gebhart/patrepeval huggingface dataset:
AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality (2017)

The absent in melanoma 2 (AIM2) inflammasome plays an important role in many viral and bacterial infections, but very little is known about its role in RNA virus infection, including influenza A virus (IAV). In this study, we have designed in vivo and in vitro studies to determine the role of AIM2 in infections with lethal doses of IAVs A/PR8/34 and A/California/07/09. In wild-type mice, IAV infection enhanced AIM2 expression, induced dsDNA release, and stimulated caspase-1 activation and release of cleaved IL-1β in the lung, which was significantly reduced in AIM2-deficient mice. Interestingly, AIM2 deficiency did not affect the transcription of caspase-1 and IL-1β. In addition, AIM2-deficient mice exhibited attenuated lung injury and significantly improved survival against IAV challenges, but did not alter viral burden in the lung. However, AIM2 deficiency did not seem to affect adaptive immune response against IAV infections. Furthermore, experiments with AIM2-specific small interfering RNA-treated and AIM2-deficient human and mouse lung alveolar macrophages and type II cells indicated a macrophage-specific function of AIM2 in regulation of IAV-stimulated proinflammatory response. Collectively, our results demonstrate that influenza infection activates the AIM2 inflammasome, which plays a critical role in IAV-induced lung injury and mortality. AIM2 might serve as a therapeutic target for combating influenza-associated morbidity and mortality without compromising the host antiviral responses.
Cognitive and neuropsychiatric disorders in extrapyramidal diseases (2012)

The affliction of basal ganglia and their associations, which underlies extrapyramidal diseases, leads not only to diverse movements, but also to a broad spectrum of neuropsychological disorders, including cognitive, emotional-personality, and psychotic ones. The basis for these disorders are most commonly dysfunction of one or a few parallel frontostriatal circuits combining the basal ganglia with the thalamus, limbic structures, frontal and other cortical regions into the uniform functional system. The pattern of neuropsychological disorders has both specific and common features, the discussion of which is the subject matter of this paper. Analysis of the specific features of neuropsychological and behavioral disorders allows one to specify the localization of a pathological process and its extent, which may be of important differential diagnostic value. Cognitive and emotional-personality impairments sometimes develop earlier than motor disorders and their detection may be of significance for the early diagnosis of Parkinson’s disease or Huntington’s disease in persons who are predisposed to these diseases. Moreover, to establish the nature of mental disorders and the degree of their disadapting effect and to identify the affected and preserved components in the psychic processes are important for the choice of adequate pharmacotherapy and the elaboration of neuropsychological rehabilitation programs.
Twenty-first aminoacyl-tRNA synthetase–suppressor tRNA pairs for possible use in site-specific incorporation of amino acid analogues into proteins in eukaryotes and in eubacteria (2001)

Two critical requirements for developing methods for the site-specific incorporation of amino acid analogues into proteins in vivo are ( i ) a suppressor tRNA that is not aminoacylated by any of the endogenous aminoacyl-tRNA synthetases (aaRSs) and ( ii ) an aminoacyl-tRNA synthetase that aminoacylates the suppressor tRNA but no other tRNA in the cell. Here we describe two such aaRS–suppressor tRNA pairs, one for use in the yeast Saccharomyces cerevisiae and another for use in Escherichia coli . The “21st synthetase–tRNA pairs” include E. coli glutaminyl-tRNA synthetase (GlnRS) along with an amber suppressor derived from human initiator tRNA, for use in yeast, and mutants of the yeast tyrosyl-tRNA synthetase (TyrRS) along with an amber suppressor derived from E. coli initiator tRNA, for use in E. coli . The suppressor tRNAs are aminoacylated in vivo only in the presence of the heterologous aaRSs, and the aminoacylated tRNAs function efficiently in suppression of amber codons. Plasmids carrying the E. coli GlnRS gene can be stably maintained in yeast. However, plasmids carrying the yeast TyrRS gene could not be stably maintained in E. coli . This lack of stability is most likely due to the fact that the wild-type yeast TyrRS misaminoacylates the E. coli proline tRNA. By using error-prone PCR, we have isolated and characterized three mutants of yeast TyrRS, which can be stably expressed in E. coli . These mutants still aminoacylate the suppressor tRNA essentially quantitatively in vivo but show increased discrimination in vitro for the suppressor tRNA over the E. coli proline tRNA by factors of 2.2- to 6.8-fold.
Shoot Meristem Function and Leaf Polarity: The Role of Class III HD–ZIP Genes (2006)

The shoot apical meristem comprises an organized cluster of cells with a central region population of self-maintaining stem cells providing peripheral region cells that are recruited to form differentiated lateral organs. Leaves, the principal lateral organ of the shoot, develop as polar structures typically with distinct dorsoventrality. Interdependent interactions between the meristem and developing leaf provide essential cues that serve both to maintain the meristem and to pattern dorsoventrality in the initiating leaf. A key component of both processes are the class III HD-ZIP genes. Current findings are defining the developmental role of members of this family and are identifying multiple mechanisms controlling expression of these genes.
Forkhead Box M1 Regulates the Transcriptional Network of Genes Essential for Mitotic Progression and Genes Encoding the SCF (Skp2-Cks1) Ubiquitin Ligase (2005)

The Forkhead box m1 (Foxm1) gene is critical for G(1)/S transition and essential for mitotic progression. However, the transcriptional mechanisms downstream of FoxM1 that control these cell cycle events remain to be determined. Here, we show that both early-passage Foxm1(-)(/)(-) mouse embryonic fibroblasts (MEFs) and human osteosarcoma U2OS cells depleted of FoxM1 protein by small interfering RNA fail to grow in culture due to a mitotic block and accumulate nuclear levels of cyclin-dependent kinase inhibitor (CDKI) proteins p21(Cip1) and p27(Kip1). Using quantitative chromatin immunoprecipitation and expression assays, we show that FoxM1 is essential for transcription of the mitotic regulatory genes Cdc25B, Aurora B kinase, survivin, centromere protein A (CENPA), and CENPB. We also identify the mechanism by which FoxM1 deficiency causes elevated nuclear levels of the CDKI proteins p21(Cip1) and p27(Kip1). We provide evidence that FoxM1 is essential for transcription of Skp2 and Cks1, which are specificity subunits of the Skp1-Cullin 1-F-box (SCF) ubiquitin ligase complex that targets these CDKI proteins for degradation during the G(1)/S transition. Moreover, early-passage Foxm1(-)(/)(-) MEFs display premature senescence as evidenced by high expression of the senescence-associated beta-galactosidase, p19(ARF), and p16(INK4A) proteins. Taken together, these results demonstrate that FoxM1 regulates transcription of cell cycle genes critical for progression into S-phase and mitosis.
Abnormalities of liver function and hepatic damage associated with total parenteral nutrition. (1992)

Liver dysfunction associated with total parenteral nutrition (TPN) probably is of multifactorial etiology. Available data justify the following recommendations. First, patients should be given balanced and complete solutions tailored to their specific needs and should not be overfed. Second, serum liver enzymes should be measured at least once a week. Third, oral or enteral intake, even if minimal, should be instituted as soon as possible. Fourth, glutamine may prove useful, although this measure is experimental. Finally, if liver dysfunction is detected, oral metronidazole, neomycin, or gentamicin may prove beneficial.
Real Time Industrial Machine Vision (1994)

Vision is a particularly useful sensor since it is non-contact, and can be used for fault detection, metrology, and object location. While machine vision techniques in general have received considerable attention, systems for carrying out this processing in real-time have not been the subject of similar effort. Real-time processing means processing vision data at camera pixel or frame rates. Rates of this order are necessary for high-speed inspection, object tracking or visual feedback control. Data processing at these speeds is generally beyond the capability of currently available fast digital signal processors and it has proved necessary to design equipment specifically for machine vision. Even in machine vision applications where real-time processing is not required, short machine cycle times still often necessitate the use of this approach. This paper examines the requirements of real-time machine vision and describes techniques and modules, which have been developed to this end in the CSIRO Division of Manufacturing Technology. Processing boards have been designed for high-speed surface defect detection and for pixel-rate single-pass scene analysis. Recent attention has been focused on boards able to be configured for quite general parallel processing and compilers and other software utilities for programming these boards have been written. Digital cameras with inbuilt pixel correction and image processing are under development. Several application projects, which could only be carried out by using these approaches are described, including surface defect analysis, quality control inspection, dynamic visual robot control and traffic monitoring.
Non-invasive dielectric measurements with the scanning potential microscope (1994)

The scanning potential microscope (SPM) is a new form of scanning microscope, which maps distributions of spatial potential by direct measurement. The SPM may be used to study, non-invasively, the electrical properties of samples through the potential distribution created near the sample in response to an applied electric field. Spatial resolution and sample to SPM spacing are both close to 1 mu m at the present stage of development of the instrument. We present an SPM study of a test sample comprising three dielectric layers with differing relative permittivities: a 35 mu m film of cellulose acetate (CA, epsilon r approximately=5); a 25 mu m film of polyvinylidenefluoride (PVDF, epsilon r approximately=8.4); and a 50 mu m film of polytetrafluoroethylene (PTFE, epsilon r approximately=2-2.1). In the experimental set-up a small, audio-frequency electric displacement was applied through the sample. SPM mapping of the resultant potential distribution close to the sample yielded values of relative permittivity that were within 2% of the material specifications.
A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung (1995)

Ischemia-reperfusion (I-R) injury of the lung occurs after lung transplantation, pulmonary thromboembolectomy, or cardiopulmonary bypass. In the heart, adenosine, A1 adenosine receptor agonists, and a brief period of preconditioning ischemia attenuate I-R injury. Moreover, in the lung, thromboxane is released during ischemia and is an important mediator of I-R injury. We previously reported that adenosine produces vasoconstriction in the feline pulmonary vascular bed by acting on A1 receptors to induce the release of thromboxane and that these vasoconstrictor responses are desensitized by low doses of A1 receptor agonists. Because A1 receptor agonists mimic the effect of preconditioning ischemia, we hypothesized, in contrast to previously proposed mechanisms, that small amounts of adenosine released during preconditioning ischemia desensitize A1 receptors. Also, we hypothesized that greater amounts of adenosine are released after longer periods of ischemia, which activate A1 receptors. Thus if desensitization of A1 receptors is the mechanism by which preconditioning attenuates I-R injury of the heart and A1 receptor activation during ischemia plays an important role in I-R injury of the lung, A1 receptor antagonists should provide a protective effect in I-R injury of the lung. In this study, 2 h of ischemia and 2 h of reperfusion of the left lower lobe in intact-chest, spontaneously breathing cats caused lung injury characterized by the presence of neutrophils, macrophages, and RBCs in alveoli and caused alveolar edema, which was blocked in a highly significant manner by the A1 receptor antagonists xanthine amine congener (XAC) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). An intralobar arterial infusion of XAC (30 min before ischemia) reduced the %injured alveoli (defined as presence of 2 or more inflammatory cells or RBCs, or edematous fluid) from 60 +/- 10 to 7 +/- 2%, which was not significantly different from controls (5 +/- 1%; P < 0.0001). DPCPX (iv) reduced the %injured alveoli to 13 +/- 7% when administered 30 min before ischemia and to 6 +/- 2% when administered after 1 h of reperfusion, not significantly different from controls (P < 0.0001). Preconditioning ischemia (10-min ischemia +10-min reperfusion) also reduced the %injured alveoli after 2 h ischemia and 2 h reperfusion to 23 +/- 13%, almost identical to 2 h ischemia and 1 h reperfusion. These data support the hypothesis that A1 receptor antagonists block I-R injury of the lung. A1 receptor antagonists may be useful in preventing I-R injury after transplant surgery and during surgical procedures associated with I-R injury of the heart, brain, kidney, and spinal cord.
Quantitative Magnetic Resonance Imaging of the Lumbar Spine (1995)

Quantitative magnetic resonance imaging (relaxation time and proton density measurements) has gained increasing interest as a noninvasive way to study changes in water content and biochemical composition of lumbar intervertebral discs and vertebral bodies. This article reviews the current methodological problems and the feasibility of quantitative magnetic resonance imaging in the lumbar spine for investigations on water content and biological composition. This technique does not allow direct quantification of water content. Although biochemical variations may sensitively influence relaxation times and proton density under in vitro conditions, it is not feasible to obtain sufficiently reliable and specific information to monitor biochemical alterations associated with lumbar disc pathology in vivo.
Kynurenine pathway abnormalities in Parkinson's disease (1992)

We measured metabolites of tyrosine and tryptophan (TRP) in the frontal cortex, putamen (PT), and pars compacta of the substantia nigra (SN) of control and Parkinson's disease (PD) brain tissues. Dopamine concentrations were significantly decreased in the PT and SN of PD tissue, regardless of L-dopa therapy. However, 3-O-methyldopa (3OMD) concentration showed a significant increase in each region of the PD group treated with L-dopa (PD[+]) as compared with both the control group and the PD group without L-dopa therapy (PD[-]). Therefore, 3OMD concentration appears to be a reliable marker of L-dopa therapy. Serotonin concentration was lower in each region of the PD groups than in the control group. Although the magnitude of decrease was greater in the PD(+) group, there was no statistical significance between the two PD groups. The same patterns of decrease were present in kynurenine (KYN) and kynurenic acid (KYA) concentrations, but the molar ratios of TRP to KYN and KYN to KYA were unchanged among three groups. In contrast, 3-hydroxykynurenine (3OHKY) concentration was increased in the PT PD(-) group and in three regions of the PD(+) group. Since the KYN pathway leads to formation of nicotinamide-adenine dinucleotide (NADH), the present results may be a further indication of a defect in NADH:ubiquinone oxidoreductase (complex I) in mitochondria in PD.
Stay Fresh: Speculative Synchronization for Fast Distributed Machine Learning (2018)

Large machine learning models are typically trained in parallel and distributed environments. The model parameters are iteratively refined by multiple worker nodes in parallel, each processing a subset of the training data. In practice, the training is usually conducted in an asynchronous parallel manner, where workers can proceed to the next iteration before receiving the latest model parameters. While this maximizes the rate of updates, the price paid is compromised training quality as the computation is usually performed using stale model parameters. To address this problem, we propose a new scheme, termed speculative synchronization. Our scheme allows workers to speculate about the recent parameter updates from others on the fly, and if necessary, the workers abort the ongoing computation, pull fresher parameters, and start over to improve the quality of training. We design an effective heuristic algorithm to judiciously determine when to restart training iterations with fresher parameters by quantifying the gain and loss. We implement our scheme in MXNet-a popular machine learning framework-and demonstrate its effectiveness through cluster deployment atop Amazon EC2. Experimental results show that speculative synchronization achieves up to 3× speedup over the asynchronous parallel scheme in many machine learning applications, with little additional communication overhead.
Deconstructing Lipid Kinase Inhibitors by Chemical Proteomics (2017)

Diacylglycerol kinases (DGKs) regulate lipid metabolism and cell signaling through ATP-dependent phosphorylation of diacylglycerol to biosynthesize phosphatidic acid. Selective chemical probes for studying DGKs are currently lacking and are needed to annotate isoform-specific functions of these elusive lipid kinases. Previously, we explored fragment-based approaches to discover a core fragment of DGK-α (DGKα) inhibitors responsible for selective binding to the DGKα active site. Here, we utilize quantitative chemical proteomics to deconstruct widely used DGKα inhibitors to identify structural regions mediating off-target activity. We tested the activity of a fragment (RLM001) derived from a nucleotide-like region found in the DGKα inhibitors R59022 and ritanserin and discovered that RLM001 mimics ATP in its ability to broadly compete at ATP-binding sites of DGKα as well as >60 native ATP-binding proteins (kinases and ATPases) detected in cell proteomes. Equipotent inhibition of activity-based probe labeling by RLM001 supports a contiguous ligand-binding site composed of C1, DAGKc, and DAGKa domains in the DGKα active site. Given the lack of available crystal structures of DGKs, our studies highlight the utility of chemical proteomics in revealing active-site features of lipid kinases to enable development of inhibitors with enhanced selectivity against the human proteome.
Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. (1994)

A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis.
Mixed backbone antisense oligonucleotides: design, biochemical and biological properties of oligonucleotides containing 2'-5'-ribo- and 3'- 5'-deoxyribonucleotide segments (1997)

We have designed and synthesized mixed backbone oligonucleotides (MBOs) containing 2'-5'-ribo- and 3'-5'-deoxyribonucleotide segments. Thermal melting studies of the phosphodiester MBOs (three 2'-5'linkages at each end) with the complementary 3'-5'-DNA and -RNA target strands suggest that 2'-5'-ribonucleoside incorporation into 3'-5'-oligodeoxyribonucleotides reduces binding to the target strands compared with an all 3'-5'-oligodeoxyribonucleotide of the same sequence and length. Increasing the number of 2'-5'linkages (from six to nine) further reduces binding to the DNA target strand more than the RNA target strand [Kandimalla,E.R. and Agrawal,S. (1996)Nucleic Acids Symp. Ser., 35, 125-126]. Phosphorothioate (PS) analogs of MBOs destabilize the duplex with the DNA target strand more than the duplex with the RNA target strand. Circular dichroism studies indicate that the duplexes of MBOs with the DNA and RNA target strands have spectral characteristics of both A- and B-type conformations. Compared with the control oligonucleotide, MBOs exhibit moderately higher stability against snake venom phosphodiesterase, S1 nuclease and in fetal calf serum. Although 2'-5'modification does not evoke RNase H activity, this modification does not effect the RNase H activation property of the 3'-5'-deoxyribonucleotide segment adjacent to the modification. In vitro studies with MBOs suggest that they have lesser effects on cell proliferation, clotting prolongation and hemolytic complement lysis than do control PS oligodeoxyribonucleotides. PS analogs of MBOs show HIV-1 inhibition comparable with that of a control PS oligodeoxyribonucleotide with all 3'-5'linkages. The current results suggest that a limited number of 2'-5'linkages could be used in conjunction with PS oligonucleotides to further modulate the properties of antisense oligonucleotides as therapeutic agents.
Myocardial Uptake of Bupivacaine (1993)

Bupivacaine, but not lidocaine, may cause severe cardiac dysrrhythmias in case of accidental intravascular injection. In an attempt to discriminate between a pharmacokinetic and a pharmacodynamic (or both) origin to these differences, we used an isolated rabbit heart model with constant coronary inflow to compare the myocardial uptake and disposition kinetics of lidocaine and bupivacaine. Drug concentration in the outflow perfusate was assayed and surface electrocardiogram was recorded. Drug uptake and disposition kinetics were modeled with a two-compartment open model. An Emax model was used to describe the increase in QRS duration in relation with drug concentration in the central compartment. Lidocaine and bupivacaine exhibited similar myocardial pharmacokinetics (i.e., a rapid decrease in the outflow concentration upon drug administration discontinuation). Bupivacaine-induced maximum increase in QRS duration (Emax) was 15 times superior to lidocaine Emax. The steady-state perfusate concentration producing half Emax was the same for both drugs. We conclude that bupivacaine-induced QRS widening decreases almost at the same rate as does lidocaine-induced QRS widening when drug administration is terminated. Therefore, the different cardiac effects of lidocaine and bupivacaine are not due to differences in myocardial uptake and disposition kinetics.