the endogenous CPT-1 inhibitor, malonyl-CoA. Perhexiline, but not oxfenicine, inhibited myocardial release of lactate during normal flow. We conclude that (a) perhexiline protects against diastolic dysfunction during ischemia in this model, independent of major changes in LCAC accumulation and (b) this may result from simultaneous effects of perhexiline on myocardial CPT-1 and CPT-2.
SAND: A Fault-Tolerant Streaming Architecture for Network Traffic Analytics (2014)

Many long-running network analytics applications impose a high-throughput and high reliability requirements on stream processing systems. However, previous stream processing systems cannot sustain high-speed traffic at the core router level. Furthermore, their fault-tolerant schemes cannot provide strong consistency which is essential for network analytics. In this paper, we present the design and implementation of SAND, a fault-tolerant distributed stream processing system for network analytics. SAND is designed to operate under high-speed network traffic, and it uses a novel check pointing protocol which can perform failure recovery based on upstream backup and check pointing. We prove our fault-tolerant scheme provides strong consistency even under multiple node failure. We implement several real-world network analytics applications on SAND, evaluate their performance using network traffic captured from commercial cellular core networks, and demonstrate that SAND can sustain high-speed network traffic and that our fault-tolerant scheme is efficient.
Prostaglandin E2 inhibits the activation of cloned T cell hybridomas. (1985)

To minimize complicating interactions inherent in heterogeneous cell populations, we used a panel of cloned murine autoreactive (E8.A1) and antigen-specific (HEL.C10, HEL.B14) T cell hybridomas to examine the effect of prostaglandin E2 (PGE2) on T cell activation. These T cells secrete interleukin 2 (IL 2) when co-cultured with a cloned population of I region-matched stimulator cells (TA3), or with mitogenic signals in the absence of TA3 stimulator cells. Physiologic concentrations of PGE2 inhibited the induction of IL 2 secretion by the T cell hybridomas tested, when they were activated either by TA3 cells or by mitogenic signals. IL 2 production was inhibited in a dose-dependent manner by concentrations of PGE2 between 10(-7) and 10(-11) M, with 50% inhibition occurring at 10(-10) M. Pretreatment of the T hybridoma cells with 10(-7) M PGE2 for 1 hr before culture also resulted in marked inhibition of IL 2 secretion. Similar pretreatment of the TA3 cells did not affect their ability to activate the T cell hybridomas. PGE2 at 10(-8) M induced a 30-fold increase in cAMP levels within 25 min of addition to culture of the E8.A1 T cell hybridoma, but caused no significant elevation of cAMP levels in TA3 cells. The direct addition of dibutyryl cAMP (dcAMP) to cultures of E8.A1 cells resulted in marked inhibition of IL 2 secretion when stimulated by TA3 or by mitogenic signals, with an average of 80% inhibition occurring at 10(-4) M dcAMP. PGE2 and dcAMP also inhibited the growth of E8.A1 cells. Initially, cell growth was virtually halted, but began to recover between 24 and 48 hr after the addition of either PGE2 or dcAMP. Neither PGE2 nor dcAMP inhibited the division of TA3 cells. High affinity binding sites for PGE2 were detected in the E8.A1 T cell hybridomas with an apparent Kd of 7.6 X 10(-10) M, which is consistent with the functional data. No specific binding was detected in the TA3 stimulator cells. These findings suggest that the immunosuppressive effects of PGE2 are localized to the T cell, are receptor regulated, and may be mediated by the associated increase of cAMP levels in the T cell hybridomas.
Video mosaics for virtual environments (1996)

As computer-based video becomes ubiquitous with the expansion of transmission, storage, and manipulation capabilities, it will offer a rich source of imagery for computer graphics applications. This article looks at one way to use video as a new source of high-resolution, photorealistic imagery for these applications. If you walked through an environment, such as a building interior, and filmed a video sequence of what you saw you could subsequently register and composite the video images together into large mosaics of the scene. In this way, you can achieve an essentially unlimited resolution. Furthermore, since you can acquire the images using any optical technology, you can reconstruct any scene regardless of its range or scale. Video mosaics can be used in many different applications, including the creation of virtual reality environments, computer-game settings, and movie special effects. I present algorithms that align images and composite scenes of increasing complexity-beginning with simple planar scenes and progressing to panoramic scenes and, finally, to scenes with depth variation. I begin with a review of basic imaging equations and conclude with some novel applications of the virtual environments created using the algorithms presented.
Caffeine Inhibits Checkpoint Responses without Inhibiting the Ataxia-Telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) Protein Kinases (2003)

The ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) kinases regulate cell cycle checkpoints by phosphorylating multiple substrates including the CHK1 and -2 protein kinases and p53. Caffeine has been widely used to study ATM and ATR signaling because it inhibits these kinases in vitro and overcomes cell cycle checkpoint responses in vivo. Thus, caffeine has been thought to overcome the checkpoint through its ability to prevent phosphorylation of ATM and ATR substrates. Surprisingly, I have found that multiple ATM-ATR substrates including CHK1 and -2 are hyperphosphorylated in cells treated with caffeine and genotoxic agents such as hydroxyurea or ionizing radiation. ATM autophosphorylation in cells is also increased when caffeine is used in combination with inhibitors of replication suggesting that ATM activity is not inhibited in vivo by caffeine. Furthermore, CHK1 hyperphosphorylation induced by caffeine in combination with hydroxyurea is ATR-dependent suggesting that ATR activity is stimulated by caffeine. Finally, the G2/M checkpoint in response to ionizing radiation or hydroxyurea is abrogated by caffeine treatment without a corresponding decrease in ATM-ATR-dependent signaling. This data suggests that although caffeine is an inhibitor of ATM-ATR kinase activity in vitro, it can block checkpoints without inhibiting ATM-ATR activation in vivo.
Effects of Clostridium difficile toxins A and B in rabbit small and large intestine in vivo and on cultured cells in vitro (1988)

Clostridium difficile is recognized as the major cause of antibiotic-associated colitis. C. difficile produces two toxins, A (enterotoxin) and B (cytotoxin), that are implicated in the pathogenesis of the colitis. We examined the dose responses, time course, and synergism of these two toxins in ligated rabbit intestinal loops and in tissue culture. In rabbit small intestinal loops, toxin A caused histologically demonstrable intestinal tissue damage as early as 2 h. The secretory response greater than or equal to 8 h was similar to that of a cholera toxin control. The effect of toxin A on tissue damage or secretion was seen even if toxin was removed after 5 min. Purified toxin A caused significant net accumulation of sodium, chloride, potassium, and total protein and slightly increased osmolality of the fluid content at 6 h; these effects were similar to those caused by crude C. difficile culture filtrates containing toxins A and B. Crude C. difficile toxin caused fluid accumulation with a delayed time course in the rabbit large intestine, and in contrast to its effect in small intestine, crude toxin caused net accumulation of bicarbonate and increased pH. In tissue culture, toxin A caused a rounding up of CHO and T-84 colonic carcinoma cells. A monoclonal antibody (PCG-4) that has no effect on tissue culture cytotoxicity with toxins A and B completely inhibited the secretory and tissue-damaging effects in the intestine. Toxins A and B were synergistic in the gut only at high doses of toxin B (greater than or equal to 10 micrograms/ml), and they were additive in tissue culture. The cytopathic effect in tissue culture was not consistently associated with trypan blue uptake. The cytopathic effect of toxin A in tissue culture did not appear to involve inhibitable Ca2+-dependent or prostaglandin synthesis pathways or intact microfilament or microtubule function for its activity and was not inhibited by reducing or lysosomotropic agents. Our results suggest that toxins A and B have independent and distinct effects in vivo and in vitro.