gebhart/patrepeval huggingface dataset:
Expanding the Scope of RNA Catalysis (1994)

The basic notions of transition state theory have been exploited in the past to generate highly selective catalysts from the vast library of antibody molecules in the immune system. These same ideas were used to isolate an RNA molecule, from a large library of RNAs, that catalyzes the isomerization of a bridged biphenyl. The RNA-catalyzed reaction displays Michaelis-Menten kinetics with a catalytic rate constant (kcat) of 2.8 x 10(-5) per minute and a Michaelis constant (Km) of 542 microM; the reaction is competitively inhibited by the planar transition state analog with an inhibition constant (Ki) value of approximately 7 microM. This approach may provide a general strategy for expanding the scope of RNA catalysis beyond those reactions in which the substrates are nucleic acids or nucleic acid derivatives.
Immunization with a Peptide Surrogate for Double-stranded DNA (dsDNA) Induces Autoantibody Production and Renal Immunoglobulin Deposition (1998)

Anti-double-stranded DNA (dsDNA) antibodies are the serologic abnormality characteristically associated with systemic lupus erythematosus (SLE) and may play an important role in disease pathogenesis. Although the anti-dsDNA antibodies present in SLE are indicative of an antigen-driven response, the antigen has not been conclusively identified. By screening a phage peptide display library, we demonstrated previously that the decapeptide DWEYSVWLSN is specifically bound by the pathogenic murine IgG2b anti-dsDNA antibody R4A. To investigate the possibility that a protein antigen might trigger lupus-like autoimmunity, we immunized BALB/c mice with DWEYSVWLSN in adjuvant. Mice developed significant titers of IgG anti-dsDNA antibodies 2-3 wk after the initial immunization. Immunized mice also developed antibodies against some other lupus autoantigens, and immunoglobulin deposition was present in renal glomeruli at 49 d. Although an immune response to peptide and dsDNA was evident in BALB/c mice, there was little response in other inbred strains. This study demonstrates that lupus-like anti-dsDNA reactivity can be generated in nonautoimmune mice by immunization with a peptide antigen. Peptide-induced autoimmunity may prove useful in understanding the spreading of antigenic specificities targeted in SLE. However, most importantly, the demonstration that a peptide antigen can initiate a SLE-like immune response opens a new chapter on the potential antigenic stimuli that might trigger SLE.
X‐linked cardioskeletal myopathy and neutropenia (Barth syndrome): An update (2004)

X-linked cardioskeletal myopathy and neutropenia (Barth syndrome, MIM302060, BTHS) is a disorder with mitochondrial functional impairments and 3-methylglutaconic aciduria that maps to Xq28. The associated G4.5 or TAZ gene has been identified but the encoded proteins have not yet been characterized. Following the prediction that the gene encodes one or more acyltransferases, lipid studies have shown a deficiency of cardiolipin, especially its tetralinoleoyl form (L(4)-CL). Deficiency of L(4)-CL was subsequently demonstrated in a variety of tissues, and determination in thrombocytes or cultured skin fibroblasts is now the most specific biochemical test available. BTHS is the first identified inborn error of metabolism that directly affects cardiolipin, a component of the inner mitochondrial membrane, necessary for proper functioning of the electron transport chain. We report here the finding of deficient docosahexaenoic acid and arachidonic acid in a proportion of patients with BTHS. The initial impression of a uniformly lethal infantile disease has to be modified. Age distribution in 54 living patients ranges between 0 and 49 years and peaks around puberty. Mortality is the highest in the first 4 years. The apex of the survival curve around puberty and the emergence of adults may reflect a dynamic shift towards increased survival. This trend is exemplified in a large pedigree previously published.
Irrevocable transactions and their applications (2008)

Transactional memory (TM) provides a safer, more modular, and more scalable alternative to traditional lock-based synchronization. Implementing high performance TM systems has recently been an active area of research. However, current TM systems provide limited, if any, support for transactions executing irrevocable actions, such as I/O and system calls, whose side effects cannot in general be rolled back. This severely limits the ability of these systems to run commercial workloads.
Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. (1994)

Osteopontin is an Arg-Gly-Asp-containing acidic phosphoprotein recently shown to be upregulated in vascular smooth muscle during rat arterial neointima formation and in human atherosclerotic plaques. Functional studies showed that osteopontin promoted adhesion of both cultured aortic endothelial cells and aortic smooth muscle cells. Adhesion of vascular cells to osteopontin was dose dependent and half maximal when solutions containing 7 and 30 nmol/L osteopontin were used to coat wells for endothelial and smooth muscle cells, respectively. Smooth muscle cells adherent to osteopontin were spread after 60 minutes, whereas endothelial cells remained round, although flattened, at this time point but were spread at 90 minutes. Cell spreading on osteopontin was accompanied by the formation of focal adhesion plaques. A newly developed anti-osteopontin antibody completely inhibited adhesion of both cell types to osteopontin but not to fibronectin or vitronectin. In addition, the peptide GRGDSP blocked adhesion to osteopontin, suggesting that integrins mediate Arg-Gly-Asp-dependent adhesion. Indeed, an antibody against the alpha v beta 3 integrin neutralized adhesion of both endothelium and smooth muscle cells to osteopontin by approximately 50%, demonstrating that alpha v beta 3 is one osteopontin receptor on vascular cells. Osteopontin also promoted the migration of smooth muscle cells in a Boyden-type chamber, with half-maximal effects observed at 77 nmol/L osteopontin. Checkerboard analysis demonstrated that this stimulus was chemotactic in nature. Our findings suggest that osteopontin may be functionally important as an adhesive and chemotactic molecule for vascular cells, particularly when levels of osteopontin are dramatically increased, as is the case after arterial angioplasty and in atherosclerotic plaques.
Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats (2000)

Parathyroid hormone (PTH) is an effective bone anabolic agent, but it must be administered parenterally. An orally active anabolic agent would provide a valuable alternative for treating osteoporosis. NPS 2143 is a novel, selective antagonist (a "calcilytic") of the parathyroid cell Ca(2+) receptor. Daily oral administration of NPS 2143 to osteopenic ovariectomized (OVX) rats caused a sustained increase in plasma PTH levels, provoking a dramatic increase in bone turnover but no net change in bone mineral density. Concurrent oral administration of NPS 2143 and subcutaneous infusion of 17beta-estradiol also resulted in increased bone turnover. However, the antiresorptive action of estrogen decreased the extent of bone resorption stimulated by the elevated PTH levels, leading to an increase in bone mass compared with OVX controls or to either treatment alone. Despite the sustained stimulation to the parathyroid gland, parathyroid cells did not undergo hyperplasia. These data demonstrate that an increase in endogenous PTH secretion, induced by antagonism of the parathyroid cell Ca(2+) receptor with a small molecule, leads to a dramatic increase in bone turnover, and they suggest a novel approach to the treatment of osteoporosis.
Cyclic AMP-cyclic AMP receptor protein as a repressor of transcription of the spf gene of Escherichia coli (1988)

The spf gene of Escherichia coli encodes an unstable 109-nucleotide RNA, spot 42 RNA; the level of this RNA was reduced three- to fivefold when cells were grown in the presence of 3',5'-cyclic AMP (cAMP). We show that this regulation occurs through reduction in transcription and depends on both cAMP and the cAMP receptor protein (CRP) but is independent of the de novo protein synthesis. Through deletion analysis of the spf gene promoter, we have identified sequences that are important in the synthesis of spot 42 RNA. Deletion of sequences upstream of -77 completely eliminated the negative control of cAMP-CRP and resulted in high constitutive levels of transcription. This region contained a sequence that both conformed to the consensus binding site for cAMP-CRP in positively regulated promoters and acted as a cAMP-CRP binding site in a gel retardation assay. Deletion of sequences between positions -77 and -60 greatly reduced the level of transcription in the presence or absence of cAMP-CRP, indicating that at least part of this region is a binding site for a positive-acting transcription factor (or RNA polymerase itself). We propose that the proximity of the two sites defined here allows for the negative control of spf gene transcription by cAMP-CRP. In particular, if only one site at a time can be occupied, the binding of cAMP-CRP would interfere with the binding of a transcription factor.
Mucoid Pseudomonas aeruginosa in cystic fibrosis: characterization of muc mutations in clinical isolates and analysis of clearance in a mouse model of respiratory infection (1997)

A distinguishing feature of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients is their mucoid, exopolysaccharide alginate-overproducing phenotype. One mechanism of conversion to mucoidy is based on mutations in the algU mucABCD cluster, encoding the stress sigma factor AlgU and its regulators. However, conversion to mucoidy in laboratory strains can be achieved via mutations in other chromosomal sites. Here, we investigated mechanisms of the emergence of mucoid P. aeruginosa in CF by analyzing the status of mucA in a collection of mucoid P. aeruginosa isolates from 53 CF patients. This negative regulator of algU, when inactivated under laboratory conditions, causes conversion to mucoidy. The overall frequency of mucA alterations in mucoid CF isolates was 84%. Nucleotide sequence analyses revealed that the majority of the alterations caused premature termination of the mucA coding sequence. Comparison of paired nonmucoid and mucoid P. aeruginosa isolates from three CF patients indicated the presence of mucA mutations only in the mucoid strains. Interestingly, mucoid P. aeruginosa isolates from urinary tract infections also had mutations in the mucA gene. Clearance of CF isolates from the murine lung was investigated in an aerosol infection model with C57BL/6J, BALB/c, and DBA/2NHsd mice. Two CF strains, selected for further study based on the dependence of their alginate production on the concentration of salt in the medium, were used to examine the effects of mucoidy on pulmonary clearance. Statistically significant improvement in recovery from the murine lung of viable mucoid P. aeruginosa cells relative to the nonmucoid bacteria was observed in the majority of mouse strains tested. Collectively, the results reported here suggest that mucA is most likely the preferential site for conversion to mucoidy in CF and that alginate overproduction in mucA-mutant P. aeruginosa improves its resistance to the innate clearance mechanisms in the lung.
S Phase of the Cell Cycle (1989)

In each cell cycle the complex structure of the chromosome must be replicated accurately. In the last few years there have been major advances in understanding eukaryotic chromosome replication. Patterns of replication origins have been mapped accurately in yeast chromosomes. Cellular replication proteins have been identified by fractionating cell extracts that replicate viral DNA templates in vitro. Cell-free systems that initiate eukaryotic DNA replication in vitro have demonstrated the importance of complex nuclear architecture in the control of DNA replication. Although the events of S phase were relatively neglected for many years, knowledge of DNA replication is now advancing rapidly in step with other phases of the cell cycle.
Noninvasive imaging of protein–protein interactions in living animals (2002)

Protein-protein interactions control transcription, cell division, and cell proliferation as well as mediate signal transduction, oncogenic transformation, and regulation of cell death. Although a variety of methods have been used to investigate protein interactions in vitro and in cultured cells, none can analyze these interactions in intact, living animals. To enable noninvasive molecular imaging of protein-protein interactions in vivo by positron-emission tomography and fluorescence imaging, we engineered a fusion reporter gene comprising a mutant herpes simplex virus 1 thymidine kinase and green fluorescent protein for readout of a tetracycline-inducible, two-hybrid system in vivo. By using micro-positron-emission tomography, interactions between p53 tumor suppressor and the large T antigen of simian virus 40 were visualized in tumor xenografts of HeLa cells stably transfected with the imaging constructs. Imaging protein-binding partners in vivo will enable functional proteomics in whole animals and provide a tool for screening compounds targeted to specific protein-protein interactions in living animals.
A Prospective Study of Dehydroepiandrosterone Sulfate and Cognitive Function in an Older Population: The Rancho Bernardo Study (1994)

The single DHEAS-memory association, restricted to women, is most likely to be spurious, consequent to multiple comparisons. We cannot exclude a true effect of low DHEAS, restricted to women and reflecting their better survival than men.
Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids (2002)

Glucocorticoids (GCs) exert their anti-inflammatory and antiproliferative effects principally by inhibiting the expression of cytokines and adhesion molecules. Mechanistically, GCs diffuse through the cell membrane, and bind to their inactive cytosolic receptors (GRs), which then undergo conformational modifications that allow for their nuclear translocation. In the nucleus, activated GRs modulate transcriptional events by directly associating with DNA elements, compatible with the GCs response elements (GRE) motif, and located in variable copy numbers and at variable distances from the TATA box, in the promoter region of GC-responsive genes. In addition, activated GRs also acted by antagonizing the activity of transcription factors, in particular nuclear factor-kappaB (NF-kappaB), by direct and indirect mechanisms. GCs induced gene transcription and protein synthesis of the NF-kappaB inhibitor, IkappaB. Activated GR also antagonized NF-kappaB activity through protein-protein interaction involving direct complexing with, and inhibition of, NF-kappaB binding to DNA (Simple Model), or association with NF-kappaB bound to the kappaB DNA site (Composite Model). In addition, and according to the Transmodulation Model, GRE-bound GR may interact with and inhibit the activity of kappaB-bound NF-kappaB via a mechanism involving cross-talk between the two transcription factors. Lastly, GR may compete with NF-kappaB for nuclear coactivators, including CREB binding protein and p300, thereby reducing and inhibiting transcriptional activation by NF-kappaB. It should be noted that, in exerting its effect, activated GR did not affect the correct assembly of the pre-initiation (DAB) complex, but acted rather more proximally in inhibiting the correct assembly of transcription factors in the promoter region, and thus transcriptional initiation.
Retro-Orbital Venous Sinus Delivery of rAAV9 Mediates High-Level Transduction of Brain and Retina Compared with Temporal Vein Delivery in Neonatal Mouse Pups (2017)

In order to pursue a clinical gene therapy for a human neurologic disease, it is often necessary to perform proof-of-concept trials in mouse models of that disease. In order to demonstrate a potential clinical efficacy, one must be able to select an appropriate vector and route of delivery for the appropriate age group in the disease model. Since many diseases require correction early in life, investigators often need to deliver recombinant adeno-associated viral (rAAV) vectors to neonatal mice. Herein, general central nervous system expression patterns of nuclear GFP following delivery of rAAV by three different routes are reported.
Selection criteria for drug‐like compounds (2003)

The fast identification of quality lead compounds in the pharmaceutical industry through a combination of high throughput synthesis and screening has become more challenging in recent years. Although the number of available compounds for high throughput screening (HTS) has dramatically increased, large-scale random combinatorial libraries have contributed proportionally less to identify novel leads for drug discovery projects. Therefore, the concept of 'drug-likeness' of compound selections has become a focus in recent years. In parallel, the low success rate of converting lead compounds into drugs often due to unfavorable pharmacokinetic parameters has sparked a renewed interest in understanding more clearly what makes a compound drug-like. Various approaches have been devised to address the drug-likeness of molecules employing retrospective analyses of known drug collections as well as attempting to capture 'chemical wisdom' in algorithms. For example, simple property counting schemes, machine learning methods, regression models, and clustering methods have been employed to distinguish between drugs and non-drugs. Here we review computational techniques to address the drug-likeness of compound selections and offer an outlook for the further development of the field.
Effect of Different Crosslinking Technologies on Hyaluronic Acid Behavior: A Visual and Microscopic Study of Seven Hyaluronic Acid Gels. (2016)

Hyaluronic acid gels are produced with a range of different crosslinking technologies. Simple laboratory tests show how these can influence a gel's behavior, and can help physicians select the optimal product for a specific treatment indication.<BR /><BR /> Versions of this paper have been previously published in French and in Dutch in the Belgian journal <EM>Dermatologie Actualité</EM>. Micheels P, Sarazin D, Tran C, Salomon D. Un gel d'acide hyaluronique est-il semblable à son concurrent? <EM>Derm-Actu</EM>. 2015;14:38-43.<BR /><BR /> <EM>J Drugs Dermatol. 2016;15(5):600-606.</EM>.
Detection of Ligands from a Dynamic Combinatorial Library by X‐ray Crystallography (2003)

A dynamic combinatorial library of ligands derived from hydrazines A and isatins B was assembled in the presence of crystals of the target protein, cyclin-dependent kinase 2 (CDK2). Unambiguous detection of potent ligands, formed as part of the library, was successfully achieved by X-ray crystallographic analysis. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2003/z51951_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Multifunctional Ca2+/calmodulin-dependent protein kinase is necessary for nuclear envelope breakdown. (1990)

The role of multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) in nuclear envelope breakdown (NEB) was investigated in sea urchin eggs. The eggs contain a 56-kD polypeptide which appears to be a homologue of neuronal CaM kinase. For example, it undergoes Ca2+/calmodulin-dependent autophosphorylation that converts it to a Ca2(+)-independent species, a hallmark of multifunctional CaM kinase. It is homologous to the alpha subunit of rat brain CaM kinase. Autophosphorylation and substrate phosphorylation by the sea urchin egg kinase are inhibited in vitro by CaMK(273-302), a synthetic peptide corresponding to the autoinhibitory domain of the neuronal CaM kinase. This peptide inhibited NEB when microinjected into sea urchin eggs. Only one mAb to the neuronal enzyme immunoprecipitated the 56-kD polypeptide. Only this antibody blocked or significantly delayed NEB when microinjected into sea urchin eggs. These results suggest that sea urchin eggs contain multifunctional CaM kinase, and that this enzyme is involved in the control of NEB during mitotic division.
Modification of hematopoietic stem cell fate by 5aza 2′deoxycytidine and trichostatin A (2004)

Efforts to change the fate of human hematopoietic stem cells (HSCs) and progenitor cells (HPCs) in vitro have met with limited success. We hypothesized that previously utilized in vitro conditions might result in silencing of genes required for the maintenance of primitive HSCs/HPCs. DNA methylation and histone deacetylation are components of an epigenetic program that regulates gene expression. Using pharmacologic agents in vitro that might possibly interfere with DNA methylation and histone deacetylation, we attempted to maintain and expand cells with phenotypic and functional characteristics of primitive HSCs/HPCs. Human marrow CD34(+) cells were exposed to a cytokine cocktail favoring differentiation in combination with 5aza 2'deoxycytidine (5azaD) and trichostatin A (TSA), resulting in a significant expansion of a subset of CD34(+) cells that possessed phenotypic properties as well as the proliferative potential characteristic of primitive HSCs/HPCs. In addition, 5azaD- and TSA-pretreated cells but not the CD34(+) cells exposed to cytokines alone retained the ability to repopulate immunodeficient mice. Our findings demonstrate that 5azaD and TSA can be used to alter the fate of primitive HSCs/HPCs during in vitro culture.
Heterologous expression of plasmodial proteins for structural studies and functional annotation (2008)

Malaria remains the world's most devastating tropical infectious disease with as many as 40% of the world population living in risk areas. The widespread resistance of Plasmodium parasites to the cost-effective chloroquine and antifolates has forced the introduction of more costly drug combinations, such as Coartem. In the absence of a vaccine in the foreseeable future, one strategy to address the growing malaria problem is to identify and characterize new and durable antimalarial drug targets, the majority of which are parasite proteins. Biochemical and structure-activity analysis of these proteins is ultimately essential in the characterization of such targets but requires large amounts of functional protein. Even though heterologous protein production has now become a relatively routine endeavour for most proteins of diverse origins, the functional expression of soluble plasmodial proteins is highly problematic and slows the progress of antimalarial drug target discovery. Here the status quo of heterologous production of plasmodial proteins is presented, constraints are highlighted and alternative strategies and hosts for functional expression and annotation of plasmodial proteins are reviewed.
Parenting skills (2003)

Clare Arnold describes an innovative project which is designed to support parents who have a learning disability
A Randomized, Controlled, Phase 2 Study of AMG 317, an IL-4Rα Antagonist, in Patients with Asthma (2010)

AMG 317 did not demonstrate clinical efficacy across the overall group of patients. Clinically significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores. AMG 317 was safe and well tolerated in this study population. Clinical trial registered with www.clinicaltrials.gov (NCT 00436670).