gebhart/patrepeval huggingface dataset:
Human Toll‐like receptor‐dependent induction of interferons in protective immunity to viruses (2007)

Five of the 10 human Toll-like receptors (TLRs) (TLR3, TLR4, TLR7, TLR8, and TLR9), and four of the 12 mouse TLRs (TLR3, TLR4, TLR7, TLR9) can trigger interferon (IFN)-alpha, IFN-beta, and IFN-lambda, which are critical for antiviral immunity. Moreover, TLR3, TLR7, TLR8, and TLR9 differ from TLR4 in two particularly important ways for antiviral immunity: they can be activated by nucleic acid agonists mimicking compounds produced during the viral cycle, and they are typically present within the cell, along the endocytic pathway, where they sense viral products in the intraluminal space. Investigations in mice have demonstrated that the TLR7/9-IFN and TLR3-IFN pathways are different and critical for protective immunity to various experimental viral infections. Investigations in humans with interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency (unresponsive to TLR7, TLR8, and TLR9), UNC-93B deficiency (unresponsive to TLR3, TLR7, TLR8, and TLR9), and TLR3 deficiency have recently shed light on the role of these two pathways in antiviral immunity in natural conditions. UNC-93B- and TLR3-deficient patients appear to be specifically prone to herpes simplex virus 1 (HSV-1) encephalitis, although clinical penetrance is incomplete, whereas IRAK-4-deficient patients appear to be normally resistant to most viruses, including HSV-1. These experiments of nature suggest that the TLR7-, TLR8-, and TLR9-dependent induction of IFN-alpha, IFN-beta, and IFN-lambda is largely redundant in human antiviral immunity, whereas the TLR3-dependent induction of IFN-alpha, IFN-beta, and IFN-lambda is critical for primary immunity to HSV-1 in the central nervous system in children but redundant for immunity to most other viral infections.
Mucosal Luminal Manipulation of T Cell Geography Switches on Protective Efficacy by Otherwise Ineffective Parenteral Genetic Immunization (2007)

Genetic immunization holds great promise for future vaccination against mucosal infectious diseases. However, parenteral genetic immunization is ineffective in control of mucosal intracellular infections, and the underlying mechanisms have remained unclear. By using a model of parenteral i.m. genetic immunization and pulmonary tuberculosis (TB), we have investigated the mechanisms that determine the failure and success of parenteral genetic immunization. We found that lack of protection from pulmonary Mycobacterium tuberculosis (M.tb) challenge by i.m. immunization with a recombinant adenovirus-vectored tuberculosis vaccine was linked to the absence of M.tb Ag-specific T cells within the airway lumen before M.tb challenge despite potent T cell activation in the systemic compartments. Furthermore, pulmonary mycobacterial challenge failed to recruit CD8 T cells into the airway lumen of i.m. immunized mice. Such defect in T cell recruitment, intra-airway CTL, and immune protection was restored by creating acute inflammation in the airway with inflammatory agonists such as virus. However, the Ag-specific T cells recruited as such were not retained in the airway lumen, resulting in a loss of protection. In comparison, airway exposure to low doses of soluble M.tb Ags not only recruited but retained Ag-specific CD8 T cells in the airway lumen over time that provided robust protection against M.tb challenge. Thus, our study reveals that mucosal protection by parenteral immunization is critically determined by T cell geography, i.e., whether Ag-specific T cells are within or outside of the mucosal lumen and presents a feasible solution to empower parenteral immunization strategies against mucosal infectious diseases.
Subdomain II of α-Isopropylmalate Synthase Is Essential for Activity (2014)

The committed step of leucine biosynthesis, converting acetyl-CoA and α-ketoisovalerate into α-isopropylmalate, is catalyzed by α-isopropylmalate synthase (IPMS), an allosteric enzyme subjected to feedback inhibition by the end product L-leucine. We characterized the short form IPMS from Leptospira biflexa (LbIPMS2), which exhibits a catalytic activity comparable with that of the long form IPMS (LbIPMS1) and has a similar N-terminal domain followed by subdomain I and subdomain II but lacks the whole C-terminal regulatory domain. We found that partial deletion of the regulatory domain of LbIPMS1 resulted in a loss of about 50% of the catalytic activity; however, when the regulatory domain was deleted up to Arg-385, producing a protein that is almost equivalent to the intact LbIPMS2, about 90% of the activity was maintained. Moreover, in LbIPMS2 or LbIPMS1, further deletion of several residues from the C terminus of subdomain II significantly impaired or completely abolished the catalytic activity, respectively. These results define a complete and independently functional catalytic module of IPMS consisting of both the N-terminal domain and the two subdomains. Structural comparison of LbIPMS2 and the Mycobacterium tuberculosis IPMS revealed two different conformations of subdomain II that likely represent two substrate-binding states related to cooperative catalysis. The biochemical and structural analyses together with the previously published hydrogen-deuterium exchange data led us to propose a conformation transition mechanism for feedback inhibition mediated by subdomains I and II that might associated with alteration of the binding affinity toward acetyl-CoA.
Efficient retrieval of the top-k most relevant spatial web objects (2009)

The conventional Internet is acquiring a geo-spatial dimension. Web documents are being geo-tagged, and geo-referenced objects such as points of interest are being associated with descriptive text documents. The resulting fusion of geo-location and documents enables a new kind of top- k query that takes into account both location proximity and text relevancy. To our knowledge, only naive techniques exist that are capable of computing a general web information retrieval query while also taking location into account. This paper proposes a new indexing framework for location-aware top- k text retrieval. The framework leverages the inverted file for text retrieval and the R-tree for spatial proximity querying. Several indexing approaches are explored within the framework. The framework encompasses algorithms that utilize the proposed indexes for computing the top- k query, thus taking into account both text relevancy and location proximity to prune the search space. Results of empirical studies with an implementation of the framework demonstrate that the paper's proposal offers scalability and is capable of excellent performance.
Zero Configuration Networking: The Definitive Guide (2005)

It used to be that two laptops, sitting side by side, couldn't communicate with each other; they may as well have been a thousand miles apart. But that was then, before the advent of Zero Configuration Networking technology. This amazing cross-platform open source technology automatically connects electronic devices on a network, allowing them to interoperate seamlessly-without any user configuration. So now you don't have to lift a finger! Needless to say, it has completely changed the way people connect to devices and programs for printing, file sharing, and other activities. Zero Configuration Networking: The Definitive Guide walks you through this groundbreaking network technology, with a complete description of the protocols and ways to implement network-aware applications and devices. Written by two Zero Configuration Networking experts, including one of Apple's own computer scientists, the book covers more than just file sharing and printing. Zero Configuration Networking also enables activities such as music and photo sharing and automatic buddy discovery on Instant Messaging applications. In fact, Zero Configuration Networking can be used for virtually any device that can be controlled by a computer. And this handy guide has the inside scoop on all of its capabilities-and how you can easily apply them in your own environment. For the technically advanced, Zero Configuration Networking: The Definitive Guide examines the three core technologies that make up Zero Configuration Networking: Link-Local Addressing, Multicast DNS, and DNS Service Discovery. It also reviews a series of APIs, including C-API, Java API, CFNetServices, and Cocoa's NSNetServices. Whether you want to understand how iTunes works, or you want to network a series of laptops and other devices at your office for maximum efficiency, you'll find all the answers in this authoritative guide.
Topic Modeling of Short Texts (2016)

Recent years have witnessed the unprecedented growth of online social media, which empower short texts as the prevalent format for information of Internet. Given the nature of sparsity, however, short text topic modeling remains a critical yet much-watched challenge in both academy and industry. Rich research efforts have been put on building different types of probabilistic topic models for short texts, among which the self aggregation methods without using auxiliary information become an emerging solution for providing informative cross-text word co-occurrences. However, models along this line are still rarely seen, and the representative one Self-Aggregation Topic Model (SATM) is prone to overfitting and computationally expensive. In light of this, in this paper, we propose a novel probabilistic model called Pseudo-document-based Topic Model (PTM) for short text topic modeling. PTM introduces the concept of pseudo document to implicitly aggregate short texts against data sparsity. By modeling the topic distributions of latent pseudo documents rather than short texts, PTM is expected to gain excellent performance in both accuracy and efficiency. A Sparsity-enhanced PTM (SPTM for short) is also proposed by applying Spike and Slab prior, with the purpose of eliminating undesired correlations between pseudo documents and latent topics. Extensive experiments on various real-world data sets with state-of-the-art baselines demonstrate the high quality of topics learned by PTM and its robustness with reduced training samples. It is also interesting to show that i) SPTM gains a clear edge over PTM when the number of pseudo documents is relatively small, and ii) the constraint that a short text belongs to only one pseudo document is critically important for the success of PTM. We finally take an in-depth semantic analysis to unveil directly the fabulous function of pseudo documents in finding cross-text word co-occurrences for topic modeling.
Impairment of Airway Mucociliary Transport in Patients with Sinobronchial Syndrome: Role of Nitric Oxide (2000)

Nitric oxide (NO) produced within the respiratory tract can stimulate ciliary motility of airway epithelial cells and hence mucociliary transport. In this study, to determine the role of NO in mucociliary dysfunction in sinobronchial syndrome (SBS), we measured NO concentrations in the exhaled air by chemiluminescence analyzer and nasal clearance time (NCT) by saccharin test. Exhaled NO concentrations in patients with SBS were 39% of those in healthy nonsmokers and 55% of those in healthy smokers. The patients also showed prolonged NCT compared with healthy subjects, and there was a significant negative correlation between exhaled NO concentrations and NCT. Furthermore, concentrations of chloride (Cl) in the sputum supernatant were higher in SBS patients than in healthy subjects, and there was a significant negative correlation between sputum Cl concentrations and exhaled NO concentrations. These results suggest that airway mucociliary clearance is impaired in patients with SBS and that this impairment might result from the reduced production of NO and the impaired availability of the molecule in the mucociliary apparatus.
Procoagulant Membrane Microparticles Correlate with the Severity of Pulmonary Arterial Hypertension (2007)

Abstract Rationale Procoagulant microparticles constitute valuable hallmarks of cell damage. Microparticles also behave as cellular effectors. Objectives We hypothesized that the extent of the vascular cell damage measured by circulating microparticles could be related to the severity of pulmonary arterial hypertension (PAH). Methods Circulating biomarkers of vascular damage and cell activation were measured in blood samples from 20 patients with PAH. Samples were withdrawn from occluded pulmonary artery and jugular vein. Peripheral venous blood samples were obtained in 23 control subjects. The microparticle procoagulant abilities were quantified by functional prothrombinase and tissue factor assays and their cellular origin was determined. Measurements and Main Results Soluble vascular cellular adhesion molecule-1 and proinflammatory markers, such as monocyte chemoattractant protein-1 and highly specific C-reactive protein, were elevated in patients with PAH compared with control subjects. Microparticles bearing active tissue factor and CD105 (endoglin) were also elevated in patients with PAH compared with control subjects (29 ± 13 vs. 16 ± 6 fmol/L, P &amp;lt; 0.001, and 1.10 ± 0.46 vs. 0.49 ± 0.33 nmol/L phosphatidylserine equivalent, P &amp;lt; 0.001, respectively). A further increase in endothelium-derived CD105 microparticles was observed in pulmonary arterial blood compared with venous blood in patients with PAH (1.73 ± 0.77, P = 0.038). Microparticles bearing active tissue factor were at a higher level in patients in functional class III and IV and who were walking fewer than 380 m with the six-minute-walk test. Conclusions Circulating markers of endothelium damage, proinflammatory markers, and cell stimulation estimated with circulating microparticles appear to be valuable tools in determining the severity of PAH.
Design and Synthesis of a Library of BODIPY-Based Environmental Polarity Sensors Utilizing Photoinduced Electron-Transfer-Controlled Fluorescence ON/OFF Switching (2007)

We systematically examined the mechanism of the solvent polarity dependence of the fluorescence ON/OFF threshold of the BODIPY (boron dipyrromethene) fluorophore and the role of photoinduced electron transfer (PeT). In a series of BODIPY derivatives with variously substituted benzene moieties at the 8-position, the oxidation potential of the benzene moiety became more positive and the reduction potential of the BODIPY fluorophore became more negative as the solvent polarity was decreased; consequently, the free energy change of PeT from the benzene moiety becomes larger in a more nonpolar environment. Utilizing this finding, we designed and synthesized a library of probes in which the threshold of fluorescence ON/OFF switching corresponds to different levels of solvent polarity. These environment-sensitive probes were used to examine bovine serum albumin (BSA) and living cells. The polarity at the surface of albumin was concluded to be similar to that of acetone, while the polarity of the internal membranes of HeLa cells was similar to that of dichloromethane.
Self-localizing dynamic microphone arrays (2002)

This paper introduces a mechanism for localizing a microphone array when the location of sound sources in the environment is known. Using the proposed spatial observability function based microphone array integration technique, a maximum likelihood estimator for the correct position and orientation of the array is derived. This is used to localize and track a microphone array with a known and fixed geometrical structure, which can be viewed as the inverse sound localization problem. Simulations using a two-element dynamic microphone array illustrate the ability of the proposed technique to correctly localize and estimate the orientation of the array even in a very reverberant environment. Using 1 s male speech segments from three speakers in a 7 m by 6 m by 2.5 m simulated environment, a 30 cm inter-microphone distance, and PHAT histogram SLF generation, the average localization error was approximately 3 cm with an average orientation error of 19/spl deg/. The same simulation configuration but with 4 s speech segments results in an average localization error less than 1cm, with an average orientation error of approximately 2/spl deg/. Experimental examples illustrate localizations for both stationary and dynamic microphone pairs.
Taxonomy of theStreptomycesstrain ZG0656 that produces acarviostatin α-amylase inhibitors and analysis of their effects on blood glucose levels in mammalian systems (2008)

Acarviostatin III03 is the most potent alpha-amylase inhibitor known to date. The oligomer will benefit the research on the relationship between alpha-amylase and various inhibitors and will offer more choices in diabetes treatments.
Structures of Ternary Complexes of Rat DNA Polymerase β, a DNA Template-Primer, and ddCTP (1994)

Two ternary complexes of rat DNA polymerase β (pol β), a DNA template-primer, and dideoxycytidine triphosphate (ddCTP) have been determined at 2.9 Å and 3.6 Å resolution, respectively. ddCTP is the triphosphate of dideoxycytidine (ddC), a nucleoside analog that targets the reverse transcriptase of human immunodeficiency virus (HIV) and is at present used to treat AIDS. Although crystals of the two complexes belong to different space groups, the structures are similar, suggesting that the polymerase-DNA-ddCTP interactions are not affected by crystal packing forces. In the pol β active site, the attacking 3′-OH of the elongating primer, the ddCTP phosphates, and two Mg 2+ ions are all clustered around Asp 190 , Asp 192 , and Asp 256 . Two of these residues, Asp 190 and Asp 256 , are present in the amino acid sequences of all polymerases so far studied and are also spatially similar in the four polymerases—the Klenow fragment of Escherichia coli DNA polymerase I, HIV-1 reverse transcriptase, T7 RNA polymerase, and rat DNA pol β—whose crystal structures are now known. A two-metal ion mechanism is described for the nucleotidyl transfer reaction and may apply to all polymerases. In the ternary complex structures analyzed, pol β binds to the DNA template-primer in a different manner from that recently proposed for other polymerase-DNA models.
Evaluation of Continuous-Infusion Gallium Nitrate and Hydroxyurea in Combination for the Treatment of Refractory Non-Hodgkin's Lymphoma (1997)

Based on preclinical studies demonstrating synergy between gallium and hydroxyurea, we evaluated the efficacy and toxicity of continuous intravenous gallium nitrate in combination with oral hydroxyurea in patients with refractory non-Hodgkin's lymphoma. Fourteen patients, median age 64 years (range 53-89), with stage III or IV low- or intermediate-grade lymphoma were treated with gallium nitrate and hydroxyurea in combination for 7 days at four different dose levels: (a) gallium nitrate, 200 mg/m2/day; hydroxyurea, 500 mg/day; (b) gallium nitrate, 250 mg/m2/day; hydroxyurea, 1,000 mg/day; (c) gallium nitrate, 300 mg/m2/day; hydroxyurea, 1,000 mg/day; and (d) gallium nitrate, 350 mg/m2/day, hydroxyurea, 1,000 mg/day. All patients had progressive disease and had been heavily pretreated. Six of 14 patients had objective tumor regression following treatment (one complete response, one near-complete response, and four partial responses) with a median duration of response of 7 weeks (range 3-38 weeks). An additional four patients had minor responses. Responses occurred at all dose levels and in both low- and intermediate-grade histologic subtypes. The predominant toxicities encountered were anemia and reversible nephrotoxicity. Combination gallium nitrate and hydroxyurea has significant activity in lymphoma and is well tolerated even by elderly patients. Because of the lack of cross-resistance to other drugs and the potential synergistic antineoplastic activity, gallium nitrate and hydroxyurea should be further evaluated in combination with other chemotherapeutic agents.
Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 (2003)

CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25- naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25- T cells into anergic/suppressor cells that are CD25+, CD45RB-/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor beta (TGF-beta). Although transcription factor Foxp3 has been shown recently to be associated with the development of Treg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-beta induced Foxp3 gene expression in TCR-challenged CD4+CD25- naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-beta and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-beta-converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-beta-induced suppressor T cells prevented house dust mite-induced allergic pathogenesis in lungs.
Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication (2009)

Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection.