gebhart/patrepeval huggingface dataset:
The PARCTAB mobile computing system (2002)

The PARCTAB is a personal digital assistant (PDA) that communicates via infrared (IR) datapackets to a network of IR transceivers. The infrared network is designed for in-building use, where each room becomes a communication cell. In contrast to the approach used by other PDAs, most PARCTAB applications run on remote hosts and therefore depend on reliable communication through the IR network. The infrastructure provides reliability as well as uninterrupted service when a PARCTAB moves from cell to cell. The PARCTAB and a supporting infrastructure has been operational since March 1993 at the Computer Science Lab at Xerox PARC. The system currently comprises thirty cells and twenty-five PARCTABs and will expand in the near future. There are three types of software components in the PARCTAB system: gateways, agents, and applications. Gateways implement a datagram service for sending and receiving packets using IR signals. Each tab is represented by an agent. An agent tracks the location of its tab and provides location independent reliable remote procedure calls. The protocols enforce security, preventing, for example, an unauthorized application from taking control of a tab.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Reconstitution of Membrane Proteins into Lipid-Rich Bilayered Mixed Micelles for NMR Studies (1995)

This paper describes a study undertaken to assess the possibility and practical consequences of reconstituting integral and peripheral membrane proteins into bilayered discoidal mixed micelles ("bicelles") composed of dimyristoylphosphatidylcholine and smaller amounts of either CHAPSO or short-chain phosphatidylcholine. The amphiphilic assemblies in these mixtures are uniquely suited for use in NMR structural studies because they can be magnetically oriented with experimentally-tunable system order. The first step of this study was to test about 15 membrane-associating polypeptides and proteins for their ability to interfere with magnetic orientation of the bicellar assemblies. A variety of results were obtained ranging from no perturbation to a complete disruption of orientation. Second, the suitability of bicelles as mimics of natural bilayers was tested by reconstituting diacylglycerol kinase, an integral membrane enzyme. The kinase was observed to be functional and completely stable for at least 24 h when incubated at 38 degrees C in bicelles. Third, the NMR spectra from a number of bicelle-reconstituted proteins were examined. In some cases, 13C NMR resonances from reconstituted proteins were extremely broad and asymmetric. In other cases, resonances from reconstituted proteins were moderately broad, but much less so than resonances from proteins reconstituted into multilayers oriented by mechanical methods. In the cases of two surface-associating proteins (cytochrome c and leucine enkephalin), oriented sample 13C NMR spectra of extremely high resolution were obtained. For these proteins it was also demonstrated that the experimentally variable order of the bicellar assemblies could be exploited to provide a means of screening for detergent-specific structural perturbations, for making spectral assignments, and for measuring chemical shift anisotropies and dipolar couplings. Taken as a whole, these results indicate that bicelles may be uniquely and effectively employed as model membranes to facilitate NMR structural studies of many, but not all, membrane proteins.
TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity (2013)

The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128-mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synuclein-induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.
Adiponectin Promotes Functional Recovery after Podocyte Ablation (2013)

Low levels of the adipocyte-secreted protein adiponectin correlate with albuminuria in both mice and humans, but whether adiponectin has a causative role in modulating renal disease is unknown. Here, we first generated a mouse model that allows induction of caspase-8-mediated apoptosis specifically in podocytes upon injection of a construct-specific agent. These POD-ATTAC mice exhibited significant kidney damage, mimicking aspects of human renal disease, such as foot process effacement, mesangial expansion, and glomerulosclerosis. After the initial induction, both podocytes and filtration function recovered. Next, we crossed POD-ATTAC mice with mice lacking or overexpressing adiponectin. POD-ATTAC mice lacking adiponectin developed irreversible albuminuria and renal failure; conversely, POD-ATTAC mice overexpressing adiponectin recovered more rapidly and exhibited less interstitial fibrosis. In conclusion, these results suggest that adiponectin is a renoprotective protein after podocyte injury. Furthermore, the POD-ATTAC mouse provides a platform for further studies, allowing precise timing of podocyte injury and regeneration.
Neuroprotective Effects of the CRF1 Antagonist R121920 after Permanent Focal Ischemia in the Rat (2001)

The neuroprotective effects of a systemically active, highly selective, corticotropin-releasing factor-1 (CRF1) receptor antagonist, R121920 ((7-(dipropylamino)-2,5-dimethyl-3- [2-(dimethylamino)-5-pyridyl] pyrazolo [1,5-a] pyrimidine), was assessed in two rat models of permanent focal cerebral ischemia, where the middle cerebral artery (MCA) was occluded either through the subtemporal approach or using the intraluminal suture technique. R121920 rapidly crossed the blood-brain barrier after intravenous (IV) bolus administration (10 mg/kg), with peak brain concentrations at 5 minutes (2.26 +/- 0.40 microg/mL), which were approximately 2-fold greater than those in plasma (0.98 +/- 0.24 microg/mL). Treatment with R121920 (10 mg/kg IV followed by 5 mg/kg subcutaneously at hourly intervals for 4 hours) significantly (P < 0.001) reduced total (by 40%) and cortical (by 37%) infarct volume at 24 hours after subtemporal MCA occlusion (MCAO). In the intraluminal suture MCAO model, IV administration of R121920 (10 mg/kg) at the time of ischemia onset (and at multiple times thereafter) reduced both hemispheric infarct volume (by 34%, P < 0.001) and brain swelling (by 50%, P < 0.001) when assessed at 24 hours. In this model of focal ischemia, significant reduction (P < 0.05) in both outcome measures was obtained when R121920 administration was delayed up to 1 hour after MCAO. These results further define the antiischemic properties of selective CRF 1 antagonists in two experimental models of permanent focal cerebral ischemia.
Predicting Multiple Metrics for Queries: Better Decisions Enabled by Machine Learning (2009)

One of the most challenging aspects of managing a very large data warehouse is identifying how queries will behave before they start executing. Yet knowing their performance characteristics - their runtimes and resource usage - can solve two important problems. First, every database vendor struggles with managing unexpectedly long-running queries. When these long-running queries can be identified before they start, they can be rejected or scheduled when they will not cause extreme resource contention for the other queries in the system. Second, deciding whether a system can complete a given workload in a given time period (or a bigger system is necessary) depends on knowing the resource requirements of the queries in that workload. We have developed a system that uses machine learning to accurately predict the performance metrics of database queries whose execution times range from milliseconds to hours. For training and testing our system, we used both real customer queries and queries generated from an extended set of TPC-DS templates. The extensions mimic queries that caused customer problems. We used these queries to compare how accurately different techniques predict metrics such as elapsed time, records used, disk I/Os, and message bytes. The most promising technique was not only the most accurate, but also predicted these metrics simultaneously and using only information available prior to query execution. We validated the accuracy of this machine learning technique on a number of HP Neoview configurations. We were able to predict individual query elapsed time within 20% of its actual time for 85% of the test queries. Most importantly, we were able to correctly identify both the short and long-running (up to two hour) queries to inform workload management and capacity planning.
Substrate‐specific binding of hook‐associated proteins by FlgN and FliT, putative chaperones for flagellum assembly (1999)

During flagellum assembly by motile enterobacteria, flagellar axial proteins destined for polymerization into the cell surface structure are thought to be exported through the 25-30 A flagellum central channel as partially unfolded monomers. How are premature folding and oligomerization in the cytosol prevented? We have shown previously using hyperflagellated Proteus mirabilis and a motile but non-swarming flgN transposon mutant that the apparently cytosolic 16. 5 kDa flagellar protein FlgN facilitates efficient flagellum filament assembly. Here, we investigate further whether FlgN, predicted to contain a C-terminal amphipathic helix typical of type III export chaperones, acts as a chaperone for axial proteins. Incubation of soluble radiolabelled FlgN from Salmonella typhimurium with nitrocellulose-immobilized cell lysates of wild-type S. typhimurium and a non-flagellate class 1 flhDC mutant indicated that FlgN binds to flagellar proteins. Identical affinity blot analysis of culture supernatants from the wild-type and flhDC, flgI, flgK, flgL, fliC or fliD flagellar mutants showed that FlgN binds to the flagellar hook-associated proteins (HAPs) FlgK and FlgL. This was confirmed by blotting artificially expressed individual HAPs in Escherichia coli. Analysis of axial proteins secreted into the culture medium by the original P. mirabilis flgN mutant demonstrated that export of FlgK and FlgL was specifically reduced, with concomitant increased release of unpolymerized flagellin (FliC), the immediately distal component of the flagellum. These data suggest that FlgN functions as an export chaperone for FlgK and FlgL. Parallel experiments showed that FliT, a similarly small (14 kDa), potentially helical flagellar protein, binds specifically to the flagellar filament cap protein, FliD (HAP2), indicating that it too might be an export chaperone. Flagellar axial proteins all contain amphipathic helices at their termini. Removal of the HAP C-terminal helical domains abolished binding by FlgN and FliT in each case, and polypeptides comprising each of the HAP C-termini were specifically bound by FlgN and FliT. We suggest that FlgN and FliT are substrate-specific flagellar chaperones that prevent oligomerization of the HAPs by binding to their helical domains before export.
Amorphous Drug Delivery Systems: Molecular Aspects, Design, and Performance (2004)

The biopharmaceutical properties-especially the solubility and permeability-of a molecule contribute to its overall therapeutic efficacy. The newer tools of drug discovery have caused a shift in the properties of drug-like compounds, resulting in drugs with poor aqueous solubility and permeability, which offer delivery challenges, thus requiring considerable pharmaceutical manning. The modulation of solubility is a more viable option for enhancing bioavailability than permeability, because of the lack of "safe" approaches to enhance the latter. Solid-state manipulation in general, and amorphization in particular, are preferred ways of enhancing solubility and optimizing delivery of poorly soluble drugs. This review attempts to address the diverse issues pertaining to amorphous drug delivery systems. We discuss the various thermodynamic phenomenon such as glass transition, fragility, molecular mobility, devitrification kinetics, and molecular-level chemical interactions that contribute to the ease of formation, the solubility advantage, and the stability of amorphous drugs. The engineering of pharmaceutical alloys by solubilizing and stabilizing carriers, commonly termed solid dispersions, provide avenues for exploiting the benefits of amorphous systems. Carrier properties, mechanisms of drug release, and study of release kinetics help to improve the predictability of performance. The review also addresses the various barriers in the design of amorphous delivery systems, use of amorphous form in controlled release delivery systems, and their in vivo performance.
Lignin monomer composition is determined by the expression of a cytochrome P450-dependent monooxygenase in Arabidopsis (1998)

The phenylpropanoid pathway provides precursors for the biosynthesis of soluble secondary metabolites and lignin in plants. Ferulate-5-hydroxylase (F5H) catalyzes an irreversible hydroxylation step in this pathway that diverts ferulic acid away from guaiacyl lignin biosynthesis and toward sinapic acid and syringyl lignin. This fact led us to postulate that F5H was a potential regulatory step in the determination of lignin monomer composition. To test this hypothesis, we have used Arabidopsis to examine the impact of F5H overexpression. Arabidopsis is a useful model system in which to study lignification because in wild-type plants, guaiacyl and syringyl lignins are deposited in a tissue-specific fashion, while the F5H-deficient fah1 mutant accumulates only guaiacyl lignin. Here we show that ectopic overexpression of F5H in Arabidopsis abolishes tissue-specific lignin monomer accumulation. Surprisingly, overexpression of F5H under the control of the lignification-associated cinnamate-4-hydroxylase promoter, but not the commonly employed cauliflower mosaic virus 35S promoter, generates a lignin that is almost entirely comprised of syringylpropane units. These experiments demonstrate that modification of F5H expression may enable engineering of lignin monomer composition in agronomically important plant species.
Abstract 4919: Myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation potentiates human lung cancer cell malignancy . (2013)

Abstract Myristoylated alanine-rich C kinase substrate (MARCKS), a substrate of protein kinase C (PKC), is a key regulatory molecule controlling mucin secretion by airway epithelial cells in vitro and in vivo. Phosphorylated MARCKS (p-MARCKS) has been reportedly to promote inflammatory cell migration in several lung diseases. However, the functionality of MARCKS and its related phosphorylation in lung cancer malignancy has not been characterized. This study demonstrated MARCKS expression and elevated p-MARCKS in various lung cancer cell lines with high malignancy, such as CL1-0-F3, CL1-5, PC9, A549 and several tyrosine kinase inhibitor (TKI) resistant cell lines (H1650 and H1975), as compared with normal human bronchial epithelial (NHBE) cells and low metastasis cancer cell line. siRNA knockdown MARCKS expression resulted in an inhibition of cell migration, accompanying with a decrease of Slug expression in these malignant lung cancer cell lines. Treatment with myristoylated 24-amino-acid MARCKS N-terminus sequence (MANS) peptide, but not the control myristoylated random N-terminal sequence (RNS) peptide, suppressed MARCKS phosphorylation and impaired cell migration and wound healing ability in these lung cancer cell lines. Importantly, MANS peptide treatment resulted in a suppression of lamellipodia/filopodia formation and an enhancement of cell-cell contacts with increased E-cadherin expression. These results confirmed a crucial role for MARCKS, specifically its phosphorylation, in potentiating lung cancer cell migration and malignancy. This study has also suggested a potential usage of MANS or the MARCKS-related peptides in the treatment of lung cancer metastasis. Citation Format: Ching-Hsien Chen, Phillip Thai, Reen Wu. Myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation potentiates human lung cancer cell malignancy . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4919. doi:10.1158/1538-7445.AM2013-4919
A small molecule‐directed approach to control protein localization and function (2008)

Protein localization is tightly linked with function, such that the subcellular distribution of a protein serves as an important control point regulating activity. Exploiting this regulatory mechanism, we present here a general approach by which protein location, and hence function, may be controlled on demand in the budding yeast. In this system a small molecule, rapamycin, is used to temporarily recruit a strong cellular address signal to the target protein, placing subcellular localization under control of the selective chemical stimulus. The kinetics of this system are rapid: rapamycin-directed nucleo-cytoplasmic transport is evident 10-12 min post-treatment and the process is reversible upon removal of rapamycin. Accordingly, we envision this platform as a promising approach for the systematic construction of conditional loss-of-function mutants. As proof of principle, we used this system to direct nuclear export of the essential heat shock transcription factor Hsf1p, thereby mimicking the cell-cycle arrest phenotype of an hsf1 temperature-sensitive mutant. Our drug-induced localization platform also provides a method by which protein localization can be uncoupled from endogenous cell signalling events, addressing the necessity or sufficiency of a given localization shift for a particular cell process. To illustrate, we directed the nuclear import of the calcineurin-dependent transcription factor Crz1p in the absence of native stimuli; this analysis directly substantiates that nuclear translocation of this protein is insufficient for its transcriptional activity. In total, this technology represents a powerful method for the generation of conditional alleles and directed mislocalization studies in yeast, with potential applicability on a genome-wide scale.
Effect of transcranial magnetic stimulation on single‐unit activity in the cat primary visual cortex (2003)

Transcranial magnetic stimulation (TMS) has become a well established procedure for testing and modulating the neuronal excitability of human brain areas, but relatively little is known about the cellular processes induced by this rather coarse stimulus. In a first attempt, we performed extracellular single-unit recordings in the primary visual cortex (area 17) of the anaesthetised and paralysed cat, with the stimulating magnetic field centred at the recording site (2 x 70 mm figure-of-eight coil). The effect of single biphasic TMS pulses, which induce a lateral-to-medial electric current within the occipital pole of the right hemisphere, was tested for spontaneous as well as visually evoked activity. For cat visual cortex we found that a single TMS pulse elicited distinct episodes of enhanced and suppressed activity: in general, a facilitation of activity was found during the first 500 ms, followed thereafter by a suppression of activity lasting up to a few seconds. Strong stimuli exceeding 50 % of maximal stimulator output could also lead to an early suppression of activity during the first 100-200 ms, followed by stronger (rebound) facilitation. Early suppression and facilitation of activity may be related to a more or less direct stimulation of inhibitory and excitatory interneurons, probably with different thresholds. The late, long-lasting suppression is more likely to be related to metabotropic or metabolic processes, or even vascular responses. The time course of facilitation/inhibition may provide clues regarding the action of repetitive TMS application.
Unsupervised Part-of-Speech Tagging with Bilingual Graph-Based Projections (2011)

We describe a novel approach for inducing unsupervised part-of-speech taggers for languages that have no labeled training data, but have translated text in a resource-rich language. Our method does not assume any knowledge about the target language (in particular no tagging dictionary is assumed), making it applicable to a wide array of resource-poor languages. We use graph-based label propagation for cross-lingual knowledge transfer and use the projected labels as features in an unsupervised model (Berg-Kirkpatrick et al., 2010). Across eight European languages, our approach results in an average absolute improvement of 10.4 % over a state-of-the-art baseline, and 16.7 % over vanilla hidden Markov models induced with the Expectation Maximization algorithm. 1
Cholesterol Requirement of Mycoplasmas (1970)

Cholesterol requirement for growth of mycoplasmas was tested in a serum-free medium supplemented with albumin, l-arginine, palmitic acid, and various concentrations of cholesterol dissolved in Tween 80. In cases in which Tween 80 was shown to inhibit growth, the test medium was supplemented with cholesterol dissolved in ethanol. Of the 31 species examined, all but Mycoplasma laidlawii, M. granularum, and Mycoplasma species strain S-743 exhibited a growth response to cholesterol. No requirement for cholesterol could be shown with the stable L-phase variants of Streptobacillus moniliformis and Proteus species. The results provide experimental support for the view that the large majority of the established Mycoplasma species require cholesterol for growth.
1-(5-Oxohexyl)-3,7-Dimethylxanthine, a Phosphodiesterase Inhibitor, Activates MAPK Cascades and Promotes Osteoblast Differentiation by a Mechanism Independent of PKA Activation (Pentoxyfilline Promotes Osteoblast Differentiation) (2001)

We have investigated the effect of 1-(5-oxohexyl)-3,7-dimethylxanthine or pentoxifylline (PeTx), a nonselective phosphodiesterase inhibitor, on osteoblastic differentiation in vitro by using two mesenchymal cell lines, C3H10T1/2 and C2C12, which are able to acquire the osteoblastic phenotype in the presence of bone morphogenetic protein-2 (BMP-2). PeTx induced the osteoblastic markers, osteocalcin and Osf2/Cbfa1, in C3H10T1/2 and C2C12 cells and enhanced BMP-2-induced expression of osteocalcin, Osf2/Cbfa1, and alkaline phosphatase. This activity was partially attributed to the fact that PeTx is able to enhance BMP-2-induced Smad1 transcriptional activity. Although PeTx clearly stimulates PKA in these cells, neither pretreatment of cells with the PKA inhibitor H89 nor transfection with the specific PKA inhibitor PKI prevented the induction or enhancement of osteoblast markers by PeTx, demonstrating that these effects were independent of PKA activation. On the other hand, PeTx induced the activation of ERK1/2 and p38 kinase pathways independently of the activation of PKA. Selective inhibitors of these MAPK cascades prevented the induction of osteoblastic markers in cells treated with PeTx, suggesting that the activation of these two pathways plays a role in the effect of PeTx on osteoblastic differentiation.