gebhart/patrepeval huggingface dataset:
siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference (2004)

siDirect (http://design.RNAi.jp/) is a web-based online software system for computing highly effective small interfering RNA (siRNA) sequences with maximum target-specificity for mammalian RNA interference (RNAi). Highly effective siRNA sequences are selected using novel guidelines that were established through an extensive study of the relationship between siRNA sequences and RNAi activity. Our efficient software avoids off-target gene silencing to enumerate potential cross-hybridization candidates that the widely used BLAST search may overlook. The website accepts an arbitrary sequence as input and quickly returns siRNA candidates, providing a wide scope of applications in mammalian RNAi, including systematic functional genomics and therapeutic gene silencing.
Eosinophilic oesophagitis in adults (2009)

Previously considered a rare condition, eosinophilic oesophagitis (EoE) has become increasingly recognized as an important cause of dysphagia and food impactions in adults. This is likely attributable to a combination of an increasing incidence of EoE and a growing awareness of the condition. EoE may occur in isolation or in conjunction with eosinophilic gastroenteritis. However, the burgeoning field is likely attributable to the variant that uniquely affects the oesophagus. Adults classically present with symptoms of dysphagia, food impactions, and heartburn. Typical endoscopic features include concentric mucosal rings, linear furrowing, white plaques or exudates and a narrow caliber oesophagus. In some cases, the endoscopic features may appear normal. For years, EoE went unrecognized because eosinophilic infiltration was accepted as a manifestation of reflux, which continues to be a confounding factor in some patients. Current consensus is that the diagnosis of EoE is established by 1) the presence of symptoms, especially dysphagia and food impactions in adults, 2) > or =15 eosinophils per high power field in oesophageal tissue, and 3) exclusion of other disorders with similar presentations such as GERD. Current understanding of EoE pathophysiology and natural history are limited but the entity has been increasingly linked to food allergies and aeroallergens. The main treatment options for EoE are proton pump inhibitors, dietary manipulation, and topical or oral glucocorticoids. This review highlights recent insights into EoE in adults although, clearly, much of the available data overlap with pediatrics and, occasionally, with eosinophilic gastroenteritis.
Detoxification of Wastewater: Catalytic Oxidation of 4-Nitrophenol in a Slurry Reactor (1996)

Destruction of 4-nitrophenol (or p-nitrophenol, pnp) in a semibatch slurry reactor employing a 5C{u}O:5Ti0{2}:100SiO{2} catalyst has been effectively carried out at relatively mild operating conditions of 373-393K and 100-150 kPa oxygen pressure. Kinetic data were collected with negligible mass transfer resistances. Analysis of the concentration-time data revealed that the autocatalytic step frequently seen during phenol oxidation was nonexistent in the reaction pathway. A redox Langmuir-Hinshelwood single-site mechanism involving the oxygen assisted cleavage of the benzene ring as the rate-controlling step offered a kinetic model that adequately described the rate data. Estimates of the adsorption equilibrium constants for both 4-nitrophenol and oxygen were also thermodynamically consistent, and activation energy was valued at 42 kJ mol{1}. The degradation rate has an order of about 1.43 with respect to p-nitrophenol concentration and relatively weakly dependent (about 0.12) on oxygen partial pressure. Excellent activity of the catalyst was attributed to synergy between surface CuO and Ti0{2} species.
Review: Biocatalytic transformations of ferulic acid: An abundant aromatic natural product (1995)

In this review we examine the fascinating array of microbial and enzymatic transformations of ferulic acid. Ferulic acid is an extremely abundant, preformed phenolic aromatic chemical found widely in nature. Ferulic acid is viewed as a commodity scale, renewable chemical feedstock for biocatalytic conversion to other useful aromatic chemicals. Most attention is focused on bioconversions of ferulic acid itself. Topics covered include cinnamoyl side-chain cleavage; nonoxidative decarboxylation; mechanistic details of styrene formation; purification and characterization of ferulic acid decarboxylase; conversion of ferulic acid to vanillin; O-demethylation; and reduction reactions. Biotransformations of vinylguaiacol are discussed, and selected biotransformations of vanillic acid including oxidative and nonoxidative decarboxylation are surveyed. Finally, enzymatic oxidative dimerization and polymerization reactions are reviewed.
A requirement of hydrophobic and basic amino acid residues for substrate recognition by Ca2+/calmodulin-dependent protein kinase Ia. (1994)

The substrate recognition determinants of Ca2+/calmodulin-dependent protein kinase Ia were investigated by using peptide analogues based on the amino acid sequence around Ser-9 of synapsin I. The Km and Vmax for the synthetic peptide Leu-Arg-Arg-Arg-Leu-Ser-Asp-Ala-Asn-Phe are 3.9 microM and 18.5 mumol/(min.mg), respectively. Deletion of Leu at the -5 position lowers the Vmax/Km by 470-fold. The requirement for a hydrophobic residue at -5 was confirmed by the 90- to 2400-fold reduction in Vmax/Km produced by Arg, Ala, or Asp substitutions, but only 2.6-fold decrease after Phe substitution at this position. A hydrophobic residue is similarly required at the +4 position. Deletion of Phe at this position produces a 67-fold reduction, and substitution of Ala for Phe a 43-fold reduction in Vmax/Km. In contrast, substitution with Leu increases Vmax/Km by 1.8-fold. Arg at -3 is also required for recognition as shown by an approximately 240-fold decrease in Vmax/Km after Ala substitution at this position. Positions -2, -4, and +1 appear to play secondary roles in substrate recognition. Arg at -2 and -4 are positive determinants, since Ala substitution at these positions decreases Vmax/Km by 4.7- and 11-fold, respectively. Asp at +1 is a negative influence, since Ala and Leu substitutions at this position increase Vmax/Km by 2.3- and 6.3-fold, respectively. Substitution of Ala for Leu at -1 or Thr for Ser at the 0 position has little effect on phosphorylation kinetics. Thus, Ca2+/calmodulin-dependent protein kinase Ia has the minimal substrate recognition motif of Hyd-Xaa-Arg-Xaa-Xaa-(Ser*/Thr*)-Xaa-Xaa-Xaa-Hyd, where Hyd represents a hydrophobic amino acid residue.
Vulnerability of125I-α-Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey (2001)

Parkinson's disease, a neurodegenerative movement disorder characterized by selective degeneration of nigrostriatal dopaminergic neurons, affects approximately 1% of the population over 50. Because nicotinic acetylcholine receptors (nAChRs) may represent an important therapeutic target for this disorder, we performed experiments to elucidate the subtypes altered with nigrostriatal damage in parkinsonian monkeys. For this purpose we used (125)I-alpha-conotoxin MII (CtxMII), a relatively new ligand that identifies alpha3 and/or alpha6 subunits containing nAChR subtypes. In brain from untreated monkeys, there was saturable (125)I-alpha-CtxMII binding to a single population of high-affinity nicotinic sites (K(d) = 0.9 nm), primarily localized in the visual, habenula-interpeduncular, and nigrostriatal-mesolimbic pathways. Administration of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine resulted in damage to the nigrostriatal system and parkinsonism. Autoradiographic analysis showed that (125)I-alpha-CtxMII sites were selectively reduced (>/=99%) in the basal ganglia and that the lesion-induced decreases correlated well with declines in the dopamine transporter, a marker of dopaminergic neuron integrity. These findings may indicate that most or all of (125)I-alpha-CtxMII-labeled nAChR subtypes in the basal ganglia are present on nigrostriatal dopaminergic neurons, in contrast to (125)I-epibatidine sites. These data suggest that the development of ligands directed to nAChR subtypes containing alpha3 and/or alpha6 subunits may yield a novel treatment strategy for parkinsonian patients with nigrostriatal dopaminergic degeneration.
Color naming models for color selection, image editing and palette design (2012)

Our ability to reliably name colors provides a link between visual perception and symbolic cognition. In this paper, we investigate how a statistical model of color naming can enable user interfaces to meaningfully mimic this link and support novel interactions. We present a method for constructing a probabilistic model of color naming from a large, unconstrained set of human color name judgments. We describe how the model can be used to map between colors and names and define metrics for color saliency (how reliably a color is named) and color name distance (the similarity between colors based on naming patterns). We then present a series of applications that demonstrate how color naming models can enhance graphical interfaces: a color dictionary & thesaurus, name-based pixel selection methods for image editing, and evaluation aids for color palette design.
Dissociation and reassociation of the phosphorylated and nonphosphorylated forms of adenosine 3':5' -monophosphate-dependent protein kinase from bovine cardiac muscle. (1976)

Adenosine 3':5' -monophosphate (cyclic AMP) -dependent protein kinase from bovine heart muscle catalyzes the phosphorylation of its regulatory, cyclic AMP-binding subunit. Phosphorylation enhances net dissociation of the enzyme by cyclic AMP. Chromatography on omega-aminohexyl-agarose was used to study the effects of phosphorylation on cyclic AMP binding and subunit dissociation and reassociation. This method permitted rapid separation of the catalytic subunit from the cyclic AMP -binding protein and holoenzyme. Phospho- and dephosphoprotein kinases were found to dissociate to the same extent at any given concentration of cyclic AMP and completely at saturation. At equilibrium, the amount of cyclic AMP bound was the same for both forms of enzyme and was directly proportional to the degree of dissociation of the holoenzyme. In the absence of cyclic AMP, phospho- and dephospho-cyclic AMP-binding proteins reassociated completely with the catalytic subunit. However, the rate of reassociation of the dephospho-cyclic AMP-binding protein was at least 5 times greater than the phospho-cyclic AMP-binding protein. Retardation of reassociation was directly proportional to the extent of phosphorylation. We conclude that the degree to which the cyclic AMP-binding protein is phosphorylated markedly affects its intrinsic ability to combine with the catalytic subunit to regenerate the inactive cyclic nucleotide-dependent kinase and that the state of phosphorylation of this subunit may be important in detemining the proportion of dissociated (active) and reassociated (inactive) protein kinase at any given time.
Therapeutic Neutralization of the NLRP1 Inflammasome Reduces the Innate Immune Response and Improves Histopathology after Traumatic Brain Injury (2009)

Traumatic brain injury elicits acute inflammation that in turn exacerbates primary brain damage. A crucial part of innate immunity in the immune privileged central nervous system involves production of proinflammatory cytokines mediated by inflammasome signaling. Here, we show that the nucleotide-binding, leucine-rich repeat pyrin domain containing protein 1 (NLRP1) inflammasome consisting of NLRP1, caspase-1, caspase-11, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), the X-linked inhibitor of apoptosis protein, and pannexin 1 is expressed in neurons of the cerebral cortex. Moderate parasagittal fluid-percussion injury (FPI) induced processing of interleukin-1beta, activation of caspase-1, cleavage of X-linked inhibitor of apoptosis protein, and promoted assembly of the NLRP1 inflammasome complex. Anti-ASC neutralizing antibodies administered immediately after fluid-percussion injury to injured rats reduced caspase-1 activation, X-linked inhibitor of apoptosis protein cleavage, and processing of interleukin-1beta, resulting in a significant decrease in contusion volume. These studies show that the NLRP1 inflammasome constitutes an important component of the innate central nervous system inflammatory response after traumatic brain injury and may be a novel therapeutic target for reducing the damaging effects of posttraumatic brain inflammation.
Pivotal trial with plant cell–expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease (2011)

Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human β-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.
2D Parametric Study Using CFD of a Circulation Control Inlet Guide Vane (2007)

Circulation control inlet guide vanes (IGVs) may provide significant benefits over current IGVs that employ mechanical means for flow turning. This paper presents the results of a two-dimensional computational study on a circulation control IGV that takes advantage of the Coanda effect for flow vectoring. The IGV in this study is an uncambered airfoil that alters circulation around itself by means of a Coanda jet that exhausts along the IGV’s trailing edge surface. The IGV is designed for an axial inlet flow at a Mach number of 0.54 and an exit flow angle of 11 degrees. These conditions were selected to match the operating conditions of the 90% span section of the IGV of the TESCOM compressor rig at the Compressor Aero Research Laboratory (CARL) located at Wright-Patterson AFB, the hardware that is being used as the baseline in this study. The goal of the optimization was to determine the optimal jet height, trailing edge radius, and supply pressure that would meet the design criteria while minimizing the mass flow rate and pressure losses. The optimal geometry that was able to meet the design requirements had a jet height of h/Cn = 0.0057 and a trailing edge Radius R/Cn = 0.16. This geometry needed a jet to inflow total pressure ratio of 1.8 to meet the exit turning angle requirement. At this supply pressure ratio the mass flow rate required by the flow control system was 0.71 percent of the total mass flow rate through the engine. The optimal circulation control IGV had slightly lower pressure losses when compared with a reference cambered IGV.
Polyadenylation Promotes Degradation of 3′-Structured RNA by theEscherichia coli mRNA Degradosome in Vitro (1999)

Polyadenylation contributes to the destabilization of bacterial mRNA. We have investigated the role of polyadenylation in the degradation of RNA by the purified Escherichia coli degradosome in vitro. RNA molecules with 3'-ends incorporated into a stable stem-loop structure could not readily be degraded by purified polynucleotide phosphorylase or by the degradosome, even though the degradosome contains active RhlB helicase which normally facilitates degradation of structured RNA. The exoribonucleolytic activity of the degradosome was due to polynucleotide phosphorylase, rather than the recently reported exonucleolytic activity exhibited by a purified fragment of RNase E (Huang, H., Liao, J., and Cohen, S. N. (1998) Nature 391, 99-102). Addition of a 3'-poly(A) tail stimulated degradation by the degradosome. As few as 5 adenosine residues were sufficient to achieve this stimulation, and generic sequences were equally effective. The data show that the degradosome requires a single-stranded "toehold" 3' to a secondary structure to recognize and degrade the RNA molecule efficiently; polyadenylation can provide this single-stranded 3'-end. Significantly, oligo(G) and oligo(U) tails were unable to stimulate degradation; for oligo(G), at least, this is probably due to the formation of a G quartet structure which makes the 3'-end inaccessible. The inaccessibility of 3'-oligo(U) sequences is likely to have a role in stabilization of RNA molecules generated by Rho-independent terminators.
Chimeric Antigen Receptor-Engineered T Cells for the Treatment of Metastatic Prostate Cancer (2015)

Cancer immunotherapy was selected as the Breakthrough of the Year 2013 by the editors of Science, in part because of the successful treatment of refractory hematological malignancies with adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells. Effective treatment of B cell leukemia may pave the road to future treatment of solid tumors, using similar approaches. The prostate expresses many unique proteins and, since the prostate gland is a dispensable organ, CAR T cells can potentially be used to target these tissue-specific antigens. However, the location and composition of prostate cancer metastases complicate the task of treating these tumors. It is therefore likely that more sophisticated CAR T cell approaches are going to be required for prostate metastasis than for B cell malignancies. Two main challenges that need to be resolved are how to increase the migration and infiltration of CAR T cells into prostate cancer bone metastases and how to counteract the immunosuppressive microenvironment found in bone lesions. Inclusion of homing (chemokine) receptors in CAR T cells may improve their recruitment to bone metastases, as may antibody-based combination therapies to normalize the tumor vasculature. Optimal activation of CAR T cells through the introduction of multiple costimulatory domains would help to overcome inhibitory signals from the tumor microenvironment. Likewise, combination therapy with checkpoint inhibitors that can reduce tumor immunosuppression may help improve efficacy. Other elegant approaches such as induced expression of immune stimulatory cytokines upon target recognition may also help to recruit other effector immune cells to metastatic sites. Although toxicities are difficult to predict in prostate cancer, severe on-target/off-tumor toxicities have been observed in clinical trials with use of CAR T cells against hematological malignancies; therefore, the choice of the target antigen is going to be crucial. This review focuses on different means of accomplishing maximal effectiveness of CAR T cell therapy for prostate cancer bone metastases while minimizing side effects and CAR T cell-associated toxicities. CAR T cell-based therapies for prostate cancer have the potential to be a therapy model for other solid tumors.
WDM channel management using programmable holographic elements (1998)

We describe results of a high-resolution (0.8 nm) holographic, digital multi-wavelength filter, based on a ferroelectric liquid crystal (FLC) spatial light modulator (SLM). The filter has applications as a wavelength-division-multiplexing (WDM) technology for use in optical telecommunications. The polarisation-insensitive FLC SLM acting as a programmable holographic element in conjunction with a highly wavelength-dispersive fixed diffractive element has been used to perform a number of important WDM functions: demultiplexing of single and multiple (up to 4), segmented passbands spaced by 0.8 nm, and dynamic erbium-doped fibre amplifier (EDFA) gain equalisation. Apodisation of the filter passband has been demonstrated, and optical add/drop multiplexing is also possible using the holographic technique. The filter offers potential low loss, excellent crosstalk characteristics, and a high resolution over a large tuning range. (6 pages)
The neuropsychology of autism (1996)

In this review, we aim to bring together major trends in autism research at three levels: biology, behaviour and cognition. We propose that cognitive theories are vital in neuropsychology, which seeks to make connections between brain abnormality and behavioural symptoms. Research at each of the three levels is incomplete, but important advances have been made. At the biological level, there is strong evidence for genetic factors, although the mechanism is, as yet, unknown. At the behavioural level, diagnosis and education are becoming more coherent and less controversial, although the possibility of autism subtypes has provoked new debate. At the cognitive level, three major theories are proving fruitful (mentalizing impairment, executive dysfunction and weak central coherence), although the relation and overlap between these is uncertain. Rapidly advancing technology and methodology (e.g. brain imaging, gene mapping), as tools of cognitive theory, may help to make autism one of the first developmental disorders to be understood at the neuropsychological level.
Attenuated Live Fowl Cholera Vaccine I. Development of Vaccine Strain M3G of Pasteurella multocida (1979)

A live cholera vaccine was developed from a virulent avian septicemia strain of Pasteurella multocida serotype 1. The virulent parental strain was mutagenized with N-methyl-N'-nitro-N-nitroso guanidine. Mutants were selected that had either smaller colonies at 37 C or temperature sensitivity for growth at 41 C. Four small-colony mutants and 2 temperature-sensitive mutants were studied. All the mutants were avirulent for turkeys. Sixteen days after turkeys were vaccinated with each mutant, both the vaccinates and unvaccinated controls were challenge-exposed to virulent P. multocida of the homologous serotype and the heterologous serotype 3. Two of the small-colony mutant strains protected against both homologous and heterologous challenge. Suggested for a live cholera vaccine is P. multocida M3G, a small-colony-forming mutant, innocuous for both mice and turkeys and stable against reversion.
Fungal infections of the small and large intestine. (1992)

Variable gross appearances are relevant for endoscopists, particularly lesions which resemble pseudomembranous colitis. Endoscopic biopsy specimens may have a role in antemortem diagnosis. Failure to diagnose these infections during life emphasises the importance of necropsy in the clinicopathological audit of deaths in this group of patients.