gebhart/patrepeval huggingface dataset:
Identification of Amino Acid Residues Responsible for the Selectivity of Tadalafil Binding to Two Closely Related Phosphodiesterases, PDE5 and PDE6 (2012)

The 11 families of the Class I cyclic nucleotide phosphodiesterases (PDEs) are critical for regulation of cyclic nucleotide signaling. PDE5 (important in regulating vascular smooth muscle contraction) and PDE6 (responsible for regulating visual transduction in vertebrate photoreceptors) are structurally similar but have several functional differences whose structural basis is poorly understood. Using evolutionary trace analysis and structural homology modeling in conjunction with site-directed mutagenesis, we have tested the hypothesis that class-specific differences between PDE5 and PDE6 account for the biochemical and pharmacological differences in the two enzyme families. Replacing human PDE5 residues in the M-loop region of the binding site for the PDE5-selective inhibitor tadalafil (Cialis®) with the corresponding class-specific cone PDE6 residues (P773E, I778V, E780L, F787W, E796V, D803P, L804M, N806D, I813L, S815K) reduces tadalafil binding affinity to levels characteristic of PDE6. These mutations fail to alter vardenafil (Levitra®) affinity for the active site. Class-specific differences in PDE5 versus cone PDE6 that contribute to the accelerated catalytic efficiency of PDE6 were identified but required heterologous expression of full-length PDE5 constructs. Introduction of PDE6 residues into the background of the PDE5 protein sequence often led to loss of catalytic activity and reduced protein solubility, supporting the idea that multiple structural elements of PDE6 are highly susceptible to misfolding during heterologous expression. This work validates the use of PDE5 as a template to identify functional differences between PDE5 and PDE6 that will accelerate efforts to develop the next generation of PDE5-selective inhibitors with fewer adverse side effects resulting from PDE6 inhibition.
Nucleolar Localization of Parathyroid Hormone-Related Peptide Enhances Survival of Chondrocytes under Conditions That Promote Apoptotic Cell Death (1995)

Parathyroid hormone-related peptide (PTHrP) is a mediator of cellular growth and differentiation as well as a cause of malignancy-induced hypercalcemia. Most of the actions of PTHrP have been attributed to its interaction with a specific cell surface receptor that binds the N-terminal domain of the protein. Here we present evidence that PTHrP promotes some of its cellular effects by translocating to the nucleolus. Localization of transiently expressed PTHrP to the nucleolus was dependent on the presence of a highly basic region at the carboxyl terminus of the molecule that bears homology to nucleolar targeting sequences identified within human retroviral (human immunodeficiency virus type 1 and human T-cell leukemia virus type 1) regulatory proteins. Endogenous PTHrP also localized to the nucleolus in osseous cells in vitro and in vivo. Moreover, expression of PTHrP in chondrocytic cells (CFK2) delayed apoptosis induced by serum deprivation, and this effect depended on the presence of an intact nucleolar targeting signal. The present findings demonstrate a unique intracellular mode of PTHrP action and a novel mechanism by which this peptide growth factor may modulate programmed cell death.
Managing rosacea: a review of the use of metronidazole alone and in combination with oral antibiotics. (2007)

Metronidazole in 0.75% strength lotion, cream, and gel and 1.0% metronidazole cream and gel are all efficacious in treating rosacea. Combination treatment with oral antibiotics at both antimicrobial and subantimicrobial doses is an efficacious means of treating rosacea. Maintenance treatment with topical metronidazole decreases relapses and allows for longer intervals between flares.
Mechanisms of Methanol Decomposition on Platinum:  A Combined Experimental and ab Initio Approach (2005)

The dual path mechanism for methanol decomposition on well-defined low Miller index platinum single crystal planes, Pt(111), Pt(110), and Pt(100), was studied using a combination of chronoamperometry, fast scan cyclic voltammetry, and theoretical methods. The main focus was on the electrode potential range when the adsorbed intermediate, CO(ad), is stable. At such "CO stability" potentials, the decomposition proceeds through a pure dehydrogenation reaction, and the dual path mechanism is then independent of the electrode-substrate surface structure. However, the threshold potential where the decomposition of methanol proceeds via parallel pathways, forming other than CO(ad) products, depends on the surface structure. This is rationalized theoretically. To gain insights into the controlling surface chemistry, density functional theory calculations for the energy of dehydrogenation were used to approximate the potential-dependent methanol dehydrogenation pathways over aqueous-solvated platinum interfaces.
Parkinson's disease--Part 1: Pathophysiology, symptoms, burden, diagnosis, and assessment. (2008)

Parkinson's disease (PD) is a chronic neurodegenerative disease associated with substantial morbidity, increased mortality, and high economic burden. Of importance to managed care is that the number of cases of PD are on the rise, paralleling the advancing age of the population, and misdiagnosis is common. Effective management of PD can minimize disability and potentially improve long-term outcomes, which would minimize long-term healthcare costs and medical resource utilization. This article provides a brief review of the epidemiology, pathophysiology, clinical course, and burden of PD.
A Framework for a Collaborative DDoS Defense (2006)

Increasing use of the Internet for critical services makes flooding distributed denial-of-service (DDoS) a top security threat. A distributed nature of DDoS suggests that a distributed mechanism is necessary for a successful defense. Three main DDoS defense functionalities -- attack detection, rate limiting and traffic differentiation -- are most effective when performed at the victim-end, core and sourceend respectively. Many existing systems are successful in one aspect of defense, but none offers a comprehensive solution and none has seen a wide deployment. We propose to harvest the strengths of existing defenses by organizing them into a collaborative overlay, called DefCOM, and augmenting them with communication and collaboration functionalities. Nodes collaborate during the attack to spread alerts and protect legitimate traffic, while rate limiting the attack. DefCOM can accommodate existing defenses, provide synergistic response to attacks and naturally lead to an Internet-wide response to DDoS threat.
Coordination middleware supporting rapid deployment of ad hoc mobile systems (2004)

This paper addresses the design and implementation of thin coordination veneers for use in the development of applications over ad hoc wireless networks. A coordination veneer is deﬁned as an adaptation layer that customizes a general-purpose coordination middleware to a particular domain with minimal development effort. This technique allows developers to build highly-tailored coordination models while leveraging established models and middleware. We present three such veneers, the coordination models they embody, and the manner in which they were implemented. The LIME middleware, which supplies tuple space based coordination in the ad hoc environment, serves as the implementation base for our veneers. These veneers cover diverse areas in ad hoc mobility: service discovery and provision, event registration and distribution, and secure tuple space access.
A spatiotemporal Ripley’s<i>K</i>-function to analyze interactions between spruce budworm and fire in British Columbia, Canada (2008)

In this paper, we extend traditional methods of spatial statistics to study spatiotemporal correlations between two different point processes. After introducing the methodology, we apply this analysis to a particular case study of interest in ecology, the interaction between damage by a particular forest pest (western spruce budworm ( Choristoneura occidentalis )) and forest fires. Our analysis, which covers parts of British Columbia in the 26-year period from 1970 to 1995, indicates that areas affected by budworm infestation have a significantly decreased risk of forest fire for the 7 years following the infestation. Conversely, forest fires decrease the risk of infestation for at least 6 years after the fire. These temporal correlations extend over a spatial range of at least 25 km. Our study rejects the common assumption that insect infestation necessarily results in increased fire risk. This case study illustrates the utility of point process modeling and spatial statistics to understanding ecosystem dynamics extending over both space and time.
[Structure, function and regulation of expression of influenza virus matrix M1 protein]. (1997)

The M1 protein of influenza virus regulates the bi-directional transport of ribonucleoprotein (RNP) into and out of the nucleus. At the beginning of infection, the incoming RNP is transported into the nucleus only after detachment from M1, where RNP is involved in transcription/replication of the viral genome. In the late stage of infection, M1 inhibits viral RNA polymerase activity by binding to RNP, which may be a signal for RNP-transport from the nucleus to the cell surface. Finally, M1 mediates the association of RNP with viral envelope glycoproteins on the inner surface of the cytoplasmic membrane, which then promotes the virion formation and budding. Thus, M1 is a multi-functional protein that plays important roles in various steps of virus replication.
THE MUTANT <i>mdx</i>: INHERITED MYOPATHY IN THE MOUSE (1987)

The mdx mutant mouse was first observed during a survey of genetic variations of pyruvate kinase in the mouse. Affected mice have high serum levels of this enzyme and although showing little disability they have widespread and severe muscle disease. Light and electron microscopy, muscle enzyme histochemistry and combined cholinesterase-silver impregnations were used for the study of affected and control animals aged 1 day to 1 year. An early ultrastructural abnormality present already at 1 day was scattered focal streaming of Z-lines. Later there was also segmental muscle fibre necrosis and regeneration. The proportion of muscle fibres showing either necrosis, regeneration or internal nuclei was assessed in several muscles, at ages ranging from 10 days to 1 year. Acute segmental necrosis and regeneration were most marked at 1 to 2 months, although they were present at all ages. The number of fibres with internal nuclei increased progressively until 3 months when 70-80% showed this abnormality. Nerve terminals were unaffected but there was a reduction in the number and depth of postsynaptic folds at motor end-plates in adult animals, confirmed by morphometric analysis. Quantitative study of L4 motor root and tibial nerve showed that fibre numbers, axonal calibres and myelin sheath thickness were normal at all ages. No qualitative abnormalities were found in the CNS or other organs. The findings strongly suggest that the mdx mutant has a primary muscle disease and that the nervous system is normal.
Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing (2006)

Besides linear RNAs, pre-mRNA splicing generates three forms of RNAs: lariat introns, Y-structure introns from trans-splicing, and circular exons through exon skipping. To study the persistence of excised introns in total cellular RNA, we used three Escherichia coli 3' to 5' exoribonucleases. Ribonuclease R (RNase R) thoroughly degrades the abundant linear RNAs and the Y-structure RNA, while preserving the loop portion of a lariat RNA. Ribonuclease II (RNase II) and polynucleotide phosphorylase (PNPase) also preserve the lariat loop, but are less efficient in degrading linear RNAs. RNase R digestion of the total RNA from human skeletal muscle generates an RNA pool consisting of lariat and circular RNAs. RT-PCR across the branch sites confirmed lariat RNAs and circular RNAs in the pool generated by constitutive and alternative splicing of the dystrophin pre-mRNA. Our results indicate that RNase R treatment can be used to construct an intronic cDNA library, in which majority of the intron lariats are represented. The highly specific activity of RNase R implies its ability to screen for rare intragenic trans-splicing in any target gene with a large background of cis-splicing. Further analysis of the intronic RNA pool from a specific tissue or cell will provide insights into the global profile of alternative splicing.
Effect of Tomato Packinghouse Wastewater Properties on Phosphorus and Cation Leaching in a Spodosol (2011)

Land application of wastewater is a common practice. However, coarse-textured soils and shallow groundwater in Florida present favorable conditions for leaching of wastewater-applied constituents. Our objective in this study was to determine phosphorus (P) and associated cations (Ca, Mg, K, Na) leaching in a Spodosol irrigated with tomato packinghouse wastewater. We packed 12 polyvinyl chloride soil columns (30 cm internal diameter × 50 cm length) with two soil horizons (Ap and A/E) and conducted 30 sequential leaching events by irrigating with wastewater at low (0.84 cm d), medium (1.68 cm d), and high (2.51 cm d) rates. The control treatment received deionized water at 1.68 cm d Leachate pH was lower (6.4-6.5) and electrical conductivity (EC) was higher in the wastewater-treated columns (0.85-1.78 dS m) than in the control treatment (pH 6.9; EC, 0.12 dS m) due to the low pH (6.2) and high EC (2.16 dS m) of applied wastewater. Mean leachate P concentrations were greatest in the control treatment (0.70 mg L), followed by the high (0.60 mg L) and low and medium wastewater-treated columns (0.28-0.33 mg L). Leachate concentrations of Na, Ca, Mg, and K were significantly ( < 0.05) greater in wastewater-treated columns than in the control. Concentrations of P, Na, and K in leachate remained lower than the concentrations in the applied wastewater, indicating their retention in the soil profile. In contrast, leachate Ca and Mg concentrations were greater than in applied wastewater during several leaching events, suggesting that additional Ca and Mg were leached from the soil. Our results suggest that tomato packinghouse wastewater can be beneficially land-applied at 1.68 cm d in Florida's Spodosols without significant P and cation leaching.
Systematic measurement of transcription factor-DNA interactions by targeted mass spectrometry identifies candidate gene regulatory proteins (2013)

Regulation of gene expression involves the orchestrated interaction of a large number of proteins with transcriptional regulatory elements in the context of chromatin. Our understanding of gene regulation is limited by the lack of a protein measurement technology that can systematically detect and quantify the ensemble of proteins associated with the transcriptional regulatory elements of specific genes. Here, we introduce a set of selected reaction monitoring (SRM) assays for the systematic measurement of 464 proteins with known or suspected roles in transcriptional regulation at RNA polymerase II transcribed promoters in Saccharomyces cerevisiae. Measurement of these proteins in nuclear extracts by SRM permitted the reproducible quantification of 42% of the proteins over a wide range of abundances. By deploying the assay to systematically identify DNA binding transcriptional regulators that interact with the environmentally regulated FLO11 promoter in cell extracts, we identified 15 regulators that bound specifically to distinct regions along ∼600 bp of the regulatory sequence. Importantly, the dataset includes a number of regulators that have been shown to either control FLO11 expression or localize to these regulatory regions in vivo. We further validated the utility of the approach by demonstrating that two of the SRM-identified factors, Mot3 and Azf1, are required for proper FLO11 expression. These results demonstrate the utility of SRM-based targeted proteomics to guide the identification of gene-specific transcriptional regulators.
Predicting Future Random Events Based on Past Performance (1981)

There are many situations where one is interested in predicting the expected number of events in period 2 given that x events occurred in period 1. For example, insurance companies must decide whether or not to cancel the insurance of drivers who had 3 or more accidents during the previous year. In analyzing marketing research data an analyst may wish to predict the number of future purchases to be made by those customers who made x purchases in the previous 3 months. The owner of a baseball team may wish to estimate the number of home runs a batter will hit this year given he hit (say) 40 home runs last year. When the events (e.g., accidents, purchase occasions, home runs) can be assumed to occur randomly over time a very general result due to Robbins (Robbins, H. 1977. Prediction and estimation for the compound Poisson distribution. Proc. National Acad Sci. USA 74 2670–2671.) is available. This approach has certain advantages and disadvantages with respect to the negative binomial model that is commonly used to analyze purchasing and accident data. The Robbins result is particularly appropriate for predicting what the zero class in period 1 will do in period 2. The main purpose of this paper is to present the Robbins result in a form that can be readily understood by applied researchers in a variety of disciplines. Data on consumer purchases, motor vehicle violations and accidents are analyzed and applications to other areas are discussed.
The Chemokine Binding Protein M3 Prevents Diabetes Induced by Multiple Low Doses of Streptozotocin (2007)

Multiple injections of low-dose streptozotocin (MLDS) induce lymphocytic insulitis and diabetes in rodents. To test whether the influx of inflammatory cells was associated with changes in the expression of chemokines, we measured the expression of all known chemokine ligands by real-time quantitative PCR in isolated islets. With the exception of CCL20 and CCL19, chemokines were not significantly expressed in islets from wild-type mice before MLDS treatment. Ten days after treatment, the expression of several chemokines, including CXCL9, CCL1, CXCL10, and CCL21, was dramatically up-regulated. The expression of CCL1, CXCL9, and CCL21 protein was confirmed by immunohistochemistry and was mostly associated with the infiltrating cells. The mouse herpesvirus 68-encoded chemokine decoy receptor M3 can broadly engage these chemokines with high affinity. To test whether a blockade of chemokine function would alter the onset or magnitude of insulitis and diabetes, we used transgenic mice expressing M3 in beta cells (rat insulin promoter (RIP)-M3 mice). RIP-M3 mice were normoglycemic and responded normally to glucose challenge but were remarkably resistant to diabetes induced by MLDS. Islets from MLDS-treated RIP-M3 mice had fewer inflammatory cells and expressed lower levels of chemokines than those from MLDS-treated controls. The role of M3 in chemokine blockade during insulitis was further supported by in vitro experiments demonstrating that multiple chemokines up-regulated during islet inflammation are high-affinity M3 ligands that can be simultaneously sequestered. These results implicate chemokines as key mediators of insulitis and suggest that their blockade may represent a novel strategy to prevent insulitis and islet destruction.
Quadratic Shape Descriptors. 1. Rapid Superposition of Dissimilar Molecules Using Geometrically Invariant Surface Descriptors (2000)

In this paper, we present a novel approach to shape-based molecular similarity searching. The method that we introduce is able to superimpose dissimilar molecules by using geometrically invariant molecular surface descriptors. The shape descriptors are calculated by least-squares fitting of a quadratic function to small sections of the molecular surface of a ligand. Invariant geometric properties of the approximated surface patch are then extracted from the fitted quadratic function. The extracted properties are used to quantify the shape and to obtain a canonical orientation for this section of surface. The superimposition algorithm uses these geometric invariants to recognize similar regions of surface shape existing on two molecules and to bring these regions (and consequently the molecules) into registration. Because these geometric descriptors are based upon local surface shape, the superimposing algorithm is insensitive to the connectivity and the relative sizes of the molecules being matched. The capabilities of our algorithm are demonstrated by superimposing dissimilar ligands known to inhibit the same enzyme system. In all cases examined the algorithm generates superpositions that are in agreement with crystallographic results. The algorithm is also applied to align the two different proteins on the basis of the shape of their active sites.
Computer modelling of weld-implant testing (1985)

A theoretical model is developed for determining the optimum notch position in an implant test used for predicting the susceptibility to hydrogen cracking during welding. Using a microcomputer for processing the equations for weld-bead geometry and heat flow during welding, a microstructural cross-section, with the notch positioned at the centre of the grain-growth zone, and an implant testing diagram, showing the notch position and microstructure as a function of welding parameters, can be generated. A single bead-on-plate weld is used to determine the unknown kinetic and geometrical constants in the equations. It is shown that notch position is very sensitive to the type of welding process employed and that implant diagrams thus can be used to position the notch with greater reliability and hence reduce the scatter in the fracture loads measured in this test.MST/46
Structure of the multidrug ABC transporter Sav1866 from <i>Staphylococcus aureus</i> in complex with AMP‐PNP (2007)

Staphylococcus aureus Sav1866 is a bacterial homolog of the human ABC transporter Mdr1 that causes multidrug resistance in cancer cells. We report the crystal structure of Sav1866 in complex with adenosine-5'-(beta,gamma-imido)triphosphate (AMP-PNP) at 3.4A resolution and compare it with the previously determined structure of Sav1866 with bound ADP. Besides differences in the ATP-binding sites, no significant conformational changes were observed. The results confirm that the ATP-bound state of multidrug ABC transporters is coupled to an outward-facing conformation of the transmembrane domains.
Realization of the Crystalline Silicon Solar Cell Using Nanocrystalline Transport Path in Ultra-thin Dielectrics for Reinforced Passivating Contact (2021)

We apply NAnocrystalline Transport path in Ultra-thin dielectrics for Reinforced passivating contact (NATURE contact) to crystalline silicon solar cells for simultaneous achievement of passivation and carrier extraction. The Si nanocrystals are formed in silicon oxide by deposition of hydrogenated amorphous silicon oxide with different oxygen concentration and subsequent annealing. NATURE contact with total layer thickness of 8 nm exhibits reasonably good passivation performance. Furthermore, we demonstrate that NATURE contact can be successfully implemented to the both sides of crystalline silicon solar cells. NATURE contact, which permits flexible structural and chemical design of a passivation contact layer, will open a possibility for various functional devices.