gebhart/patrepeval huggingface dataset:
Human carboxylesterase 1: from drug metabolism to drug discovery (2003)

Human carboxylesterase 1 (hCE1) is a serine esterase involved in both drug metabolism and activation, as well as other biological processes. hCE1 catalyses the hydrolysis of heroin and cocaine, and the transesterification of cocaine in the presence of ethanol to the toxic metabolite cocaethylene. We have determined the crystal structures of hCE1 in complex with either the cocaine analogue homatropine or the heroin analogue naloxone. These are the first structures of a human carboxylesterase, and they provide details about narcotic metabolism in humans. hCE1's active site contains rigid and flexible pockets, explaining the enzyme's ability to act both specifically and promiscuously. hCE1 has also been reported to contain cholesteryl ester hydrolase, fatty acyl-CoA hydrolase and acyl-CoA:cholesterol acyltransferase activities, and thus appears to be involved in cholesterol metabolism. Since the enzyme may be useful as a treatment for cocaine overdose, and may afford protection against chemical weapons like Sarin, Soman and VX gas, hCE1 could serve as both a drug and a drug target. Selective hCE1 inhibitors targeted to several sites on the enzyme may also pave the way for novel clinical tools to manage cholesterol homoeostasis in humans.
Orientation of Colorado potato beetle to natural and synthetic blends of volatiles emitted by potato plants (2000)

Summary 1 Behavioural responses of the Colorado potato beetle (CPB), Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae), to volatiles emitted from solanaceous host plants (potato and tomato), a non‐host legume (soybean), and 13 synthetic blends or three individual chemicals emitted by potato plants were investigated in laboratory bioassays. 2 Both male and female CPB were attracted to volatiles emitted by mechanically damaged potato foliage, but not to mechanically damaged tomato foliage; CPB offered a choice between the two damaged solanaceous plants did not show a preference. 3 Among 16 odourous blends or individual chemical components of potato plant emissions tested, six blends were attractive, two were repellent, and eight elicited no preference in laboratory bioassays. Volatile blends containing relatively high amounts of the green leaf volatiles ( E )‐2‐hexen‐1‐ol and ( Z )‐3‐hexen‐1‐ol, or the sesquiterpene β‐ caryophyllene, were unattractive or repellent. Minimal blends attractive to CPB were comprised of ( Z )‐3‐hexenyl acetate (±)‐linalool and methyl salicylate: the combination of all three chemicals elicited sexually dimorphic attraction of males; two component blends comprised of ( Z )‐3‐hexenyl acetate and either (±)‐linalool and methyl salicylate attracted both sexes. Individual compounds were inactive. No significant difference was noted between two attractive blends, or an attractive synthetic blend vs. mechanically damaged potato foliage. 4 These results show that CPB are attracted to blends of specific chemicals emitted by their host plants and provide a basis for the use of plant attractants as a component of integrated management of pestiferous populations.
Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin (2002)

Cells respond to DNA damage by activating a network of signaling pathways that control cell cycle progression and DNA repair. Genetic studies in yeast suggested that several checkpoint proteins, including the RFC-related Rad17 protein, and the PCNA-related Rad1-Rad9-Hus1 protein complex might function as sensors of DNA damage. In this study, we show that the human Rad17 protein recruits the Rad9 protein complex onto chromatin after damage. Rad17 binds to chromatin prior to damage and is phosphorylated by ATR on chromatin after damage but Rad17's phosphorylation is not required for Rad9 loading onto chromatin. The chromatin associations of Rad17 and ATR are largely independent, which suggests that they localize to DNA damage independently. Furthermore, the phosphorylation of Rad17 requires Hus1, suggesting that the Rad1-Rad9-Hus1 complex recruited by Rad17 enables ATR to recognize its substrates. Our data are consistent with a model in which multiple checkpoint protein complexes localize to sites of DNA damage independently and interact to trigger the checkpoint-signaling cascade.
Evolution from OB Associations and Moving Groups to the Field Population (2001)

If we want to understand the evolution from star clusters to the Galactic field star population, the Solar neighbourhood is an ideal place to start. It contains objects from dense, very young clusters to old and almost dissolved moving groups. I describe the observational evidence for the ongoing dissolution of OB associations and open clusters. Subsequently, the interpretation of the local phase space distribution of stars in terms of old moving groups is discussed, emphasising the present limitations. Finally, I discuss future observational requirements and the possibilities offered by upcoming astrometric space missions.
A Model of Host-Microbial Interactions in an Open Mammalian Ecosystem (1996)

The maintenance and significance of the complex populations of microbes present in the mammalian intestine are poorly understood. Comparison of conventionally housed and germ-free NMRI mice revealed that production of fucosylated glycoconjugates and an alpha1, 2-fucosyltransferase messenger RNA in the small-intestinal epithelium requires the normal microflora. Colonization of germ-free mice with Bacteroides thetaiotaomicron, a component of this flora, restored the fucosylation program, whereas an isogenic strain carrying a transposon insertion that disrupts its ability to use L-fucose as a carbon source did not. Simplified models such as this should aid the study of open microbial ecosystems.
Confidence bounds for the generalization performances of linear combination of functions (1999)

This paper presents new results about confidence bounds on the generalization performances of linear combination of functions belonging to a set H. It is shown that when learning with monomial loss functions, the probability that the generalization error be greater than the empirical error plus /spl epsiv/, depends on the covering number of H and the magnitude of the coefficients of the combination. The classification case is studied by approximating a step function with polynomials.
Tumor Necrosis Factor Receptor-IgG Fusion Protein for Targeted Drug Delivery across the Human Blood−Brain Barrier (2009)

The tumor necrosis factor-alpha receptor (TNFR) extracellular domain (ECD) is a decoy receptor that could be developed as a neurotherapeutic for stroke, brain injury, or chronic neurodegeneration. However, the TNFR ECD is a large molecule therapeutic that does not cross the blood-brain barrier (BBB). Human TNFR ECD was re-engineered by fusion of the receptor protein to the carboxyl terminus of the chimeric monoclonal antibody (mAb) to the human insulin receptor (HIR). The HIRMAb-TNFR fusion protein is bifunctional, and binds both the HIR, to trigger receptor-mediated transport across the BBB, and TNFalpha, to sequester this cytotoxic cytokine. COS cells were dual transfected with the heavy chain (HC) and light chain fusion protein expression plasmids, and the HC of the fusion protein was immunoreactive with antibodies to both human IgG and TNFR. The HIRMAb-TNFR fusion protein bound to the extracellular domain of the HIR with an affinity comparable to the HIRMAb, and bound TNFalpha with a K(D) of 0.34 +/- 0.17 nM. Both the TNFR:Fc fusion protein and the HIRMAb-TNFR fusion protein blocked the cytotoxic actions of TNFalpha on human cells in a bioassay. In conclusion, these studies describe the re-engineering of the TNFR ECD to make this decoy receptor transportable across the human BBB.
Mitochondria in the life and death of neurons (1998)

A prolonged decrease in ATP levels underlies a number of neurodegenerative disorders. Defects in oxidative phosphorylation are associated with a number of neurodegenerative disorders. Mitochondria also play an important role in mediating the initiation of apoptosis.
Suppression of cytokines in mice by protein A-V antigen fusion peptide and restoration of synthesis by active immunization (1995)

It is established that an approximately 70-kb Lcr plasmid enables Yersinia pestis, the causative agent of bubonic plague, to multiply in focal necrotic lesions within visceral organs of mice by preventing net synthesis of the cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma), thereby minimizing inflammation (Lcr+). Rabbit antiserum raised against cloned staphylococcal protein A-V antigen fusion peptide (PAV) is known to passively immunize mice against 10 minimum lethal doses of intravenously injected Lcr+ cells of Y. pestis. In this study, injected PAV suppressed TNF-alpha and IFN-gamma in mice challenged with avirulent V antigen-deficient Y. pestis (lcrV or Lcr-) and promoted survival in vivo of these isolates as well as salmonellae and Listeria monocytogenes (with which the outcome was lethal). Active immunization of mice with PAV protected against 1,000 minimum lethal doses of intravenously injected Lcr+ cells of Y. pestis and Yersinia pseudotuberculosis but not Yersinia enterocolitica. The progressive necrosis provoked by Lcr+ cells of Y. pestis in visceral organs of nonimmunized mice was replaced after active immunization with PAV by massive infiltration of neutrophils and mononuclear cells (which generated protective granulomas indistinguishable from those formed against avirulent Lcr- mutants in nonimmunized mice). Distinct multiple abscesses typical of Lcr+ cells of Y. pseudotuberculosis were prevented by similar immunization. Significant synthesis of TNF-alpha and IFN-gamma occurred in spleens of mice actively immunized with PAV after challenge with Lcr+ cells of Y. pestis. These findings suggest that V antigen contributes to disease by suppressing the normal inflammatory response.
Differential Roles of the Pseudomonas aeruginosa PA14 rpoN Gene in Pathogenicity in Plants, Nematodes, Insects, and Mice (2001)

We cloned the rpoN (ntrA, glnF) gene encoding the alternate sigma factor sigma(54) from the opportunistic multihost pathogen Pseudomonas aeruginosa strain PA14. A marker exchange protocol was used to construct the PA14 rpoN insertional mutation rpoN::Gen(r). PA14 rpoN::Gen(r) synthesized reduced levels of pyocyanin and displayed a variety of phenotypes typical of rpoN mutants, including a lack of motility and the failure to grow on nitrate, glutamate, or histidine as the sole nitrogen source. Compared to wild-type PA14, rpoN::Gen(r) was ca. 100-fold less virulent in a mouse thermal injury model and was significantly impaired in its ability to kill the nematode Caenorhabditis elegans. In an Arabidopsis thaliana leaf infectivity assay, although rpoN::Gen(r) exhibited significantly reduced attachment to trichomes, stomata, and the epidermal cell surface, did not attach perpendicularly to or perforate mesophyll cell walls, and proliferated less rapidly in Arabidopsis leaves, it nevertheless elicited similar disease symptoms to wild-type P. aeruginosa PA14 at later stages of infection. rpoN::Gen(r) was not impaired in virulence in a Galleria mellonella (greater wax moth) pathogenicity model. These data indicate that rpoN does not regulate the expression of any genes that encode virulence factors universally required for P. aeruginosa pathogenicity in diverse hosts.
Assessment of the physiological condition of Salvinia natans L. exposed to copper(II) ions (2015)

Salvinia natans L. is a known bioaccumulator of metal ions from the aquatic environment. Exposure of plants to prolonged impact of toxins along with a large dose of the metal affects the physiological condition of the plants. The changes occurring in the plants in the phytoremediation process in contaminated medium culture of 5, 10, 15 and 20 mg Cu/dm 3 show two basic physiological parameters: the assimilation pigment content (chlorophyll a and b) responsible for the production of energy in the process of photosynthesis, and the total protein level as the main constituent of the plant. Conducted studies confirmed a negative effect of high concentrations of copper(II) on Salvinia natans L. plants which in these conditions are capable to bioaccumulate metal from each contaminated culture medium.
Evidence for the involvement of p59fyn and p53/56lyn in collagen receptor signalling in human platelets (1999)

The binding of collagen to platelet glycoprotein VI (GPVI) leads to the subsequent activation of phospholipase Cγ2 through a pathway that is dependent on the Fc receptor γ (FcR γ) chain and the tyrosine kinase p72syk. We have investigated the role of platelet Src-family kinases in this signalling pathway. The selective Src-family kinase inhibitor PP1 prevented collagen-stimulated increases in whole-cell tyrosine phosphorylation and tyrosine phosphorylation of the FcR γ chain and p72syk. A similar set of observations was made for a collagen-related peptide (CRP), which binds to GPVI but not to the integrin α2β1 (GPIa/IIa). These effects were seen at a concentration of PP1 that inhibited platelet aggregation, dense granule release and Ca2+ mobilization induced by CRP, but not aggregation and Ca2+ mobilization mediated by the G-protein-coupled receptor agonist thrombin. After stimulation by CRP or collagen, the Src-family kinases p59fyn and p53/56lyn became associated with several tyrosine-phosphorylated proteins including the FcR γ chain. This was not true of the other platelet Src-family kinases. The association between the FcR γ chain and p59fyn was also seen under basal conditions, and was stable only in the weak detergent Brij96 but not in Nonidet P40, suggesting a non-SH2-dependent interaction. These results provide strong evidence for the involvement of p59fyn and p53/56lyn in signalling via GPVI, with p59fyn possibly acting upstream of FcR γ chain phosphorylation.
A1CSA: An energy-efficient fast adder architecture for cell-based VLSI design (2011)

Energy-efficient fast adders are needed in the design of battery-powered portable devices. Although many fast adder architectures exist, most of them require transistor-level optimizations that prevent their synthesis in a standard-cell flow. This paper presents two energy-efficient Add-One Carry-Select Adders (A1CSA and A1CSAH) suited for standard-cells synthesis. Synthesis results showed that the A1CSA is the smallest fast adder requiring, on average, 22.2% less area than the Carry-Select Adder. They also showed that the A1CSAH is, on average, 10.8% faster and 3.4% more energy-efficient than the Carry-Lookahead Adder, thus corresponding to the best choice for high speed and high efficiency addition.
Mutants of Pertussis Toxin Suitable for Vaccine Development (1989)

Immunization with chemically detoxified pertussis toxin can prevent severe whooping cough with an efficacy similar to that of the cellular pertussis vaccine, which normally gives unwanted side effects. To avoid the reversion to toxicity and the loss of immunogenicity that may follow chemical treatment of pertussis toxin, inactive toxins were constructed by genetic manipulation. A number of genetically engineered alleles of the pertussis toxin genes, constructed by replacing either one or two key amino acids within the enzymatically active S1 subunit, were introduced into the chromosome of strains of Bordetella pertussis, B. parapertussis, and B. bronchiseptica. These strains produce mutant pertussis toxin molecules that are nontoxic and immunogenic and that protect mice from the intracerebral challenge with virulent Bordetella pertussis. Such molecules are ideal for the development of new and safer vaccines against whooping cough.
Pain relief from nasal salmon calcitonin in osteoporotic vertebral crush fractures (1997)

We examined the analgesic effect of nasal salmon calcitonin in patients with acute pain due to recent, nontraumatic osteoporotic vertebral crush fractures. 32 men and 68 postmenopausal women were studied using a prospective, double-blind, placebo-controlled clinical design. Men and women taking 200 IU of nasal salmon calcitonin daily for a period of 28 days had a dramatic decrease of spinal pain. This analgesic effect was accompanied by early mobilization and gradual restoration of the locomotor functions, such as sitting, standing and walking. Patients receiving the placebo nasal spray remained in bed for almost the entire period of observation. The consumption of high doses of paracetamol did not help placebo patients to get out of bed during the 4 weeks of hospitalization. Nasal salmon calcitonin and early mobilization also reduced hydroxyproline excretion, thus preventing massive bone loss during the period of bedrest.
Photoconductive terahertz transceiver (2000)

A photoconductive dipole antenna can be used as a transceiver, which alternately transmits pulsed electromagnetic radiation and receives the return signal. Preliminary results of using a photoconductive terahertz transceiver with femtosecond optics are reported.
Membrane complement regulators protect against the development of type II collagen-induced arthritis in rats (2001)

Our findings indicate that in rats with CIA and severely inflamed synovium, local expression of MCR is reduced. The MCRs Crry and CD59 appear to suppress the development of CIA.
Nanoparticle-mediated gene delivery: state of the art (2004)

With the development of genomic and proteomic technologies, the prospect for gene therapy has progressed rapidly. This has been partly possible due to the emergence of a diverse array of polymeric and non-polymeric nanoparticles that are being investigated for their ability to deliver genes and drugs. In this review, particles have been pragmatically divided as chitosan-related and chitosan-unrelated nanomaterials. The state of the art in terms of the development, characterisation and evaluation of their in vitro and/or in vivo potential is discussed for each of these various particles. Although substantial progress has been made, the potential of these particles in the clinical arena and human responses remain to be evaluated. It is hoped that this review will provide an impetus for further studies of these particles, with the ultimate intent that one or more of these diverse nanoparticle-based non-viral approaches for gene transfer will translate from 'bench to bedside' in the future.
Similarity and Differences in the Lactobacillus acidophilus Group Identified by Polyphasic Analysis and Comparative Genomics (2006)

A set of lactobacilli were investigated by polyphasic analysis. Multilocus sequence analysis, DNA typing, microarray analysis, and in silico whole-genome alignments provided a remarkably consistent pattern of similarity within the Lactobacillus acidophilus complex. On microarray analysis, 17 and 5% of the genes from Lactobacillus johnsonii strain NCC533 represented variable and strain-specific genes, respectively, when tested against four independent isolates of L. johnsonii. When projected on the NCC533 genome map, about 10 large clusters of variable genes were identified, and they were enriched around the terminus of replication. A quarter of the variable genes and two-thirds of the strain-specific genes were associated with mobile DNA. Signatures for horizontal gene transfer and modular evolution were found in prophages and in DNA from the exopolysaccharide biosynthesis cluster. On microarray hybridizations, Lactobacillus gasseri strains showed a shift to significantly lower fluorescence intensities than the L. johnsonii test strains, and only genes encoding very conserved cellular functions from L. acidophilus hybridized to the L. johnsonii array. In-silico comparative genomics showed extensive protein sequence similarity and genome synteny of L. johnsonii with L. gasseri, L. acidophilus, and Lactobacillus delbrueckii; moderate synteny with Lactobacillus casei; and scattered X-type sharing of protein sequence identity with the other sequenced lactobacilli. The observation of a stepwise decrease in similarity between the members of the L. acidophilus group suggests a strong element of vertical evolution in a natural phylogenetic group. Modern whole-genome-based techniques are thus a useful adjunct to the clarification of taxonomical relationships in problematic bacterial groups.
Monitoring of viral susceptibility: new challenges with the development of influenza NA inhibitors (2000)

With the clinical development of anti-viral agents, monitoring for the continued susceptibility of wild-type strains has become important in disease management. Various methods have been used to monitor viral susceptibility; the advantages and disadvantages of which depend on the virus, the target and the scale of the research being undertaken. The plaque-reduction assay is valuable for measuring susceptibility of most viruses but is not ideal for large-scale monitoring. Yield-reduction, measuring specific virus antigens, and dye-uptake assays, measuring virus cytopathic effects, are more suitable for high-throughput requirements, but the IC(50) value (the concentration that inhibits 50% of virus) varies with the viral inoculum. Surveillance of influenza susceptibility to rimantadine/amantadine in the clinic has predominantly used EIA-based assays, since plaquing of influenza clinical isolates is variable. With development of the influenza NA inhibitors it became apparent that current cell-based assays were unsuitable for monitoring susceptibility to this new class of drugs. Variability may result from virus spread directly from cell to cell in culture by-passing the NA function. Furthermore, mutations selected in the HA, while not apparently contributing to phenotypic resistance in vivo, may result in cell-culture based resistance, and may mask NA resistance in cell culture by modifying receptor-binding specificity. One important distinction between NA inhibitors and other antiviral enzyme inhibitors is that both target enzyme and inhibitor work extracellularly. NA assays are therefore most representative of the in vivo situation for monitoring susceptibility, supported by HA sequencing. As the clinical use of NA inhibitors escalates, a major change will be required in approaches used to monitor susceptibility of influenza isolates in virology laboratories world-wide.
Determining the Molecular Basis for the pH-dependent Interaction between the Link Module of Human TSG-6 and Hyaluronan (2007)

TSG-6 is an inflammation-associated hyaluronan (HA)-binding protein that has anti-inflammatory and protective functions in arthritis and asthma as well as a critical role in mammalian ovulation. The interaction between TSG-6 and HA is pH-dependent, with a marked reduction in affinity on increasing the pH from 6.0 to 8.0. Here we have investigated the mechanism underlying this pH dependence using a combined approach of site-directed mutagenesis, NMR, isothermal titration calorimetry and microtiter plate assays. Analysis of single-site mutants of the TSG-6 Link module indicated that the loss in affinity above pH 6.0 is mediated by the change in ionization state of a histidine residue (His(4)) that is not within the HA-binding site. To understand this in molecular terms, the pH-dependent folding profile and the pK(a) values of charged residues within the Link module were determined using NMR. These data indicated that His(4) makes a salt bridge to one side-chain oxygen atom of a buried aspartate residue (Asp(89)), whereas the other oxygen is simultaneously hydrogen-bonded to a key HA-binding residue (Tyr(12)). This molecular network transmits the change in ionization state of His(4) to the HA-binding site, which explains the loss of affinity at high pH. In contrast, simulations of the pH affinity curves indicate that another histidine residue, His(45), is largely responsible for the gain in affinity for HA between pH 3.5 and 6.0. The pH-dependent interaction of TSG-6 with HA (and other ligands) provides a means of differentially regulating the functional activity of this protein in different tissue microenvironments.