gebhart/patrepeval huggingface dataset:
Selective DNA demethylation by fusion of TDG with a sequence-specific DNA-binding domain (2012)

Our ability to selectively manipulate gene expression by epigenetic means is limited, as there is no approach for targeted reactivation of epigenetically silenced genes, in contrast to what is available for selective gene silencing. We aimed to develop a tool for selective transcriptional activation by DNA demethylation. Here we present evidence that direct targeting of thymine-DNA-glycosylase (TDG) to specific sequences in the DNA can result in local DNA demethylation at potential regulatory sequences and lead to enhanced gene induction. When TDG was fused to a well-characterized DNA-binding domain [the Rel-homology domain (RHD) of NFκB], we observed decreased DNA methylation and increased transcriptional response to unrelated stimulus of inducible nitric oxide synthase (NOS2). The effect was not seen for control genes lacking either RHD-binding sites or high levels of methylation, nor in control mock-transduced cells. Specific reactivation of epigenetically silenced genes may thus be achievable by this approach, which provides a broadly useful strategy to further our exploration of biological mechanisms and to improve control over the epigenome.
Demineralized bone matrix as a template for mineral-organic composites (1995)

Mineralizing biological tissues are complex bioceramic-biopolymer composites engineered for a variety of functions. The organic and inorganic constituents, morphology, location, orientation, crystallinity and interactions exhibit materials or extremely fine microstructure, unique mechanical and physical properties with high strength and fracture toughness compared to the individual constituents. An understanding of mineralization, ultrastructural organization and interfacial bonding forces in mineralizing biological composite tissues, such as bone, may provide new strategies and techniques for the production of a novel class of man-made organic-ceramic composites. The present study explores the use of the organic matrix remaining after removal of the mineral phase by chelation with EDTA or solubilizing in HCl as a template for mineral deposition and the production of mineral-organic composites. Different pH conditions are employed to alter the inorganic phase which is deposited within the organic matrix. Mechanical testing and ultrastructural evaluations are carried out for characterization.
Role of whole-body hyperthermia in the treatment of neoplastic disease: its current status and future prospects. (1984)

Modern cancer therapy has included surgery, radiotherapy, chemotherapy, and most recently, immunotherapy and hyperthermia. As neoplastic diseases are heterogeneous in regard to each cell subpopulation's response to a given therapy, a multimodality treatment approach should enhance the changes of all subpopulations of cells being killed. The potential of hyperthermia as a treatment modality for cancer was first predicted following observations that several types of cancer cells were more sensitive to temperatures in excess of 41 degrees than were their normal cell counterparts. Beyond these studies, there now is preclinical evidence as well as the clinical suggestion that hyperthermia potentiates radiation and/or drugs for the treatment of cancer. As most cancers refractory to conventional therapy are systemic diseases, the proposal that whole-body hyperthermia in combination with other therapies be used to treat metastatic disease is an inherently attractive approach. The basis and the practicality of this proposal is presented here with suggestions for its application to current preclinical and clinical research.
A Small Molecule that Promotes Cardiac Differentiation of Human Pluripotent Stem Cells under Defined, Cytokine- and Xeno-free Conditions (2012)

Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, are potentially useful in regenerative therapies for heart disease. For medical applications, clinical-grade cardiac cells must be produced from hPSCs in a defined, cost-effective manner. Cell-based screening led to the discovery of KY02111, a small molecule that promotes differentiation of hPSCs to cardiomyocytes. Although the direct target of KY02111 remains unknown, results of the present study suggest that KY02111 promotes differentiation by inhibiting WNT signaling in hPSCs but in a manner that is distinct from that of previously studied WNT inhibitors. Combined use of KY02111 and WNT signaling modulators produced robust cardiac differentiation of hPSCs in a xeno-free, defined medium, devoid of serum and any kind of recombinant cytokines and hormones, such as BMP4, Activin A, or insulin. The methodology has potential as a means for the practical production of human cardiomyocytes for regeneration therapies.
Targeting oncolytic adenoviral agents to the epidermal growth factor pathway with a secretory fusion molecule. (2001)

Cancer gene therapy with conditionally replicating adenoviruses is a powerful way of overcoming low tumor transduction. However, one of the main remaining obstacles is the highly variable level of the coxsackie-adenovirus receptor expression on human primary cancers. In contrast, the epidermal growth factor receptor (EGFR) is overexpressed in various tumor types, and its expression correlates with metastatic behavior and poor prognosis. We constructed an adenovirus expressing a secretory adaptor capable of retargeting adenovirus to EGFR, resulting in a more than 150-fold increase in gene transfer. A replication-competent dual-virus system secreting the adaptor displayed increased oncolytic potency in vitro and therapeutic gain in vivo. This approach could translate into increased efficacy and specificity in the treatment of EGFR overexpressing human cancers.
An improved method for labeling monoclonal antibodies with samarium-153: use of the bifunctional chelate 2-(p-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1992)

Samarium-153 (153Sm) radioimmunoconjugates of the monoclonal antibody K-1-21 were produced using the bifunctional chelate 2-(p-isothiocyanatobenzyl)-6- methyldiethylenetriaminepentaacetic acid (Mx-DTPA). The specific activity (up to 150 MBq mg-1) and percent retained immunoreactivity (greater than 75%) were similar to that of 153Sm-K-1-21 conjugates formed with cyclic DTPA anhydride (cDTPAa). In vivo biodistribution studies showed specific localization of 153Sm-Mx-DTPA-K-1-21 to target antigen implants and higher blood pool and lower uptake in liver, spleen, kidney, and bone when compared to 153Sm-cDTPAa-K-1-21. The improved in vivo distribution of 153Sm-Mx-DTPA-K-1-21 should result in lower radiotoxicity to nontarget tissues when used for radioimmunotherapy purposes.
Transcriptional Analysis of Multiple Sclerosis Brain Lesions Reveals a Complex Pattern of Cytokine Expression (2000)

Multiple sclerosis (MS) is a common and severe neurological disorder associated with an autoimmune response directed against myelin components within the CNS. Lymphocyte activation, extravasation, and recruitment, as well as effector function, involves the turning on and off of a number of genes, thus triggering specific transcriptional pathways. The characterization of the transcriptome in MS lesions should provide a better understanding of the mechanisms that generate and sustain the pathogenic immune response in this disease. Here we performed transcriptional profiling of 56 relevant genes in brain specimens from eight MS patients and eight normal controls by kinetic RT-PCR. Results showed a high transcriptional activity for the gene coding for myelin basic protein (MBP); however, it was not differentially expressed in MS samples, suggesting that remyelination is an active process also in the noninflammatory brain. CD4 and HLA-DRalpha transcripts were dramatically increased in MS as compared with controls. This reveals a robust MHC class II up-regulation and suggests that Ag is being presented locally to activated T cells. Although analysis of cytokine and cytokine receptor genes expression showed predominantly increased levels of several Th1 molecules (TGF-ss, RANTES, and macrophage-inflammatory protein (MIP)-1alpha) in MS samples, some Th2 genes (IL-3, IL-5, and IL-6/IL-6R) were found to be up-regulated as well. Similarly, both proinflammatory type (CCR1, CCR5) and immunomodulatory type (CCR4, CCR8) chemokine receptors were differentially expressed in the MS brain. Overall, our data suggest a complex regulation of the inflammatory response in human autoimmune demyelination.
Stimulation‐induced reset of hippocampal theta in the freely performing rat (2002)

Previous research has suggested that visual and auditory stimuli in a working memory task have the ability to reset hippocampal theta, perhaps allowing an organism to encode the incoming information optimally. The present study examined two possible neural pathways involved in theta resetting. Rats were trained on a visual discrimination task in an operant chamber. At the beginning of a trial, a light appeared over a centrally located lever that the rat was required to press to receive a water reward. There was a 30-s intertrial interval before the next light stimulus appeared. After learning the task, all rats received surgical implantation of stimulating electrodes in both the fornix and the perforant path and recording electrodes, bilaterally in the hippocampus. After surgery, theta was recorded before and after the light stimulus to determine whether resetting to the visual stimulus occurred. During the intertrial interval, rats received single-pulse electrical stimulation of either the fornix or perforant path. Theta was recorded both before and after the electrical stimulation to determine whether resetting occurred. In this experiment, hippocampal theta was reset after all three stimulus conditions (light, perforant path, and fornix stimulation), with the greatest degree of reset occurring after the fornix stimulation. The results suggest that activation of the perforant path and fornix may underlie theta reset and provide a mechanism by which the hippocampus may enhance cognitive processing.
The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. (1993)

Lethal yellow (Ay) is a mutation at the mouse agouti (a) locus that is associated with an all-yellow coat color, obesity, diabetes, tumors in heterozygotes, and preimplantation embryonic lethality in homozygotes. Previously, we cloned and characterized the wild-type agouti gene and demonstrated that it expresses a 0.8-kb mRNA in neonatal skin. In contrast, Ay expresses a 1.1-kb transcript that is ectopically overexpressed in all tissues examined. The Ay mRNA is identical to the wild-type a transcript for the entire coding region, but the 5'-untranslated sequence of the a gene has been replaced by novel sequence. Here, we demonstrate that the novel 5' sequence in the Ay mRNA corresponds to the 5'-untranslated sequence of another gene that is normally tightly linked to a in mouse chromosome 2. This other gene (Raly) has the potential to encode a novel RNA-binding protein that is normally expressed in the preimplantation embryo, throughout development, and in all adult tissues examined. Importantly, the Ay mutation disrupts the structure and expression of the Raly gene. The data suggest that the Ay mutation arose from a DNA structural alteration that affects the expression of both agouti and Raly. We propose that the dominant pleiotropic effects associated with Ay may result from the ectopic overexpression of the wild-type a gene product under the control of the Raly promoter and that the recessive embryonic lethality may be the result of the lack of Raly gene expression in the early embryo.
C-5 Modified Nucleosides: Direct Insertion of Alkynyl-Thio Functionality in Pyrimidines (2003)

A route is presented to append, in a single step, alkynyl thioesters to the 5-position of a pyrimidine ring of a nucleoside that is unprotected. These products should be useful to support in vitro selection experiments with functionalized DNA.
A Fluorescence Polarization Assay for Binding to Macrophage Migration Inhibitory Factor and Crystal Structures for Complexes of Two Potent Inhibitors (2016)

Human macrophage migration inhibitory factor (MIF) is both a keto-enol tautomerase and a cytokine associated with numerous inflammatory diseases and cancer. Consistent with observed correlations between inhibition of the enzymatic and biological activities, discovery of MIF inhibitors has focused on monitoring the tautomerase activity using l-dopachrome methyl ester or 4-hydroxyphenyl pyruvic acid as substrates. The accuracy of these assays is compromised by several issues including substrate instability, spectral interference, and short linear periods for product formation. In this work, we report the syntheses of fluorescently labeled MIF inhibitors and their use in the first fluorescence polarization-based assay to measure the direct binding of inhibitors to the active site. The assay allows the accurate and efficient identification of competitive, noncompetitive, and covalent inhibitors of MIF in a manner that can be scaled for high-throughput screening. The results for 22 compounds show that the most potent MIF inhibitors bind with Kd values of ca. 50 nM; two are from our laboratory, and the other is a compound from the patent literature. X-ray crystal structures for two of the most potent compounds bound to MIF are also reported here. Striking combinations of protein-ligand hydrogen bonding, aryl-aryl, and cation-π interactions are responsible for the high affinities. A new chemical series was then designed using this knowledge to yield two more strong MIF inhibitors/binders.
Loss of M2 Muscarine Receptors in the Cerebral Cortex in Alzheimer's Disease and Experimental Cholinergic Denervation (1985)

Cerebral cortex samples from patients with Alzheimer's disease and from rats after experimental cholinergic denervation of the cerebral cortex exhibited reductions in the presynaptic marker choline acetyltransferase activity and in the number of M2 muscarine receptors, with no change in the number of M1 receptors. These results are in keeping with evidence that M2 receptors function in cholinergic nerve terminals to regulate the release of acetylcholine, whereas M1 receptors are located on postsynaptic cells and facilitate cellular excitation. New M1-selective agonists and M2-selective antagonists directed at post- or presynaptic sites deserve consideration as potential agents for the treatment of the disease.
Pharmacology of Appetite Suppression: Implication for the Treatment of Obesity (2001)

Given the current global epidemic of obesity there is a demand for new antiobesity drugs to overcome the problem. Many pharmacological agents reduce food intake and significantly decrease body mass when administered to animals but affect feeding behaviour in a profoundly different way indicating the variety of biological mechanisms by which such agents act (appetite verses non-appetite). More limited clinical data demonstrates that some of the same drugs produce decreases in food intake and weight loss in humans. A few of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). These drugs that modify the daily flux of appetite could be considered as ‘appetite suppressants’ with clinical potential as anti-obesity agents. Drugs that can be considered suitable candidates for appetite suppressants are agents that enhance peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin, CART and Melanocortins) or monoamine neurotransmitters (such as serotonin, nor-adrenaline and possibly dopamine). Recently, the hormone leptin has become regarded as a key hormonal signal linking adipose tissue status with a number of key central nervous system circuits (NPY, CART, CRF, Melanocortins and possibly Orexins). This tonic system may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, such modulation of appetite will involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with life style changes and dietary intervention may be critical in dealing with the rising world epidemic of obesity.
Crystal Structure of the C-type Lectin-like Domain from the Human Hematopoietic Cell Receptor CD69 (2001)

CD69, one of the earliest specific antigens acquired during lymphoid activation, acts as a signal-transducing receptor involved in cellular activation events, including proliferation and induction of specific genes. CD69 belongs to a family of receptors that modulate the immune response and whose genes are clustered in the natural killer (NK) gene complex. The extracellular portion of these receptors represent a subfamily of C-type lectin-like domains (CTLDs), which are divergent from true C-type lectins and are referred to as NK-cell domains (NKDs). We have determined the three-dimensional structure of human CD69 NKD in two different crystal forms. CD69 NKD adopts the canonical CTLD fold but lacks the features involved in Ca(2+) and carbohydrate binding by C-type lectins. CD69 NKD dimerizes noncovalently, both in solution and in crystalline state. The dimer interface consists of a hydrophobic, loosely packed core, surrounded by polar interactions, including an interdomain beta sheet. The intersubunit core shows certain structural plasticity that may facilitate conformational rearrangements for binding to ligands. The surface equivalent to the binding site of other members of the CTLD superfamily reveals a hydrophobic patch surrounded by conserved charged residues that probably constitutes the CD69 ligand-binding site.
Is Intake of Flavonoid-Based Food Supplements During Pregnancy Safe for the Developing Child? A Literature Review (2016)

Due to potential health benefits and the general assumption that natural products are safe, there is an increasing trend in the general population - including pregnant women - to supplement their diet with flavonoid-based food supplements. In addition, preclinical studies aim to prevent developmental adverse effects induced by toxic substances, infections, maternal or genetic diseases of the unborn child by administration of flavonoids at doses far above those reached by normal diets. Because these substances do not undergo classical risk assessment processes, our aim was to review the available literature on the potential adverse effects of maternal diet supplementation with flavonoid-based products for the developing child. A systematic literature search was performed in three databases and screened following four exclusion criteria. Selected studies were classified into two groups: 1. Studies on the developmental toxicity of single flavonoids in vitro or in animals in vivo, and 2. Studies on the developmental toxicity of single flavonoids or on flavonoid-mixtures in humans. The data collected indicate that there is a concern for the safety of some flavonoids within realistic human exposure scenarios. This concern is accompanied by a tremendous lack of studies on safety of these compounds during development making definite safety decisions impossible. Besides studies of survival, especially the more specific developmental processes like nervous system development need to be addressed experimentally. Before new high-dose, flavonoid-based therapeutic strategies are developed for pregnant women further research on the safety of these compounds is clearly needed.
Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis (2009)

Tyrosine kinase 2 (Tyk2), a member of the JAK family, is involved in IL-12- and IL-23-mediated signaling. In the present study, we examined the roles of Tyk2 in the development of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) by using Tyk2 knockout (KO) mice. In vitro differentiation of Th1 but not Th17 cells was severely impaired in Tyk2 KO CD4 T cells, although Tyk2 KO Th17 cells did not respond to IL-23. Tyk2 KO mice showed complete resistance against EAE with no infiltration of CD4 T cells in the spinal cord. Surprisingly, the number of MOG-specific Th17 cells in the periphery was comparable between KO and wild-type (WT) mice, whereas Th1 cells were greatly reduced in Tyk2 KO mice. Adoptive transfer of MOG-primed WT T cells induced EAE in Tyk2 KO recipients, indicating that Tyk2 in the environment was dispensable for the infiltration of effector T cells into the spinal cord. A reduced but significant number of Tyk2 KO T cells were detected in the spinal cord of mice with EAE, which had been reconstituted with bone marrow cells of WT and KO mice. Furthermore, MOG-immunized Tyk2 KO mice developed EAE after adoptive transfer of MOG-primed WT Th1 cells, which might trigger local inflammation that recruits Th17 cells. Taken together, these results indicate that Tyk2 is critically involved in the pathogenic CD4 T cell responses and thus could be a target molecule for the treatment of autoimmune diseases.
Significance of urinary epidermal growth factor and its receptor expression in human bladder cancer. (1997)

Although measurement of U-EGF levels did not have any independent prognostic value, our data support the importance of urine EGF/urothelial EGFR interaction in the biological behavior of bladder cancer.
A Novel Type I Receptor Serine-Threonine Kinase Predominantly Expressed in the Adult Central Nervous System (1996)

Receptor serine-threonine kinases (RSTK) mediate inhibitory as well as stimulatory signals for growth and differentiation by binding to members of the transforming growth factor-beta (TGF-beta) superfamily. Over 12 different RSTKs have been isolated so far, displaying wide expression in peripheral tissues and in the nervous system. Here we report the isolation and characterization of a novel type I RSTK termed activin receptor-like kinase-7 (ALK-7) that, unlike other members of this receptor family, is predominantly expressed in the adult central nervous system. The ALK-7 gene encodes a 55-kDa cell-surface protein that exhibits up to 78% amino acid sequence identity in the kinase domain to previously isolated type I receptors for TGF-beta and activin. In the extracellular domain, however, ALK-7 is more divergent, displaying comparable similarities with all members of the ALK subfamily. RNase protection and in situ hybridization studies demonstrated a highly specific mRNA distribution restricted to neurons in several regions of the adult rat central nervous system, including cerebellum, hippocampus, and nuclei of the brainstem. Receptor reconstitution and cross-linking experiments indicated that ALK-7 can form complexes with type II RSTKs for TGF-beta and activin in a ligand-dependent manner, although direct binding of ALK-7 to ligand in these complexes could not be demonstrated. The specific expression pattern of ALK-7, restricted to the postnatal central nervous system, indicates that this receptor may play an important role in the maturation and maintenance of several neuronal subpopulations.