gebhart/patrepeval huggingface dataset:
Resolved Single-Molecule Detection of Individual Species within a Mixture of anti-Biotin Antibodies Using an Engineered Monomeric Nanopore (2015)

Oligomeric protein nanopores with rigid structures have been engineered for the purpose of sensing a wide range of analytes including small molecules and biological species such as proteins and DNA. We chose a monomeric β-barrel porin, OmpG, as the platform from which to derive the nanopore sensor. OmpG is decorated with seven flexible loops that move dynamically to create a distinct gating pattern when ionic current passes through the pore. Biotin was chemically tethered to the most flexible one of these loops. The gating characteristic of the loop's movement in and out of the porin was substantially altered by analyte protein binding. The gating characteristics of the pore with bound targets were remarkably sensitive to molecular identity, even providing the ability to distinguish between homologues within an antibody mixture. A total of five gating parameters were analyzed for each analyte to create a unique fingerprint for each biotin-binding protein. Our exploitation of gating noise as a molecular identifier may allow more sophisticated sensor design, while OmpG's monomeric structure greatly simplifies nanopore production.
Information Dissemination Needs of Indonesian Migrant Domestic Workers in Malaysia (2012)

Substantial numbers of Indonesian women are seeking employment as domestic workers in Malaysia in order to escape poverty and unemployment and to be able to support their families back home. Most Indonesian domestic workers in Malaysia face unpleasant working conditions with long working hours and no freedom to move or communicate; some find themselves in a situation of abuse. In many cases, the decision to work abroad is made without being properly informed about what to expect. Furthermore, most of the Indonesian migrant domestic workers do not know about process and procedures and are not aware of their rights and the possibilities of seeking assistance when problems occur. In order to empower the target group, relevant information need to be disseminated. Current strategies do not seem to achieve the desired effect. Many of the affected women come from remote areas, are poor and have a low level of education; therefore, their skills to make use of written or even digital information are limited. Appropriate strategies are suggested to utilise traditional and commonly used information dissemination channels such as cultural performances, group discussions and radio. Educational measures should be combined with aspects of local entertainment culture in order to attract attention and to provoke identification with the issues discussed. Further research is necessary to actually develop an appropriate information dissemination strategy with regard to the target group and to evaluate its benefits by conducting pilot projects.
Leflunomide in juvenile idiopathic arthritis (2006)

The gold standard of therapy for patients with juvenile idiopathic arthritis (JIA), previously referred to as juvenile rheumatoid arthritis (JRA), has been methotrexate and, if methotrexate fails, a biological agent. Leflunomide, an oral pyrimidine synthesis inhibitor, has been shown to be well tolerated and effective in both short-term and long-term studies of adult rheumatoid arthritis (RA). This article reviews the current state-of-the-art use of leflunomide in JIA. A Phase Ib study demonstrated that leflunomide is effective in patients who have either failed methotrexate or are intolerant of methotrexate (50% American College Rheumatology [ACR] Pedi 30). Following the encouraging results of this initial study, a large, multicentered comparator study of leflunomide versus methotrexate was performed. This study demonstrated that both drugs had excellent response rates (ACR Pedi 30 rates of 68 and 89%, respectively) although there was a statistically significant higher response rate for methotrexate.
Flexible Search and Navigation using Faceted Metadata (2002)

We have developed an in6 vative searchin terface that allowsnAOz5z ert users to move through large in97z86 tion spacesin a flexible manle without feelin lost. The design goal was to o#er users a &amp;quot;browsin the shelves&amp;quot; experien5 seamlessly in tegrated with focused search. Key to achievin our goal is the explicit exposure of hierarchical faceted metadatain a manz6 that is in tuitive an in vitin to users. After several iteration of design an testinA the usability results are strikinA] positive. We believe our approach marks a major step forward in search userin terfacesan can serve as a model for web-based collection of up to 100,000 items.
Prostaglandin F2α: A bone remodeling mediator (2012)

Prostaglandin F2α (PGF2α) plays multiple roles on bone metabolism by regulating a wide range of signaling pathways. PGF2α, via activation of PKC, stimulates Na-dependent inorganic phosphate (Pi) transport system in osteoblasts; up-regulates interleukin (IL)-6 synthesis; increases vascular endothelial growth factor (VEGF). In addition, PGF2α acts as a strong mitogenic and survival agent on osteoblasts, and these effects are, at least in part, mediated by the binding of fibroblast growth factor-2 (FGF-2) to the specific receptor FGFR1. The understanding of PGF2α intracellular network, albeit complex to clarify, provides molecular bases useful to identify the players of osteoblast proliferation, apoptosis, and the associated angiogenic processes. Indeed, the molecular mechanism that underline PGF2α-regulated bone metabolism may be a promising platform for the development of novel targeted therapies in the treatment of bone disorders and disease.
Cloning, distribution and functional analysis of the type III sodium channel from human brain (2000)

The type III voltage-gated sodium channel was cloned from human brain. The full-length cDNA has 89% identity with rat type III, and the predicted protein (1951 amino acids) has 55 differences. The expression pattern of human type III mRNA was determined in adult brain tissue and, in contrast to rat, was detected in many regions, including caudate nucleus, cerebellum, hippocampus and frontal lobe. The human type III channel was stably expressed in Chinese hamster ovary (CHO) cells and its biophysical properties compared to the human type II channel using identical conditions. The voltage dependence and kinetics of activation were found to be similar to that of type II. The kinetics of inactivation of the two human subtypes were also similar. However, type III channels inactivated at more hyperpolarized potentials and were slower to recover from inactivation than type II. When expressed in human embryonic kidney (HEK293T) cells, type III channels produced currents with a prominent persistent component, which were similar to those reported for rat type II [Ma et al. (1997) Neuron, 19, 443-452]. However, unlike type II, this was prominent even in the absence of coexpressed G-proteins, suggesting type III may adopt this gating mode more readily. The distinct properties of the channel, together with its wide distribution in adult brain, suggest that in humans, type III may have important physiological roles under normal, and perhaps also pathological conditions.
Pharmacological Suppression of Premature Stop Mutations that Cause Genetic Diseases (2005)

Aminoglycoside antibiotics have long been used as antibacterial agents due to their ability to inhibit bacterial translation. However, aminoglycosides also stimulate translation errors in mammalian cells. Aminoglycosides bind to a pocket formed in a domain of the ribosomal RNA (rRNA) of the small ribosomal subunit that constitutes the decoding site in both prokaryotes and eukaryotes. Normally, accurate base pairing takes place between each successive codon and its cognate aminoacyl-tRNA within this region of the ribosome. When aminoglycosides bind to the decoding site, a conformational change decreases discrimination between cognate and near-cognate tRNAs, leading to errors in the decoding process. The ability of aminoglycosides to bind to the decoding site and induce translational misreading in eukaryotic cells is less efficient than in prokaryotic cells due to subtle differences in the sequence of the decoding site rRNA. The observation that aminoglycosides induce low levels of misreading in eukaryotic cells has inspired many investigations to determine whether aminoglycosides can suppress nonsense mutations that cause human diseases. Disease models in which aminoglycosides have been shown to efficiently suppress nonsense mutations include cystic fibrosis, Duchenne muscular dystrophy, Hurler syndrome, infantile neuronal lipfuscinosis, cystinosis, x-linked nephrogenic insipidus, spinal muscular atrophy, and cancer. However, if aminoglycosides are to be used clinically for suppression therapy, their efficacy must be improved and their toxicity reduced. The co-administration of other compounds that reduce aminoglycoside toxicity or the development of new compounds that suppress stop mutations may allow the realization of suppression therapy as a clinical treatment to suppress disease-causing stop mutations.
Broad-Spectrum Inhibitors against 3C-Like Proteases of Feline Coronaviruses and Feline Caliciviruses (2015)

Feline infectious peritonitis virus (FIPV) is the leading cause of death in young cats, and virulent, systemic feline calicivirus (vs-FCV) causes a highly fatal disease in cats for which no preventive or therapeutic measure is available. The genomes of these distinct viruses, which belong to different virus families, encode a structurally and functionally conserved 3C-like protease (3CLpro) which is a potential target for broad-spectrum antiviral drug development. However, no studies have previously reported a structural platform for the design of antiviral drugs with activities against these viruses or on the efficacy of 3CLpro inhibitors against coronavirus infection in experimental animals. In this study, we explored the structure-activity relationships of the derivatives of 3CLpro inhibitors and identified inhibitors with potent dual activities against these viruses. In addition, the efficacy of the 3CLpro inhibitors was demonstrated in mice infected with a murine coronavirus. Overall, our study provides the first insight into a structural platform for anti-FIPV and anti-FCV drug development.
Nanostructured Polymer Duplexes via the Covalent Casting of 1-Dimensional H-Bonding Motifs:  A New Strategy for the Self-Assembly of Macromolecular Precursors (2000)

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTNanostructured Polymer Duplexes via the Covalent Casting of 1-Dimensional H-Bonding Motifs: A New Strategy for the Self-Assembly of Macromolecular PrecursorsEric A. Archer, Noah T. Goldberg, Vincent Lynch, and Michael J. KrischeView Author Information University of Texas at Austin Department of Chemistry and Biochemistry Austin, Texas 78712 Cite this: J. Am. Chem. Soc. 2000, 122, 20, 5006–5007Publication Date (Web):May 5, 2000Publication History Received3 March 2000Published online5 May 2000Published inissue 1 May 2000https://doi.org/10.1021/ja000777sCopyright © 2000 American Chemical SocietyRequest reuse permissionsArticle Views530Altmetric-Citations34LEARN 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 InReddit Read OnlinePDF (87 KB) Get e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Polymerization,Polymers,Precursors,Self organization,X-rays Get e-Alerts
A role for proteinase-activated receptor 2 and PKC-ε in thrombin-mediated induction of decay-accelerating factor on human endothelial cells (2005)

Thrombin, an important mediator of thrombosis and inflammation, may also enhance vascular cytoprotection. Thus thrombin induces expression of the complement-inhibitory protein decay-accelerating factor (DAF) in human umbilical vein endothelial cells (HUVECs), thus increasing protection against complement-mediated injury. Using PKC isozyme-specific peptide antagonists and adenoviral constructs, we have shown in the present study that PKC-epsilon is the primary isozyme involved in DAF induction by thrombin. Experiments with proteinase-activated receptor-1 (PAR1) and PAR2 activating peptides (APs) showed that DAF expression induced by PAR1-AP was PKC-alpha-dependent; in contrast, PAR2-AP induction of DAF required activation of PKC-epsilon. PAR1-AP and PAR2-AP in combination exerted an additive effect on DAF protein expression, which was equivalent to that observed with thrombin alone. These data implied a specific role for PAR2 in DAF induction, which was supported by the observation that upregulation of endothelial cell (EC) PAR2-enhanced DAF induction by thrombin. ERK1/2, p38, and JNK MAPK were also involved in thrombin-induced DAF upregulation, with evidence of interdependence between ERK1/2 and JNK. A role for transactivation of PAR2 by PAR1 was suggested by partial inhibition of thrombin-induced DAF expression by the PAR1 signaling antagonists BMS-200261 and SCH79797, whereas inhibition of thrombin-induced cleavage of PAR1 by specific MAbs or hirudin completely abrogated the response. Together, these data imply that the predominant pathway for thrombin-induced DAF expression involves transactivation of PAR2 by PAR1 and signaling via PKC-epsilon/MAPK. This may represent an important, novel pathway for endothelial cytoprotection during inflammation and angiogenesis and suggests that PAR2 may play a central role in some thrombin-induced responses.
Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial (2002)

Risk assessment in acute myeloid leukemia (AML) using pretreatment characteristics may be improved by incorporating parameters of early response to therapy. In the 1992 trial of the German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449 patients 16 to 76 years of age (median, 53 years) with de novo AML entered the trial and were evaluable. Treatment included TAD/HAM (thioguanine, cytosine arabinoside, and daunorubicin/high-dose cytosine arabinoside and mitoxantrone) double induction, TAD consolidation, and randomly either maintenance therapy or S-HAM consolidation. Cytogenetics were favorable, intermediate, unfavorable and not available in 10.0%, 48.3%, 13.1%, and 28.5%, respectively. Day 16 blasts ranged from 0% to 100% (median, 5%, mean +/- SD, 18.6 +/- 28.5%). Complete remission (CR) rate was 72.6%, 17.6% had persistent leukemia (PL), and 9.8% succumbed to hypoplastic death. Median overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were 18, 9, and 15 months with 28.4%, 21.6%, and 30.1% at 5 years, respectively. As a continuous variable, day 16 blasts were related to CR rate (P < 0.0001), PL rate (P < 0.0001), OS (P < 0.0001), EFS (P < 0.0001), and RFS (P = 0.0049). Multivariate analyses identified the following parameters to be associated with the respective end points. CR rate: day 16 blasts (P <.0001), age (P =.0036), and LDH (P =.0072); OS: unfavorable cytogenetics (P <.0001), day 16 blasts (P <.0001), age (P <.0001), and LDH (P =.0040); EFS: unfavorable cytogenetics (P <.0001), LDH (P <.0001), day 16 blasts (P <.0001), and age (P =.0061); RFS: unfavorable cytogenetics (P <.0001), LDH (P <.0001), and day 16 blasts (P =.0359). The prognostic significance of day 16 blasts is independent of pretherapeutic parameters and predicts outcome even in patients achieving a CR.
Transdermal neuromodulation of noradrenergic activity suppresses psychophysiological and biochemical stress responses in humans (2015)

We engineered a transdermal neuromodulation approach that targets peripheral (cranial and spinal) nerves and utilizes their afferent pathways as signaling conduits to influence brain function. We investigated the effects of this transdermal electrical neurosignaling (TEN) method on sympathetic physiology under different experimental conditions. The TEN method involved delivering high-frequency pulsed electrical currents to ophthalmic and maxillary divisions of the right trigeminal nerve and cervical spinal nerve afferents. Under resting conditions, TEN significantly suppressed basal sympathetic tone compared to sham as indicated by functional infrared thermography of facial temperatures. In a different experiment, subjects treated with TEN reported significantly lower levels of tension and anxiety on the Profile of Mood States scale compared to sham. In a third experiment when subjects were experimentally stressed TEN produced a significant suppression of heart rate variability, galvanic skin conductance, and salivary α-amylase levels compared to sham. Collectively these observations demonstrate TEN can dampen basal sympathetic tone and attenuate sympathetic activity in response to acute stress induction. Our physiological and biochemical observations are consistent with the hypothesis that TEN modulates noradrenergic signaling to suppress sympathetic activity. We conclude that dampening sympathetic activity in such a manner represents a promising approach to managing daily stress.
Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor. (1993)

The effect of human eosinophil major basic protein (MBP) as well as other eosinophil proteins, on binding of [3H]N-methyl-scopolamine ([3H]NMS: 1 x 10(-10) M) to muscarinic M2 receptors in heart membranes and M3 receptors in submandibular gland membranes was studied. MBP inhibited specific binding of [3H]NMS to M2 receptors but not to M3 receptors. MBP also inhibited atropine-induced dissociation of [3H]NMS-receptor complexes in a dose-dependent fashion, demonstrating that the interaction of MBP with the M2 muscarinic receptor is allosteric. This effect of MBP suggests that it may function as an endogenous allosteric inhibitor of agonist binding to the M2 muscarinic receptor. Inhibition of [3H]NMS binding by MBP was reversible by treatment with heparin, which binds and neutralizes MBP. Eosinophil peroxidase (EPO) also inhibited specific binding of [3H]NMS to M2 receptors but not to M3 receptors and inhibited atropine-induced dissociation of [3H]NMS-receptor complexes. On a molar basis, EPO is less potent than MBP. Neither eosinophil cationic protein nor eosinophil-derived neurotoxin affected binding of [3H]NMS to M2 receptors. Thus both MBP and EPO are selective allosteric antagonists at M2 receptors. The effects of these proteins may be important causes of M2 receptor dysfunction and enhanced vagally mediated bronchoconstriction in asthma.
Intratumoral depletion of regulatory T cells using CD25-targeted photodynamic therapy in a mouse melanoma model induces antitumoral immune responses (2017)

Tumor immunotherapy aims to overcome the immunosuppressive microenvironment within tumors, and various approaches have been developed. Tumor-associated T regulatory cells (Tregs) suppress the activation and expansion of tumor antigen-specific effector T cells, thus, providing a permissive environment for tumor growth. Therefore, optimal strategies need to be established to deplete tumor-infiltrated Tregs because systemic depletion of Tregs can result in reduced anti-tumor effector cells and autoimmunity. Here, to selectively deplete Tregs in tumors, we intratumorally injected anti-CD25 antibodies conjugated to Chlorin e6 (Ce6), a photosensitizer that absorbs light to generate reactive oxygen species. Local depletion of tumor-associated Tregs with photodynamic therapy (PDT) inhibited tumor growth, which was likely due to the altered tumor immune microenvironment that was characterized by increased infiltration of CD8+ effector T cells and the expression of IFN-γ and CD107a, which is a cytolytic granule exocytosis marker in tumor tissues. Furthermore, PDT-induced intratumoral Treg depletion did not influence adaptive immune responses in a murine influenza infection model. Thus, our results show that intratumoral Treg-targeted PDT could specifically modulate tumor microenvironments by depleting Tregs and could be used as a novel cancer immunotherapy technique.
Interleukin 4 inhibits growth and induces apoptosis in human breast cancer cells. (1998)

Interleukin-4 (IL-4) is a pleiotropic cytokine produced by mast cells and T lymphocytes that promotes proliferation and immunoglobulin class-switching in B cells. IL-4 receptors (IL-4Rs) are also expressed by nonhematopoietic cells as well as some tumor cells. Unlike its mitogenic effect on B cells, IL-4 inhibits the growth of some cancer cells in vitro. In this study, we show that IL-4R is expressed by breast and ovarian cancer cell lines. Furthermore, anchorage-dependent and -independent growth of breast cancer cell lines MCF-7 and MDA-MB-231 is inhibited by IL-4 treatment, and this effect requires IL-4R. Interestingly, IL-4 only inhibited proliferating breast cancer cells and had no effect on basal, unstimulated growth. We therefore characterized the effect of IL-4 on breast cancer cell growth stimulated by either estradiol or insulin-like growth factor I (IGF-I). In both anchorage-dependent and -independent growth assays, IL-4 inhibited estradiol-stimulated growth. The antiestrogen effect of IL-4 was not due to IL-4 interference with the estrogen receptor, because IL-4 did not interfere with estrogen receptor-mediated reporter gene transactivation. In contrast, IL-4 had no effect on IGF-I-stimulated proliferation. Because IGF-I is known to inhibit programmed cell death, we examined apoptosis as a possible mechanism of IL-4 action. We established that IL-4 induced apoptosis in breast cancer cells by five independent criteria: (a) morphological indicators including pyknotic nuclei and cytoplasmic condensation; (b) DNA fragmentation; (c) the formation of DNA laddering; (d) the cleavage of poly(ADP-ribose) polymerase; and (e) the presence of cells with sub-G1 DNA content. IL-4 increased the percentage of apoptotic cells in MCF-7 and MDA-MB-231 cells 6.0- and 6.7-fold over that of the control, respectively. Finally, the addition of IGF-I reversed IL-4-induced apoptosis, suggesting that the mechanism of IL-4-induced growth inhibition in human breast cancer cells is the induction of programmed cell death.