gebhart/patrepeval huggingface dataset:
Physical effects of cholesterol on arterial smooth muscle membranes: evidence of immiscible cholesterol domains and alterations in bilayer width during atherogenesis (1998)

Small angle X-ray diffraction was used to examine arterial smooth muscle cell (SMC) plasma membranes isolated from control and cholesterol-fed (2%) atherosclerotic rabbits. A microsomal membrane enriched with plasma membrane obtained from animals fed cholesterol for up to 13 weeks showed a progressive elevation in the membrane unesterified (free) cholesterol:phospholipid (C/PL) mole ratio. Beyond 9 weeks of cholesterol feeding, X-ray diffraction patterns demonstrated a lateral immiscible cholesterol domain at 37 degrees C with a unit cell periodicity of 34 A coexisting within the liquid crystalline lipid bilayer. On warming, the immiscible cholesterol domain disappeared, and on cooling it reappeared, indicating that the immiscible cholesterol domain was fully reversible. These effects were reproduced in a model C/PL binary lipid system. In rabbits fed cholesterol for less than 9 weeks, lesser increases in membrane C/PL mole ratio were observed. X-ray diffraction analysis demonstrated an increase in membrane bilayer width that correlated with the C/PL mole ratio. This effect was also reproduced in a C/PL binary lipid system. Taken together, these findings demonstrate that in vivo, feeding of cholesterol causes cholesterol-phospholipid interactions in the membrane bilayer that alter bilayer structure and organization. This interaction results in an increase in bilayer width peaking at a saturating membrane cholesterol concentration, beyond which lateral phase separation occurs resulting in the formation of separate cholesterol bilayer domains. These alterations in structure and organization in SMC plasma membranes may have significance in phenotypic modulation or aortic SMC during early atherogenesis.
Characterization and Fermentation of Dilute-Acid Hydrolyzates from Wood (1997)

Dilute-acid hydrolyzates from alder, aspen, birch, willow, pine, and spruce were fermented without prior detoxification. The hydrolyzates were prepared by a one-stage hydrolysis process using sulfuric acid (5 g/L) at temperatures between 188 and 234 °C and with a holding time of 7 min. The fermentations were carried out anaerobically by Saccharomyces cerevisiae (10 g of d.w./L) at a temperature of 30 °C and an initial pH of 5.5. The fermentabilities were quite different for the different wood species, and only hydrolyzates of spruce produced at 188 and 198 °C, hydrolyzates of pine produced at 188 °C, and hydrolyzates of willow produced at 198 °C could be completely fermented within 24 h. From the sum of the concentrations of the known inhibitors furfural and 5-(hydroxymethyl)furfural (HMF), a good prediction of the maximum ethanol production rate could be obtained, regardless of the origin of the hydrolyzate. Furthermore, in hydrolyzates that fermented well, furfural and HMF were found to be taken up and converted by the yeast, concomitant with the uptake of glucose.
Structure of the L5 lipopolysaccharide core oligosaccharides of Neisseria meningitidis. (1990)

Three different oligosaccharides were isolated by mild acid hydrolysis of the lipopolysaccharides, obtained from Neisseria meningitidis serotype 5, and their structures were elucidated by combined chemical and physical techniques. The use of 500-MHz 1H NMR in both one-dimensional and two-dimensional modes as well as nuclear Overhauser effect experiments were employed. To assist in the structural assignments the purified oligosaccharides were also degraded by chemical and enzymatic procedures to smaller fragments. The largest of the three original oligosaccharides is a triantennary partially O-acetylated decasaccharide in which the largest antenna terminates in a lacto-N-neotetraose unit. The smaller oligosaccharides (heptasaccharide and octasaccharide) except for terminal glycose deletions from the longest antenna are structural replicas of the larger
Inhibition of Human Caspases by Peptide-based and Macromolecular Inhibitors (1998)

Studies with peptide-based and macromolecular inhibitors of the caspase family of cysteine proteases have helped to define a central role for these enzymes in inflammation and mammalian apoptosis. A clear interpretation of these studies has been compromised by an incomplete understanding of the selectivity of these molecules. Here we describe the selectivity of several peptide-based inhibitors and the coxpox serpin CrmA against 10 human caspases. The peptide aldehydes that were examined (Ac-WEHD-CHO, Ac-DEVD-CHO, Ac-YVAD-CHO, t-butoxycarbonyl-IETD-CHO, and t-butoxycarbonyl-AEVD-CHO) included several that contain the optimal tetrapeptide recognition motif for various caspases. These aldehydes display a wide range of selectivities and potencies against these enzymes, with dissociation constants ranging from 75 pM to >10 microM. The halomethyl ketone benzyloxycarbonyl-VAD fluoromethyl ketone is a broad specificity irreversible caspase inhibitor, with second-order inactivation rates that range from 2.9 x 10(2) M-1 s-1 for caspase-2 to 2.8 x 10(5) M-1 s-1 for caspase-1. The results obtained with peptide-based inhibitors are in accord with those predicted from the substrate specificity studies described earlier. The cowpox serpin CrmA is a potent (Ki < 20 nM) and selective inhibitor of Group I caspases (caspase-1, -4, and -5) and most Group III caspases (caspase-8, -9, and -10), suggesting that this virus facilitates infection through inhibition of both apoptosis and the host inflammatory response.
Predictors of Hepatitis B Cure Using Gene Therapy to Deliver DNA Cleavage Enzymes: A Mathematical Modeling Approach (2013)

Most chronic viral infections are managed with small molecule therapies that inhibit replication but are not curative because non-replicating viral forms can persist despite decades of suppressive treatment. There are therefore numerous strategies in development to eradicate all non-replicating viruses from the body. We are currently engineering DNA cleavage enzymes that specifically target hepatitis B virus covalently closed circular DNA (HBV cccDNA), the episomal form of the virus that persists despite potent antiviral therapies. DNA cleavage enzymes, including homing endonucleases or meganucleases, zinc-finger nucleases (ZFNs), TAL effector nucleases (TALENs), and CRISPR-associated system 9 (Cas9) proteins, can disrupt specific regions of viral DNA. Because DNA repair is error prone, the virus can be neutralized after repeated cleavage events when a target sequence becomes mutated. DNA cleavage enzymes will be delivered as genes within viral vectors that enter hepatocytes. Here we develop mathematical models that describe the delivery and intracellular activity of DNA cleavage enzymes. Model simulations predict that high vector to target cell ratio, limited removal of delivery vectors by humoral immunity, and avid binding between enzyme and its DNA target will promote the highest level of cccDNA disruption. Development of de novo resistance to cleavage enzymes may occur if DNA cleavage and error prone repair does not render the viral episome replication incompetent: our model predicts that concurrent delivery of multiple enzymes which target different vital cccDNA regions, or sequential delivery of different enzymes, are both potentially useful strategies for avoiding multi-enzyme resistance. The underlying dynamics of cccDNA persistence are unlikely to impact the probability of cure provided that antiviral therapy is given concurrently during eradication trials. We conclude by describing experiments that can be used to validate the model, which will in turn provide vital information for dose selection for potential curative trials in animals and ultimately humans.
Endovascular manipulation to restrict restenosis (1998)

The processes that take place following damage to the vessel wall are well understood. Endovascular manipulation by its very nature induces such damage and the repair process can lead to a recurrence of symptoms. There have been many clinical trials of drugs chosen for their known impact on preventing excess vessel wall response. With one or two exceptions none of these trials has shown any benefit, partly because only low doses could be given systemically to avoid side effects. Local drug delivery allows high doses to be given where needed, at the site of the process, without inducing systemic complications. There are various drugs and agents that have been shown to be effective in models of vessel wall damage, including heparin, nitric oxide, inhibitors of platelet function and the antisense oligonucleotides. Some of these agents are now being tested in clinical trials. Methods of delivering the agent include devices that bathe the luminal layer, deliver the agent to the media or inject it into the adventitia where a reservoir can form. Stents improve the outcome after angioplasty, but can also induce a proliferative vessel wall response. To overcome this, stents have recently been considered as local delivery devices with radiation being delivered and polymer coated stents, loaded with agents, being developed. While local drug delivery provides great promise as a way of reducing the adverse effect of response of the vessel wall to damage, the results of clinical trials in humans are awaited.
Anatomy and Physiology of Pain Referral Patterns in Primary and Cervicogenic Headache Disorders (2005)

The clinical presentation of pain in primary headache disorders, such as migraine and cervicogenic headache, shows that the trigeminal and cervical innervation territories frequently are not respected during an attack. Here we review evidence that trigeminal afferents innervating the meninges, and cervical afferents in the greater occipital nerve (GON), have synaptic convergent input onto the same second‐order neurons in the trigeminocervical complex. Furthermore, dynamic changes of excitability in terms of a sensitization to noxious input may occur on the central neuron level. The possible role of segmental mechanisms in the spinal cord and of inhibitory projections from brainstem structures such as the periaqueductal gray (PAG) in pain processing is discussed in view of data using neurostimulation of peripheral nerves in pain modulation. Recent experimental animal and human studies have facilitated our understanding of the role of these basic mechanisms in the spread, referral, and maintenance of pain in headache.
Novel Heterocyclic-Fused Pyridazinones as Potent and Selective Phosphodiesterase IV Inhibitors (1997)

A series of 6-aryl-4,5-heterocyclic-fused pyridazinones were designed and synthesized as selective phosphodiesterase (PDE) IV inhibitors. Biological evaluation of these compounds demonstrated a good selectivity profile toward the PDE IV family and greatly attenuated affinity for the Rolipram high-affinity binding site that seems to be responsible for undesiderable side effects. Structure-activity relationships (SARs) studies showed that the presence of an ethyl group at pyridazine N-2 is associated with the best potency and selectivity profile.
Putting fixed priority scheduling theory into engineering practice for safety critical applications (2002)

Describes the approach proposed by the York University Technology Centre for introducing fixed-priority scheduling into industrial safety-critical hard real-time systems. The work has been performed within the context of a class A (safety-critical) system as defined by civil aircraft software standard DO178B. Traditionally, class A systems have been scheduled by a cyclic executive. However, many such systems can be re-designed using a fixed-priority scheduler. This saves time and money, with no significant increase in risk. Also, significant technical benefits are apparent. This paper describes the timing requirements of the system, provides a potential scheduling approach (including appropriate timing analysis), and outlines an approach for gathering the necessary evidence for presentation to certification authorities.
Prevalence of Chronic Pruritus in Germany: Results of a Cross-Sectional Study in a Sample Working Population of 11,730 (2010)

Chronic pruritus is a prevalent symptom in the working age population. A high proportion of people affected are not medically treated.
The interacting multiple model algorithm for systems with Markovian switching coefficients (1988)

An important problem in filtering for linear systems with Markovian switching coefficients (dynamic multiple model systems) is the management of hypotheses, which is necessary to limit the computational requirements. A novel approach to hypotheses merging is presented for this problem. The novelty lies in the timing of hypotheses merging. When applied to the problem of filtering for a linear system with Markovian coefficients, the method is an elegant way to derive the interacting-multiple-model (IMM) algorithm. Evaluation of the IMM algorithm shows that it performs well at a relatively low computational load. These results imply a significant change in the state of the art of approximate Bayesian filtering for systems with Markovian coefficients.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Retroviral expression of FGF-2 (bFGF) affects patterning in chick limb bud (1993)

To investigate the role of fibroblast growth factor-2 (basic fibroblast growth factor) in chick limb development, we constructed a replication-defective spleen necrosis virus to ectopically express fibroblast growth factor-2 in stage 20-22 chick limb bud. Because infecting cells in vivo proved to be inefficient, limb bud cells were dissociated, infected in vitro, and then grafted back into host limbs. This procedure caused duplications of anterior skeletal elements, including proximal humerus, distal radius, and digits 2 and 3. Eighty-nine percent of host wings receiving infected grafts at their anterior borders had duplications of one or more of these elements. The frequency of duplication declined dramatically when infected cells were grafted to progressively more posterior sites of host limb buds, and grafting to the posterior border had no effect at all. Several techniques were used to determine the role of infected tissue in forming skeletal duplications. First, staining with an fibroblast growth factor-2 specific monoclonal antibody showed higher than endogenous levels of fibroblast growth factor-2 expression associated with extra elements. Second, the host/donor composition of duplicated elements was determined by simultaneously infecting donor cells with viruses encoding fibroblast growth factor-2 or beta-galactosidase; donor tissue was then visualized by X-gal staining. Patterns of ectopic fibroblast growth factor-2 expression and X-gal staining confirmed the presence of infected donor tissue near duplicated structures, but the duplicated skeletal elements themselves showed very little staining. Similar results were obtained in duplications caused by infected quail wing bud cells grafted to the chick wing bud. These observations suggest that fibroblast growth factor-2-expressing donor tissue induced host tissue to form normally patterned extra elements. In support of this conclusion, implanting beads containing fibroblast growth factor-2 caused partial duplications of digit 2. These data provide the first direct evidence that fibroblast growth factor-2 plays a role in patterning in the limb bud.
Cyclosporin A Treatment Following Spinal Cord Injury to the Rat: Behavioral Effects and Stereological Assessment of Tissue Sparing (2001)

The immunosuppressant drug cyclosporin A (CsA) has significant neuroprotective properties following CNS injury. In the present study, we assessed the efficacy of CsA therapy following a moderate spinal cord injury (SCI). Adult female rats were injured with the NYU impactor from a height of 12.5 mm, and CsA or vehicle therapy was initiated 15 min after the injury. All animals were behaviorally tested with the BBB locomotor rating scale prior to morphological assessment of changes in the spinal cord. CsA therapy failed to significantly improve the behavioral recovery following the injury. Using a unique stereological approach to assess tissue damage, it was determined that CsA did not alter the amount of spared tissue. The possible neuroprotective effects of CsA, observed in other models of CNS injury, do not appear to influence SCI pathology, perhaps reflecting both anatomical and physiological differences between these distinct regions of the CNS.
Kinetic, Raman, NMR, and Site-Directed Mutagenesis Studies of the Pseudomonas Sp. Strain CBS3 4-Hydroxybenzoyl-CoA Thioesterase Active Site (2002)

4-Hydroxybenzoyl-coenzyme A (4-HBA-CoA) thioesterase catalyzes the hydrolysis of 4-HBA-CoA to 4-hydroxybenzoate and CoA. X-ray crystallographic analysis of the liganded enzyme has shown that the benzoyl thioester and pantetheine moieties of the substrate ligand are bound in a narrow crevice while the nucleotide moiety rests on the protein surface (Thoden, J. B., Holden, H. M., Zhuang, Z. and Dunaway-Mariano, D. (2002) X-ray Crystallographic Analyses of Inhibitor and Substrate Complexes of Wild-type and Mutant 4-Hydroxybenzoyl-CoA Thioesterase, J. Biol. Chem., in press). Asp17 is positioned in the crevice, close to the substrate thioester C=O, which in turn interacts with the positive pole of an alpha-helix macrodipole. In this paper we report the results from spectral, mutagenesis, and kinetic studies which show (1) that substrate activation involves restricted thioester C=O conformational freedom and a modest enhancement of C=O bond polarization, (2) that the nucleotide unit of the substrate is bound through interaction with the protein surface, and (3) that Asp17 contributes a rate factor of 10(4), consistent with its proposed role of general base or nucleophile.
Kernel partial least squares regression in reproducing kernel hilbert space (2002)

A family of regularized least squares regression models in a Reproducing Kernel Hilbert Space is extended by the kernel partial least squares (PLS) regression model. Similar to principal components regression (PCR), PLS is a method based on the projection of input (explanatory) variables to the latent variables (components). However, in contrast to PCR, PLS creates the components by modeling the relationship between input and output variables while maintaining most of the information in the input variables. PLS is useful in situations where the number of explanatory variables exceeds the number of observations and/or a high level of multicollinearity among those variables is assumed. Motivated by this fact we will provide a kernel PLS algorithm for construction of nonlinear regression models in possibly high-dimensional feature spaces.We give the theoretical description of the kernel PLS algorithm and we experimentally compare the algorithm with the existing kernel PCR and kernel ridge regression techniques. We will demonstrate that on the data sets employed kernel PLS achieves the same results as kernel PCR but uses significantly fewer, qualitatively different components.
Organic Long‐Persistent Luminescence from a Flexible and Transparent Doped Polymer (2018)

Long-persistent luminescence (LPL) materials have a wide range of applications, such as in architectural decorations, safety signs, watch dials, and glow-in-the-dark toys. Present LPL materials based on inorganics must be processed into powders and blended with polymer matrices before use. However, micropowders of inorganic LPL materials show poor compatibility with common polymers, limiting the mechanical properties and transparency of the composites. Here, a polymer-based organic LPL (OLPL) system that is flexible, transparent, and solution processable is reported. Following low-power excitation at room temperature, this polymer-based OLPL system exhibits LPL after phosphorescence from the donor.
Radiosynthesis and Evaluation of 11C-Labeled Diaryl-Substituted Imidazole and Indole Derivatives for Mapping Cyclooxygenase-2 (2006)

11C-labeled analogs of 4-chloro-5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole ([11C]1), 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide ([11C]2) and 2-(4-aminosulfonylphenyl)-3-(4-methoxyphenyl)indole ([11C]3), which have been shown to have excellent potency and high selectivity for cyclooxygenase isoform 2 (COX-2) inhibiting activity, were prepared and evaluated in rats as potential radiopharmaceuticals for imaging the COX-2 enzyme by positron emission tomography. These 11C-labeled COX-2 inhibitors were synthesized in high radiochemical yields by O-[11C]methylation of phenolic precursors with [11C]methyl triflate in acetone containing NaOH as a base. In vivo evaluation in rats bearing AH109A hepatoma showed no specific binding of any tracer to COX-2 in any tissue such as the brain, heart, lung, kidney, and AH109A hepatoma. In ex vivo autoradiography, [11C]1 showed regionally different distribution in the brain, while [11C]2 and [11C]3 were not substantially taken up by the brain. In in vitro monolayer efflux assays, compound 3 was found to be a substrate for the P-glycoprotein (P-gp) efflux pump, but pretreatment of rats with the potent P-gp inhibitor, cyclosporine A, did not have any significant influence on the cerebral uptake of [11C]3. These results indicate that all three tracers were not suitable for in vivo imaging of COX-2. There seem to be some obstacles to finding a useful candidate for in vivo imaging application of COX-2 selective inhibitors only by standard consideration of in vitro affinity and selectivity, and the lipophilicity of the compound.
Stable and efficient cassette exchange under non-selectable conditions by combined use of two site-specific recombinases (2002)

Work of the last decade has proven the 'one gene- one product-one function' hypothesis an oversimplification. To further unravel the emerging 'one gene-multiple products-even more functions' concept, new methods (such as subtle knock-in and tightly regulated conditional mutations) for the analysis of gene function in health and disease are required. Another class of improvements (such as tetraploid fusion and cassette exchange) addresses the efficiency with which targeted mutant strains can be generated. Recombinase-mediated cassette exchange (RMCE), which in theory is well suited for the rapid generation of multiple alleles of a given locus, is hampered by its low efficiency in the absence of selection and, especially in vivo, by the promiscuity of the participating recombinase recognition sites. Here we present a novel approach which circumvents this problem by the use of two independent recombinase systems. The strategy, which uses loxP on one and FRT on the other side of the cassette together with a Cre/Flpe expression vector, prevents excisive events and results in higher rates of cassette integration without selection than previously described. This method has a huge potential for the generation of allelic series in embryonic stem cells and, importantly, in pre-implantation embryos in vivo.
Burger's medicinal chemistry, drug discovery, and development (2010)

"Burger's is a flagship reference source for medicinal chemists and pharmaceutical professionals. This updated and expanded 8th edition has been thoroughly revised and improved to incorporate the concepts of drug hunting along with its existing coverage of the entire process of drug discovery and development. Bringing in a new and expert editorial board, this new edition updates existing chapters and adds 35 new ones, with topics including: opioid addiction treatments, antibody and gene therapy for cancer, blood-brain barrier, HIV treatments, and industrial-academic collaboration structures"--