gebhart/patrepeval huggingface dataset:
Functional Bone Engineering Using ex Vivo Gene Therapy and Topology-Optimized, Biodegradable Polymer Composite Scaffolds (2005)

Bone tissue engineering could provide an alternative to conventional treatments for fracture nonunion, spinal fusion, joint replacement, and pathological loss of bone. However, this approach will require a biocompatible matrix to allow progenitor cell delivery and support tissue invasion. The construct must also support physiological loads as it degrades to allow the regenerated tissue to bear an increasing load. To meet these complex requirements, we have employed topology-optimized design and solid free-form fabrication to manufacture biodegradable poly(propylene fumarate)/beta-tricalcium phosphate composites. These scaffolds were seeded with primary human fibroblasts transduced with an adenovirus expressing bone morphogenetic protein-7 and implanted subcutaneously in mice. Specimens were evaluated by microcomputed tomography, compressive testing, and histological staining. New bone was localized on the scaffold surface and closely followed its designed contours. Furthermore, the total stiffness of the constructs was retained for up to 12 weeks after implantation, as scaffold degradation and tissue invasion took place.
Multiple Metal—Carbon Bonds for Catalytic Metathesis Reactions (Nobel Lecture 2005) (2007)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
Pharmacokinetic analysis of absorption, distribution and disappearance of ingested water labeled with D2O in humans (2011)

The kinetic parameters of absorption and distribution of ingested water (300 ml labeled with D(2)O; osmolality <20 mOsm kg(-1)) in the body water pool (BWP) and of its disappearance from this pool were estimated in 36 subjects from changes in plasma or urine deuterium to protium ratio (D/H) over 10 days using one- and two-compartment and a non-compartmental pharmacokinetic models (1-CM, 2-CM and N-CM which applied well to 58, 42 and 100% of the subjects, respectively). Compared with the volume and turnover of the BWP computed with the slope-intercept method (60.7 ± 4.1% body mass or 72.7 ± 3.2% lean body mass; turnover 4.58 ± 0.80 l day(-1): i.e., complete renewal in ~50 days; n = 36), the values were accurately estimated with the N-CM and 1-CM and were slightly overestimated and underestimated, respectively, with the 2-CM (~7-8% difference, significant for water clearance only). Ingested water appeared in plasma and blood cells within 5 min and the half-life of absorption (~11-13 min) indicates a complete absorption within ~75-120 min. The 2-CM showed that in 42% of the subjects, ingested water quickly distributed within a central compartment before diffusing with a very short half-life (12.5 ± 4.3 min) to a peripheral compartment (18.5 ± 4.3 and 31.6 ± 6.4 L, respectively), which were in complete equilibrium within ~90 min. Pharmacokinetic analyses of water labeled with D(2)O can help describe water absorption and distribution, for which there is no well defined reference method and value; depending on the characteristics of the subjects and the drinks, and of environmental conditions.
Immunotoxicology of immunomodulators. (1992)

Immunotoxicology is the study of the immune system as a target organ for the toxicity of drugs and chemicals. As immunotoxicologists focused most of their interest on immunosuppression, the toxic consequences of immunomodulation are less clearly established. However, a number of immunopharmacologically-mediated side-effects including influenza-like symptoms, exacerbation of underlying diseases, e.g. autoimmune diseases, increase in hypersensitivity reactions against unrelated antigens and inhibition of hepatic drug metabolism have been described and may be used as a basis for further safety evaluation. Current pre-clinical assessment of immunotoxicity is usually performed in the rat during sub-chronic testing. The relevance of these protocols as far as immunomodulators are concerned is unknown. Careful attention should be paid to safety pharmacology testing, e.g. cytokine release, effects on animal models of auto-immune and hypersensitivity reactions, and hepatic drug metabolism. The role of post-marketing drug surveillance should also be emphasized. Advances in our understanding of the mechanism(s) of immunomodulation together with the development of more active immunomodulators are expected to improve the current pre-clinical safety assessment of these compounds.
The Molecular Receptive Ranges of Human TAS2R Bitter Taste Receptors (2009)

Humans perceive thousands of compounds as bitter. In sharp contrast, only approximately 25 taste 2 receptors (TAS2R) bitter taste receptors have been identified, raising the question as to how the vast array of bitter compounds can be detected by such a limited number of sensors. To address this issue, we have challenged 25 human taste 2 receptors (hTAS2Rs) with 104 natural or synthetic bitter chemicals in a heterologous expression system. Thirteen cognate bitter compounds for 5 orphan receptors and 64 new compounds for previously identified receptors were discovered. Whereas some receptors recognized only few agonists, others displayed moderate or extreme tuning broadness. Thus, 3 hTAS2Rs together were able to detect approximately 50% of the substances used. Conversely, though 63 bitter substances activated only 1-3 receptors, 19 compounds stimulated up to 15 hTAS2Rs. Our data suggest that the detection of the numerous bitter chemicals is related to the molecular receptive ranges of hTAS2Rs.
Cyclosporin enhancement of cisplatin chemotherapy in patients with refractory gynecologic cancer. A gynecologic oncology group study (1994)

Cyclosporin at a dose of 4 mg/kg per day given for 2 consecutive days in association with 75 mg/m2 of cisplatin can be given with reasonable assurance of safety.
Discrimination of Single Base Substitutions in a DNA Strand Immobilized in a Biological Nanopore (2009)

Nanopores have been explored as highly sensitive sensors for detection and rapid sequencing of single molecules of DNA. To sequence DNA with a nanopore requires that adenine (A), cytosine (C), thymine (T), and guanine (G) produce distinct current signals as they traverse the pore. Recently, we demonstrated that homopolymers of adenine, cytosine, and thymine immobilized in the nanopore protein alpha-hemolysin (alphaHL) produced distinct current blockades dependent on their chemical orientation. To probe the detection limit of alphaHL, we examined immobilized single strands of T(40) DNA (polyT) with single base substitutions of A, C, and G at 12 positions on the strand occupying the stem region of alphaHL. We find blockade currents sensitive to base identity over most of these positions with the most sensitive region near the pore constriction. Adenine substitutions increase the measured blockade current to values intermediate to the polyT and polyA currents at a number of positions, while C substitutions increase the current to a level intermediate to polyT and polyC values in some positions, but decrease it below polyT in others. These changes in blockade current were also observed for G substitutions. These results indicate that total blockade currents measured in alphaHL arise from nucleotides at multiple locations and thus are not uniquely attributable to an individual base in a specific position, a finding consistent with a recently published study. The measurements of C and G substitutions also suggest that blockade current may be modulated through interactions between nucleotides and the pore interior at multiple sites in alphaHL.
Ansamycin Inhibitors of Hsp90: Natures Prototype for Anti-Chaperone Therapy (2009)

The ansamycin class of natural products is well known for its anti-tumor effects and has been extensively studied by cancer researchers for nearly four decades. The first description of geldanamycin in the scientific literature appeared in 1970 and nearly thirty years later the semi-synthetic derivative 17-AAG, or tanespimycin, entered Phase 1 clinical trials. In the subsequent years, three additional geldanamycin derivatives have entered clinical evaluation. Kosan Biosciences developed 17-DMAG or alvespimycin hydrochloride for clinical evaluation as both an intravenous and oral product. Infinity Pharmaceuticals is developing IPI-504 or retaspimycin hydrochloride as an intravenous product, which is in several Phase 2 clinical trials; IPI-504 is the hydroquinone hydrochloride salt of 17-AAG. More recently, Infinity Pharmaceuticals initiated a Phase 1 clinical trial with an oral formulation of 17-AG (IPI-493), the major metabolite of 17-AAG and IPI-504. Since a vast amount of scientific literature exists regarding the ansamycin field and Hsp90 inhibition, this review will survey key milestones in the development of the natural product class as anti-cancer drugs including discovery of the compounds and their anti-tumor effects, identification of Hsp90 as their biological target, the structure-activity relationships that have been identified in this interesting class of compounds, and development of clinical candidates for the treatment of cancer patients. A brief overview of important pre-clinical development data from each clinical lead is also provided.
Cytoplasmic LPS Activates Caspase-11: Implications in TLR4-Independent Endotoxic Shock (2013)

Inflammatory caspases, such as caspase-1 and -11, mediate innate immune detection of pathogens. Caspase-11 induces pyroptosis, a form of programmed cell death, and specifically defends against bacterial pathogens that invade the cytosol. During endotoxemia, however, excessive caspase-11 activation causes shock. We report that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers caspase-11 activation in mice. Specifically, caspase-11 responds to penta- and hexa-acylated lipid A, whereas tetra-acylated lipid A is not detected, providing a mechanism of evasion for cytosol-invasive Francisella. Priming the caspase-11 pathway in vivo resulted in extreme sensitivity to subsequent LPS challenge in both wild-type and Tlr4-deficient mice, whereas Casp11-deficient mice were relatively resistant. Together, our data reveal a new pathway for detecting cytoplasmic LPS.
Innate immunity in inflammatory bowel disease: a disease hypothesis (2007)

Crohn's disease arises from a defective interaction between the highly concentrated mass of bacteria in the gastrointestinal tract and the underlying tissues. It has generally been believed to result from an excessively exuberant inflammatory response or from 'autoimmunity'. Recent evidence has emerged that the problem is instead a failure of the way in which the body responds to the penetration of bacteria and other bowel contents through the intestinal mucosal barrier. Rather than Crohn's disease being caused by excessive inflammation, the primary mechanism is actually that of an immunodeficiency. Failure of inflammatory mediator production leads to insufficient recruitment of neutrophils, resulting in inadequate removal of bacteria and other debris. This impairment of acute inflammation can be compensated in some circumstances by signalling through NOD2. If not cleared, the foreign material in the bowel wall is taken up within macrophages, eliciting a granulomatous reaction and the local and systemic sequelae so characteristic of Crohn's disease.
Selective isolation of cosmid clones by homologous recombination in Escherichia coli. (1984)

A procedure for selection of specific cosmid clones by homologous recombination between cosmid clones from a library and sequences cloned into a plasmid has been developed. Cosmid libraries constructed in a rec- host strain are packaged in vivo into lambda particles. Appropriate aliquots are then introduced into a rec+ host containing the sequence used for selection cloned into a plasmid vector without sequence homology to the cosmid vector. After a short time for recombination, the cosmids are packaged in vivo. Cosmids that have taken up the plasmid by homologous recombination are isolated by plating under conditions selecting for the antibiotic resistance markers carried by both vectors. The recombined cosmids can lose the inserted sequence by another homologous recombination event and, after packaging in vivo, these revertants can be identified on appropriate indicator plates.
A Study of the Dissolution of SiO[sub 2] in Acidic Fluoride Solutions (1971)

Data are presented on the dissolution rates of films in a variety of acidic fluoride solutions. It is shown that the rate of dissolution is linearly dependent on the concentration of and HF in relatively dilute fluoride solutions. Both reactions have a similar temperature dependence characterized by an activation energy of 9.1 and 8.1 kcal/mole, respectively. The reaction with is about four to five times as fast as that with HF. Extrapolation to more concentrated solutions suggests that higher polymeric species of the type may also be active in the dissolution process. Raman data indicates that no single product species is formed although the product spectrum is consistent with the presence of some .
Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis (2009)

We studied patients with myeloid neoplasm associated with ringed sideroblasts and/or thrombocytosis. The combination of ringed sideroblasts 15% or greater and platelet count of 450 x 10(9)/L or greater was found in 19 subjects fulfilling the diagnostic criteria for refractory anemia with ringed sideroblasts (RARS) associated with marked thrombocytosis (RARS-T), and in 3 patients with primary myelofibrosis. JAK2 and MPL mutations were detected in circulating granulocytes and bone marrow CD34+ cells, but not in T lymphocytes, from 11 of 19 patients with RARS-T. Three patients with RARS, who initially had low to normal platelet counts, progressed to RARS-T, and 2 of them acquired JAK2 (V617F) at this time. In female patients with RARS-T, granulocytes carrying JAK2 (V617F) represented only a fraction of clonal granulocytes as determined by X-chromosome inactivation patterns. RARS and RARS-T patient groups both consistently showed up-regulation of ALAS2 and down-regulation of ABCB7 in CD34+ cells, but several other genes were differentially expressed, including PSIP1 (LEDGF), CXCR4, and CDC2L5. These observations suggest that RARS-T is indeed a myeloid neoplasm with both myelodysplastic and myeloproliferative features at the molecular and clinical levels and that it may develop from RARS through the acquisition of somatic mutations of JAK2, MPL, or other as-yet-unknown genes.
Retrovirus promoter-trap vector to induce lacZ gene fusions in mammalian cells (1991)

A retrovirus promoter-trap vector (U3LacZ) has been developed in which Escherichia coli lacZ coding sequences were inserted into the 3' long terminal repeat (LTR) of an enhancerless Moloney murine leukemia virus. The U3LacZ virus contains the longest reported LTR (3.4 kbp); nevertheless, lacZ sequences did not interfere with the ability of the virus to transduce a neomycin resistance gene expressed from an internal promoter. Duplication of the LTR placed lacZ sequences in the 5' LTR just 30 nucleotides from the flanking cellular DNA. Approximately 0.4% of integrated proviruses expressed beta-galactosidase as judged by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal) staining, and individual clones expressing lacZ were isolated by fluorescence-activated cell sorting. In all clones examined, beta-galactosidase expression resulted from the fusion of lacZ sequences to transcriptional promoters located in the flanking cellular DNA. Furthermore, by differential sorting of neomycin-resistant cell populations, clones were isolated in which lacZ expression was induced and repressed in growth-arrested and log phase cells, respectively.
Mining navigation history for recommendation (2000)

Although a user's navigation history contains a lot of hidden information about the relationship between web pages and between users, this information is usually not exploited. The information hidden in the history can be an invaluable source of knowledge in assisting a user to better surf the Web. We presented a system which actively monitors and tracks a user's navigation. Once a user's navigation history is captured, we apply data mining techniques to discover the hidden knowledge contained in the history. The knowledge is then used to suggest potentially interesting web pages to users.
[Effects of Ejiao (colla corii asini) on the hemodynamics, hemorheology and microcirculation during endotoxin shock in dogs]. (1989)

This paper reports the effects of Ejiao (Colla Corii Asini) on endotoxin shocks in dogs. The results showed that Ejiao obviously suppresses the increase of blood viscosity during shocks, improves microcirculation, and recovers and stabilizes blood pressure rather quickly.
The safety and efficacy of oral docosahexaenoic acid supplementation for the treatment of primary sclerosing cholangitis – a pilot study (2011)

Oral DHA supplementation is associated with an increase in serum DHA levels and a significant decline in alkaline phosphatase levels in patients with PSC. These data support the need for a rigorous trial of DHA therapy in PSC.
Formation of a high affinity heregulin binding site using the soluble extracellular domains of ErbB2 with ErbB3 or ErbB4 (1998)

ErbB2 functions as a shared signal transducing component for other ErbB receptor family members. Two of these receptors, ErbB3 and ErbB4, bind the heregulin (HRG) or neuregulin family of polypeptide growth factors. Cells expressing ErbB3 alone display a single class of low affinity HRG binding sites, whereas both high and low affinity binding sites can be measured on cells that co-express both ErbB3 and ErbB2. To assess the interaction of the extracellular domains of ErbB receptors, a series of soluble homodimeric and heterodimeric IgG fusion proteins were constructed. Heregulin binding analysis revealed that a heterodimer composed of either ErbB3 or ErbB4 with ErbB2 is sufficient for the formation of a high affinity binding state. In contrast, heterodimeric ErbB3/4-IgG, as well as homodimeric ErbB3-IgG or ErbB4-IgG, contained only low affinity HRG binding sites. Further evidence for the unique specificity of ErbB2 in generating this high affinity binding site was determined by inhibiting HRG binding with an ErbB2 monoclonal antibody.
Longitudinal magnetic resonance imaging study of rhesus monkey brain development (2006)

To examine early brain development, T1-weighted structural MRI scans of seven rhesus monkeys (Macaca mulatta) were obtained longitudinally between the ages of 1 week and 4 years at 12 age points. Total brain volume, calculated at each age point, increased significantly, by 56%, between 1 week and 4 years. The greatest increase of 22% occurred between 1 week and 1 month, followed by further significant increases between 1 and 2 months, and 3 and 4 months. Gradually smaller increases continued up to 3 years with no further significant changes thereafter. A robust maturation of white matter occurred between 1 week, at which the only easily identifiable fibre tracts were internal capsule and optic radiations, and 3 months, at which most large fibre tracts were visible; only at this age reproducible measurements were possible for all cases. White matter volume increased by 126% between 3 months and 4 years, with the biggest increase between 3 and 4 months (32%) followed by smaller but significant increases up to 4 years. The macaque brain development parallels that of humans by reaching the maximum in total brain volume around the age of sexual maturity (in macaques 3-4 years) and by the increases in white matter continuing beyond this age. The most rapid growth in both total brain volume and white matter from birth to approximately 4 months is consistent with the emergence of various cognitive abilities in macaques at that age.
Connexin45 Interacts with Zonula Occludens-1 and Connexin43 in Osteoblastic Cells (2001)

The relative expression of connexin43 and connexin45 modulates gap junctional communication and production of bone matrix proteins in osteoblastic cells. It is likely that changes in gap junction permeability are determined by the interaction between these two proteins. Cx43 interacts with ZO-1, which may be involved in trafficking of Cx43 or facilitating interactions between Cx43 and other proteins. In this study we sought to identify proteins that associate with Cx45 by coprecipitation in non-denaturing conditions. Cx45 was isolated with a 220-kDa protein that we identified as ZO-1. Under the same conditions, Cx43 also was isolated with anti-Cx45 antiserum from Cx45-transfected ROS cells (ROS/Cx45 cells). Cx43 antiserum could also coprecipitate ZO-1 in the transfected and untransfected ROS cells. Double label immunofluorescence studies showed that ZO-1, Cx43, and Cx45 colocalized at appositional membranes in ROS/Cx45 cells suggesting that all three proteins are normally associated in the cells. Additionally, we found that in vitro translated ZO-1 binds to the carboxyl-terminal of Cx45 indicating that there is a direct interaction between the carboxyl-terminal of Cx45 and ZO-1. These studies demonstrate that ZO-1 interacts with Cx45 as well as with Cx43, and suggest that the interaction of connexins with ZO-1 may play a role in regulating the composition of the gap junction and may modulate connexin-connexin interactions.
Small Molecule Subgraph Detector (SMSD) toolkit (2009)

Presently this tool can be applied to various areas of bioinformatics and chemo-informatics for finding exhaustive MCS matches. For example, it can be used to analyse metabolic networks by mapping the atoms between reactants and products involved in reactions. It can also be used to detect the MCS/substructure searches in small molecules reported by metabolome experiments, as well as in the screening of drug-like compounds with similar substructures.Thus, we present a robust tool that can be used for multiple applications, including the discovery of new drug molecules. This tool is freely available on http://www.ebi.ac.uk/thornton-srv/software/SMSD/
Nucleotide Requirements for the in Vitro Activation of the Apoptosis Protein-activating Factor-1-mediated Caspase Pathway (2000)

Adenine deoxynucleosides, such as 2-chlorodeoxyadenosine (2CdA) and fludarabine, induce apoptosis in quiescent lymphocytes, and are thus useful drugs for the treatment of indolent lymphoproliferative diseases. We previously demonstrated that that the 5'-triphosphate metabolite of 2CdA (2CdATP), similar to dATP, can cooperate with cytochrome c and apoptosis protein-activating factor-1 (APAF-1) to trigger a caspase pathway in a HeLa cell-free system. We used a fluorometry-based assay of caspase activation to extend the analysis to several other clinically relevant adenine deoxynucleotides in B-chronic lymphocytic leukemia extracts. The nucleotide-induced caspase activation displayed typical Michaelis-Menten kinetics. As estimated by the V(max)/K(m) ratios, the relative efficiencies of different nucleotides were Ara-ATP > 9-fluoro-9-beta-D-arabinofuranosyladenine 5'-triphosphate > dATP > 2CdATP > 9-beta-D-arabinofuranosylguanine 5'-triphosphate > dADP > ATP. In contrast to dADP, both ADP and its nonhydrolyzable alpha, beta-methylphosphonate analog were strong inhibitors of APAF-1-dependent caspase activation. The hierarchy of nucleotide activation was confirmed in a fully reconstituted system using recombinant APAF-1 and recombinant procaspase-9. These results suggest that the potency of adenine deoxynucleotides as co-factors for APAF-1-dependent caspase activation is due both to stimulation by the 5'-triphosphates and lack of inhibition by the 5'-diphosphates. The capacity of adenine deoxynucleoside metabolites to activate the apoptosome pathway may be an additional biochemical mechanism that plays a role in the chemotherapy of indolent lymphoproliferative diseases.