gebhart/patrepeval huggingface dataset:
ATP Activates a Reactive Oxygen Species-dependent Oxidative Stress Response and Secretion of Proinflammatory Cytokines in Macrophages (2006)

Secretion of the proinflammatory cytokines, interleukin (IL)-1beta and IL-18, usually requires two signals. The first, due to microbial products such as lipopolysaccharide, initiates transcription of the cytokine genes and accumulation of the precursor proteins. Cleavage and secretion of the cytokines is mediated by caspase-1, in association with an inflammasome containing Nalp3, which can be activated by binding of extracellular ATP to purinergic receptors. We show that treatment of macrophages with ATP results in production of reactive oxygen species (ROS), which stimulate the phosphatidylinositol 3-kinase (PI3K) pathway and subsequent Akt and ERK1/2 activation. ROS exerts its effect through glutathionylation of PTEN (phosphatase and tensin homologue deleted from chromosome 10), whose inactivation would shift the equilibrium in favor of PI3K. ATP-dependent ROS production and PI3K activation also stimulate transcription of genes required for an oxidative stress response. In parallel, ATP-mediated ROS-dependent PI3K is required for activation of caspase-1 and secretion of IL-1beta and IL-18. Thus, an increase in ROS levels in ATP-treated macrophages results in activation of a single pathway that promotes both adaptation to subsequent exposure to oxidants or inflammation, and processing and secretion of proinflammatory cytokines.
Production of multivalent protein binders using a self‐trimerizing collagen‐like peptide scaffold (2008)

A class of multivalent protein binders was designed to overcome the limitations of low-affinity therapeutic antibodies. These binders, termed "collabodies," use a triplex-forming collagen-like peptide to drive the trimerization of a heterologous target-binding domain. Different forms of collabody, consisting of the human single-chain variable fragment (scFv) fused to either the N or C terminus of the collagen-like peptide scaffold (Gly-Pro-Pro)(10), were stably expressed as soluble secretory proteins in mammalian cells. The collabody consisting of scFv fused to the N terminus of collagen scaffold is present as a homotrimer, whereas it exhibited a mixture of trimer and interchain disulfide-bonded hexamer when cysteine residues were introduced and flanked the scaffold. The collagenous motif in collabody is prolyl-hydroxylated, with remarkable thermal and serum stabilities. The collabody erb_scFv-Col bound to the extracellular domain of epidermal growth factor receptor with a binding strength approximately 20- and 1000-fold stronger than the bivalent and monovalent counterparts, respectively. The trimeric collagen scaffold does not compromise the functionality of the binding moieties of parental immunoglobulin G (IgG); therefore, it could be applied to fuse other protein molecules to acquire significantly improved targeting-binding strengths.
The Ubiquitin-Conjugation System (1992)

We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often incomplete. This is a problem because it limits our ...Read More
Antenna-based ultrahigh vacuum microwave frequency scanning tunneling microscopy system (2011)

The instrumental synthesis of high resolution scanning tunneling microscopy (STM) with the ability to measure differential capacitance with atomic scale resolution is highly desirable for fundamental metrology and for the study of novel physical characteristics. Microwave frequency radiation directed at the tip-sample junction in an STM system allows for such high-resolution differential capacitance information. This ability is particularly critical in ultrahigh vacuum environments, where the additional parameter space afforded by including a capacitance measurement would prove powerful. Here we describe the modifications made to a commercial scanning tunneling microscope to allow for broad microwave frequency alternating current scanning tunneling microscopy (ACSTM) in ultrahigh vacuum conditions using a relatively simple loop antenna and microwave difference frequency detection. The advantages of our system are twofold. First, the use of a removable antenna on a commercial STM prevents interference with other UHV processes while providing a simple method to retrofit any commercial UHV-STM with UHV-ACSTM capability. Second, mounting the microwave antenna on a translator allows for specific tuning of the system to replicate experimental conditions between samples, which is particularly critical in sensitive systems like organic thin films or single molecules where small changes in incident power can affect the results. Our innovation therefore provides a valuable approach to give nearly any commercial STM, be it an ambient or UHV system, the capability to measure atomic-scale microwave studies such as differential capacitance or even single molecule microwave response, and it ensures that experimental ACSTM conditions can be held constant between different samples.
[Transmission-blocking vaccine candidate of Plasmodium vivax Pvs25 is highly conservative among Chinese isolates]. (2004)

The results suggest that Pvs25 has limited antigenic polymorphism, especially compared with candidate antigens expressed by hepatic and erythrocytic stage, which may support the development and application of Pvs25-based transmission-blocking vaccine in China.
Assessment of autonomic regulation of heart rate variability by the method of complex demodulation (1989)

Complex demodulation was used to examine the effect of both divisions of the autonomic nervous system (sympathetic and parasympathetic) on heart rate. Data were analyzed from dogs during classical conditioning procedures which caused different changes in the autonomic regulation of heart rate. Two significant peaks in the heart rate variability spectrum were examined by this technique. The amplitude of the peak at the respiration frequency showed parasympathetic changes, while the amplitude of the low frequency peak (0-0.124 Hz) showed both sympathetic and parasympathetic effects. Complex demodulation results at these frequencies clearly showed the activities of both branches of the autonomic nervous system in regulating heart rate. During the CS+ period, when trained dogs were presented with a tone predicting a subsequent shock, the observed tachycardia was due to decreased parasympathetic activity and a transient increase in sympathetic activity. During the CS- period where a different tone predicts no shock, parasympathetic and sympathetic activities were unchanged from the baseline condition. The use of complex demodulation enables us to examine autonomic contributions to heart rate regulation in conditioning and a variety of other physiological and environmental conditions where autonomic input can be expected to change rapidly.
Establishment of two permanent human bone marrow stromal cell lines with long-term post irradiation feeder capacity (1994)

We describe the establishment of two permanent Simian virus 40- transformed human stromal cell lines, designated L87/4 and L88/5, derived from the bone marrow of a hematologically normal male patient. Both cell lines show a fibroblastoid morphology and do not express hematopoietic cell markers. L87/4 but not L88/5 expresses the macrophage marker CD68. The most remarkable feature of these new stromal cell lines is their ability to persist as growth-arrested adherent feeder cells after ionizing-irradiation at doses up to, and exceeding 20 Gy (L87/4). This renders them particularly useful for studying aspects of feeder dependence of hematopoietic cell development in long-term culture. Both cell lines are able to function as feeder cells, supporting the long-term proliferation of CD34+ human cord blood cells as well as the clonogenic growth of the human Burkitt lymphoma B- cell line BL70.
Structural and Functional Aspects of Metal Sites in Biology (1996)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructural and Functional Aspects of Metal Sites in BiologyRichard H. Holm, Pierre Kennepohl, and Edward I. SolomonView Author Information Departments of Chemistry, Harvard University, Cambridge, Massachusetts 02138, and Stanford University, Stanford, California 94305 Cite this: Chem. Rev. 1996, 96, 7, 2239–2314Publication Date (Web):November 7, 1996Publication History Received10 June 1996Revised3 September 1996Published online7 November 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/cr9500390https://doi.org/10.1021/cr9500390research-articleACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views16245Altmetric-Citations2150LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Copper,Iron,Ligands,Metals,Peptides and proteins Get e-Alerts
Opposite effects of Zn on the in vitro binding of [3H]LY354740 to recombinant and native metabotropic glutamate 2 and 3 receptors (2005)

We investigated the effect of Zn on agonist binding to both recombinant and native mGlu2 and mGlu3 receptors. Zn had a biphasic inhibitory effect on recombinant mGlu2 with IC(50) values for the high- and low-affinity components of 60 +/- 10 microM and 2 +/- 0.7 mM, respectively. Zn induced a complex biphasic effect of inhibition and enhancement of [(3)H]LY354740 binding to mGlu3. Observations with a series of chimeric mGlu2/3 receptors suggest that the Zn effect resides in the N-terminal domain of mGlu2 and mGlu3. We observed that the His56 of mGlu2, which corresponds to Asp63 in mGlu3 was largely accountable for the second phase of the Zn effect. As revealed by quantitative receptor radioautography, the addition of up to 100 microm Zn to brain sections of wild-type mice resulted in significant decreases in binding density in most brain regions. In particular, the mid-molecular layer of the dentate gyrus (DGmol) and the CA1 lacunosum moleculare of hippocampus (CA1-LMol) showed reductions of 62 and 67%, respectively. In contrast, the addition of 300 microM Zn to brain sections of mGlu2(-/-) mice caused large increases in binding density of 289 and 242% in DGmol and CA1-LMol, respectively. Therefore, Zn might play a role as a physiological modulator of group II mGlu receptor function.
A neural network model extracting features from speech signals (1988)

Abstract A feature‐extracting model for the auditory nervous system was constructed using neurons with nonlinear inhibitory mechanisms as the elements. The operation was verified by computer simulation. The model is composed of the bandpass filters corresponding to basilar membrane, the half‐wave rectifiers corresponding to the hair cells, and the feature‐extracting neurons. The feature detector is a multilayered network, where several neural layers composed of a one‐dimensional array of neurons of the same response are connected in cascade. Each neuron performs the spatio‐temporal addition for the excitatory and inhibitory inputs through spatial connections in the input‐side layer and the first‐order delay. Then, the neuron produces an output through the nonlinear inhibitory mechanism (shunt inhibition) and the analog threshold characteristics. Considering the physiological knowledge and characters of the speech, three kinds of feature‐detecting neural groups were constructed. These are: CF group to detect the interval where the frequency is kept constant; FM group to detect the interval where the frequency is varying; and the fricative noise group to detect the fricative noise. These three correspond to the features of the vowel formant, the transition from consonant to vowel or the contracted sound, and the features of most of the consonants, respectively. Computer simulation was performed with actual speech input, and it was verified that the proposed model correctly extracts the various features contained in the speech.
Pharmacodynamics of acute intranasal administration of verapamil: Comparison with IV and oral administration (1985)

The present study was conducted in order to examine the intranasal administration of verapamil and compare this route to oral and intravenous administration in a 3 way crossover protocol in five dogs. Unanesthetized, adult mongrel dogs were given verapamil intravenously (0.5 mg/kg), orally (2.5 mg/kg) and intranasally (0.75 mg/kg) with at least a 3-4 day washout period between each administration. Blood samples were collected over a 10 hour period and analyzed for verapamil using HPLC with fluorescence detection. A lead II ECG was monitored to determine the effects of verapamil on heart rate and P-R interval. Following intravenous administration, verapamil was distributed according to a two compartment model. Bioavailability (corrected for dose and elimination rate constant) following intranasal administration (36% +/- 7%) was approximately 3 fold that after oral administration (13% +/- 3%). Absorption from the nasal cavity appeared instantaneous compared to an absorption half-life of 50 +/- 6 min after oral administration. All three routes of administration resulted in significant increases in heart rate and increases in the P-R interval. Maximal P-R interval prolongation occurred after peak plasma concentrations of verapamil. The results of this study suggest that the intranasal route is a viable alternative route of administration for verapamil.
Substituted 3beta-phenylethynyl derivatives of 3alpha-hydroxy-5alpha-pregnan-20-one: remarkably potent neuroactive steroid modulators of gamma-aminobutyric acidA receptors. (1998)

Neuroactive steroids are positive allosteric modulators of gamma-aminobutyric acidA (GABAA) receptor complexes. Synthetic modification generally does not increase neuroactive steroid potency beyond that of the naturally occurring progesterone metabolite, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P). Recently, it has been shown that introduction of appropriately para-substituted phenylethynyl groups at the 3beta-position of 5beta steroids increases receptor potency. The present report presents the synthesis and pharmacological profile of an analogous series of 5alpha steroids. The most striking feature of this series is the further enhancement of in vitro and in vivo potency obtained. In particular, 3beta-(p-acetylphenylethynyl)-3alpha-hydroxy-5alpha-pr egnan-20-one (Co 152791) was 11-, 16- and 49-fold more potent than 3alpha, 5alpha-P in modulating the binding of [35S]TBPS, [3H]flunitrazepam and [3H]muscimol, respectively, in rat brain membranes (Co 152791 IC50 or EC50 = 2-7.5 nM). Similarly, Co 152791 was 3- to 20-fold more potent than 3alpha,5alpha-P as an inhibitor of [35S]TBPS binding in human recombinant receptor combinations containing alpha1, alpha2, alpha3 or alpha5 and beta2gamma2L subunits (Co 152791 IC50 1.4-5.7 nM). Co 152791 displayed low efficacy and 3alpha,5alpha-P had low potency at alpha4/6beta3gamma2L GABAA receptor complexes. Interestingly, Co 152791 demonstrated remarkable potency as a potentiator of GABA-evoked currents in Xenopus oocytes expressing alpha1beta2gamma2L receptors (EC50 0.87 nM), being 184-fold more potent than 3alpha,5alpha-P. High in vitro potency was also reflected in enhanced in vivo activity in that Co 152791 exhibited exceptional anticonvulsant potency, protecting mice from pentylenetetrazol-induced seizures at a approximately 5-fold lower dose than 3alpha,5alpha-P after i.p. administration (Co 152791 ED50 0.6 mg/kg). Moreover, Co 152791 was orally active (ED50 1.1 mg/kg) and exhibited a therapeutic index of 7 relative to rotorod impairment. The remarkable potency of Co 152791 as a positive allosteric modulator of GABAA receptors may be explained by its interaction with an auxiliary binding pocket in the neuroactive steroid binding site. In addition, modification at the 3beta-position probably hinders metabolism of the 3alpha-hydroxy group contributing to the exceptional anticonvulsant potency of this compound relative to other neuroactive steroids.
Venous Thromboembolism and Other Venous Disease in the Tecumseh Community Health Study (1973)

The prevalence and incidence of venous thromboembolism and other venous disease has been determined as part of a longitudinal study of health and disease in a Michigan community. When these data are extrapolated to 1970 U.S. census figures, a rough estimate of annual incidence of clinically recognized deep venous thrombosis is over 250,000 cases while that of superficial thrombophlebitis is over 123,000. An estimated 24 million US citizens have "significant" varicose veins while 6 to 7 million have stasis changes in the skin of the legs and 400,000 to 500,000 have or have had a varicose ulcer. The relatively high frequency of these conditions in the adult population of Tecumseh, Michigan, indicates that they represent several of the more common medical problems encountered by the practicing physician.
DNA Damage Detection and Repair Pathways—Recent Advances with Inhibitors of Checkpoint Kinases in Cancer Therapy (2008)

Insights from cell cycle research have led to the hypothesis that tumors may be selectivity sensitized to DNA-damaging agents, resulting in improved antitumor activity and a wider therapeutic margin. The theory relies primarily on the observation that the majority of tumors are deficient in the G(1)-DNA damage checkpoint pathway, resulting in reliance on S and G(2) phase checkpoints for DNA repair and cell survival. The S and G(2) phase checkpoints are predominantly regulated by checkpoint kinase 1; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G(1) checkpoint signaling pathway that allows for DNA repair and cell survival. There is now a large body of preclinical evidence showing that checkpoint kinase inhibitors do indeed enhance the efficacy of both conventional chemotherapy and radiotherapy, and several agents have recently entered clinical trials. Excitingly, additional therapeutic opportunities for checkpoint kinase inhibitors continue to emerge as biology outside their pivotal role in cell cycle arrest is further elucidated.
Detection of wild-type contamination in a recombinant adenoviral preparation by PCR. (1995)

A rapid and sensitive method of detecting wild-type virus contamination is needed for the preparation of recombinant adenoviruses for adenoviral vector applications in which purified vectors free of wild-type virus are required for preclinical studies and clinical trials. In response to this demand, we developed a PCR assay that uses two pairs of primers in the same reaction to detect adenoviral E1 DNA with co-amplification of E2B DNA as an internal control. Template DNA preparation was simplified and required only 365 microL of culture medium of 293 cells that displayed a cytopathic effect following adenovirus infection. Evaluation of the sensitivity of the assay demonstrated that it detected the E1 DNA in a reconstruction of one plaque-forming unit (pfu) of wild-type virus in 10(9) pfu of recombinant viruses. This method may be useful for quality control in the production of adenoviral vectors free of wild-type virus for gene therapy applications.
Effects of soluble interleukin-1 type II receptor on rabbit antigen-induced arthritis: clinical, biochemical and histological assessment. (1999)

These results demonstrate that IL-1 plays an important role in the pathogenesis of rabbit antigen-induced arthritis, thus confirming it as an excellent animal model with respect to evaluating anti-cytokine therapies for rheumatoid arthritis.
Defined spatial structure stabilizes a synthetic multispecies bacterial community (2008)

This paper shows that for microbial communities, "fences make good neighbors." Communities of soil microorganisms perform critical functions: controlling climate, enhancing crop production, and remediation of environmental contamination. Microbial communities in the oral cavity and the gut are of high biomedical interest. Understanding and harnessing the function of these communities is difficult: artificial microbial communities in the laboratory become unstable because of "winner-takes-all" competition among species. We constructed a community of three different species of wild-type soil bacteria with syntrophic interactions using a microfluidic device to control spatial structure and chemical communication. We found that defined microscale spatial structure is both necessary and sufficient for the stable coexistence of interacting bacterial species in the synthetic community. A mathematical model describes how spatial structure can balance the competition and positive interactions within the community, even when the rates of production and consumption of nutrients by species are mismatched, by exploiting nonlinearities of these processes. These findings provide experimental and modeling evidence for a class of communities that require microscale spatial structure for stability, and these results predict that controlling spatial structure may enable harnessing the function of natural and synthetic multispecies communities in the laboratory.
Custom-made knee endoprosthetics using subtraction data of three-dimensional CT scans.A new approach (2000)

A new method is presented which allows the construction and implantation of highly precise custom-made endoprostheses for knee joints. The procedure is based on a computer-aided subtraction process of three-dimensional CT data. Using the differences of the CT scans, the endprosthetic components are modelled by means of a newly developed software package. The implants are manufactured by CNC machines and stereolithography. The method enables the surgeon to reduce bone resections and ensures an exact profile of the bone-implant interface. Incorrect positioning will be avoided and the implantation process can be performed more easily while the size of the operative approach will be minimized. Better postoperative kinematics and reduction of shearing effects will lead to better results in the long run. The procedure offers a series of new possibilities to optimize monocondylar and bicondylar knee joint endoprostheses.