gebhart/patrepeval huggingface dataset:
The BMP/BMPR/Smad pathway directs expression of the erythroid-specific EKLF and GATA1 transcription factors during embryoid body differentiation in serum-free media (2002)

Erythroid cell-specific gene regulation during terminal differentiation is controlled by transcriptional regulators, such as EKLF and GATA1, that themselves exhibit tissue-restricted expression patterns. Their early expression, already in evidence within multipotential hematopoietic cell lines, has made it difficult to determine what extracellular effectors and transduction mechanisms might be directing the onset of their own transcription during embryogenesis. To circumvent this problem, we have taken the novel approach of investigating whether the ability of embryonic stem (ES) cells to mimic early developmental patterns of cellular expression during embryoid body (EB) differentiation can address this issue. We first established conditions whereby EBs could form efficiently in the absence of serum. Surprisingly, in addition to mesoderm, these cells expressed hemangioblast and hematopoietic markers. However, they did not express the committed erythroid markers EKLF and GATA1, nor the terminally differentiated beta-like globin markers. Using this system, we determined that EB differentiation in BMP4 was necessary and sufficient to recover EKLF and GATA1 expression and could be further stimulated by the inclusion of VEGF, SCF, erythropoietin and thyroid hormone. EBs were competent to respond to BMP4 only until day 4 of differentiation, which coincides with the normal onset of EKLF expression. The direct involvement of the BMP/Smad pathway in this induction process was further verified by showing that erythroid expression of a dominant negative BMP1B receptor or of the inhibitory Smad6 protein prevented induction of EKLF or GATA1 even in the presence of serum. Although Smad1, Smad5 and Smad8 are all expressed in the EBs, BMP4 induction of EKLF and GATA1 transcription is not immediate. These data implicate the BMP/Smad induction system as being a crucial pathway to direct the onset of EKLF and GATA1 expression during hematopoietic differentiation and demonstrate that EB differentiation can be manipulated to study induction of specific genes that are expressed early within a lineage.
Processing of semantic information in fluently spoken language (2002)

We are interested in constructing machines which learn to understand and act upon fluently spoken input. For any particular task, certain linguistic events are critical to recognize correctly, others not so. This notion can be quantified via salience, which measures the information content of an event for a task. In previous papers, salient words have been exploited to team the mapping from spoken input to machine action for several tasks. In this work, a new algorithm is presented which automatically acquires salient grammar fragments for a task, exploiting both linguistic and extra-linguistic information in the inference process. Experimental results are reported for a database of fluently spoken customer requests to operators, responding to the open-ended prompt, 'Hello, this is AT&T. How may I help you?'.
Quorum Sensing in the Dimorphic Fungus Candida albicans Is Mediated by Farnesol (2001)

The inoculum size effect in the dimorphic fungus Candida albicans results from production of an extracellular quorum-sensing molecule (QSM). This molecule prevents mycelial development in both a growth morphology assay and a differentiation assay using three chemically distinct triggers for germ tube formation (GTF): L-proline, N-acetylglucosamine, and serum (either pig or fetal bovine). In all cases, the presence of QSM prevents the yeast-to-mycelium conversion, resulting in actively budding yeasts without influencing cellular growth rates. QSM exhibits general cross-reactivity within C. albicans in that supernatants from strain A72 are active on five other strains of C. albicans and vice versa. The QSM excreted by C. albicans is farnesol (C(15)H(26)O; molecular weight, 222.37). QSM is extracellular, and is produced continuously during growth and over a temperature range from 23 to 43 degrees C, in amounts roughly proportional to the CFU/milliliter. Production is not dependent on the type of carbon source nor nitrogen source or on the chemical nature of the growth medium. Both commercial mixed isomer and (E,E)-farnesol exhibited QSM activity (the ability to prevent GTF) at a level sufficient to account for all the QSM activity present in C. albicans supernatants, i.e., 50% GTF at ca. 30 to 35 microM. Nerolidol was ca. two times less active than farnesol. Neither geraniol (C(10)), geranylgeraniol (C(20)), nor farnesyl pyrophosphate had any QSM activity.
Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3 (2014)

We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
Effect of DHA-containing formula on growth of preterm infants to 59 weeks postmenstrual age (1999)

Between May 1993, and September 1994, a randomized, blinded clinical trial was conducted to evaluate measures of growth and body composition in 63 (32 males; 31 females) healthy, low-birth-weight infants (940-2250 g) who were randomly assigned to an infant formula with docosahexaenoic acid (22:6n3, DHA, 0.2 wt%) from fish oil or to a control formula. A preterm formula with or without DHA was fed beginning at 7-10 days prior to hospital discharge through 43 weeks postmenstrual age (PMA). Then, from 43-59 weeks PMA, infants were fed a term infant formula with or without a corresponding amount of DHA. Growth (weight, length, head circumference), regional body fatness (triceps, subscapular, suprailiac skinfold thicknesses), circumferences (arm, abdominal, chest), and estimates of body composition determined by total body electrical conductivity (TOBEC) (fat-free mass [FFM]) were evaluated. Growth was slower in males fed the DHA formula. They had significantly (P < 0.05) smaller gains in weight, length, and head circumference between study enrollment to 59 weeks PMA than those fed the control formula. At 51 weeks PMA, males in the DHA group had significantly smaller head circumferences (P < 0.05) and lower FFM (P < 0.05). At 59 weeks PMA, males in the DHA group weighed less (P < 0.05), had shorter recumbent lengths (P < 0.01), smaller head circumferences (P < 0.05), and lower FFM (P < 0.01) than those fed the control formula. Energy intakes from formula (kcal/d), however, were lower at 51 weeks (P < 0.05) and 59 weeks (P < 0.05) PMA in males fed the DHA formula. Adjusted for body weight (kcal/kg/d), mean energy intakes from formula at 51 and 59 weeks PMA were not significantly different between feeding groups. The differences in recumbent length, head circumference, and FFM remained statistically significant after controlling for energy and protein intakes (P < 0.01). For all males, neither FFM nor total body fat (TBF), when expressed as a percentage of total body weight, differed significantly between feeding groups. Among females, there were no significant differences between the feeding groups in measures of growth, body composition, or energy intake. The results indicated that infant formula with fish oil containing DHA and EPA in a 5:1 ratio had a significant, negative effect on growth and body composition in males during the first 6 months of life. It is not clear why the growth deficits were limited to males and not females. The eicosanoids, bioactive metabolites of omega-3 and omega-6 fatty acids, may mediate several important growth hormones. The present results do not support the addition of DHA alone in infant formulas. Am. J. Hum. Biol. 11:457-467, 1999. Copyright 1999 Wiley-Liss, Inc.
Visualization of gene expression of short and long forms of prolactin receptor in the rat (1993)

PRL receptor gene expression was visualized in various tissues by in situ hybridization, using 35S-labeled probes unique to each form of receptor. Tissues were removed rapidly from adult male and female rats and placed in liquid nitrogen. Cryostat sections (10 microns) were prepared, fixed, pretreated, and dehydrated before incubation with the various probes. Hybridization was performed overnight, after which the slides were first exposed to autoradiographic film and then dipped in nuclear emulsion and exposed for 1-2 weeks. The specificity of the signal was studied by competition and using radiolabeled heterologous probes. Some tissues show no expression of either form of receptor mRNA, such as olfactory bulb and penis. Macroautoradiogram signals (optical density) were compared to a standard curve to observe the variation in mRNA expression, which was expressed in arbitrary units. Sex differences in the expression of PRL receptors were seen in a number of tissues, such as adrenal gland and pituitary. Expression of mRNAs specific to the long form of PRL receptor was predominant in adrenal gland, pituitary, thymus, spleen, skin, heart, and skeletal muscle, whereas the short form was expressed to a greater extent in kidney and lung. At the light microscopic level, the silver grains observed by epipolarization or light field were seen in the specific regions or cells that express PRL receptor mRNAs. In conclusion, the long form transcript predominates in most tissues, except kidney and lung. The advantage of in situ hybridization is that it allows the identification of specific regions or cells expressing mRNAs to be identified. The actions of PRL have not been identified in all tissues expressing PRL receptor transcripts, nor has any definitive correlation been made with the expression of short and long forms of PRL receptor and function.
Direct Measurements of Base Stacking Interactions in DNA by Single-Molecule Atomic-Force Spectroscopy (2007)

We investigate the elasticity of two types of single-stranded synthetic DNA homopolydeoxynucletides, poly(dA) and poly(dT), by AFM-based single-molecule force spectroscopy. We find that poly(dT) exhibits the expected entropic elasticity behavior, while poly(dA) unexpectedly displays two overstretching transitions in the force-extension relationship. We suggest that these transitions, which occur at approximately 23 pN and approximately 113 pN, directly capture, for the first time, the mechanical signature of base-stacking interactions among adenines in DNA, in the absence of base pairing.
Fluorescence of experimental atheromatous plaques with hematoporphyrin derivative. (1983)

Fluorescence of hematoporphyrin derivative (HPD) has been used clinically to localize malignant neoplasms because of its selective accumulation in these tissues. We tested the hypothesis that HPD may also be selectively concentrated within atheromatous plaques. 48 h after HPD injection in a variety of species, selective fluorescence of atheromatous plaques of the aorta was seen in each animal (rabbits and Patas monkey) exhibiting such lesions. No fluorescence could be demonstrated in aortic segments free of atheromatous involvement. Since the efficacy of photodynamic destruction of malignant tumors with HPD has been demonstrated in clinical studies, the observations of the present study may have therapeutic implications in atheromatosis.
Quantification of Retro- and Lentiviral Reverse Transcriptase Activity by Real-time PCR (2013)

Quantification of retroviral reverse transcriptase activity in retrovirus containing supernatant by quantitative reverse transcription PCR as a method for titration of HIV, lenti- and retroviral vectors is described here.. The procedure was optimized for use with LightCycler 480 (Roche, Vilvoorde, Belgium) and ABI 7300 real-time PCR system (reagents and procedures that are system specific will be marked accordingly in the protocol).
Heterobivalent ligands target cell-surface receptor combinations in vivo (2012)

A challenge in tumor targeting is to deliver payloads to cancers while sparing normal tissues. A limited number of antibodies appear to meet this challenge as therapeutics themselves or as drug-antibody conjugates. However, antibodies suffer from their large size, which can lead to unfavorable pharmacokinetics for some therapeutic payloads, and that they are targeted against only a single epitope, which can reduce their selectivity and specificity. Here, we propose an alternative targeting approach based on patterns of cell surface proteins to rationally develop small, synthetic heteromultivalent ligands (htMVLs) that target multiple receptors simultaneously. To gain insight into the multivalent ligand strategy in vivo, we have generated synthetic htMVLs that contain melanocortin (MSH) and cholecystokinin (CCK) pharmacophores that are connected via a fluorescent labeled, rationally designed synthetic linker. These ligands were tested in an experimental animal model containing tumors that expressed only one (control) or both (target) MSH and CCK receptors. After systemic injection of the htMVL in tumor-bearing mice, label was highly retained in tumors that expressed both, compared with one, target receptors. Selectivity was quantified by using ex vivo measurement of Europium-labeled htMVL, which had up to 12-fold higher specificity for dual compared with single receptor expressing cells. This proof-of-principle study provides in vivo evidence that small, rationally designed bivalent htMVLs can be used to selectively target cells that express both, compared with single complimentary cell surface targets. These data open the possibility that specific combinations of targets on tumors can be identified and selectively targeted using htMVLs.
Antiviral Activity of N-Phenyl-N′-arylthiourea Derivatives against some Rhinoviruses (1977)

The effect of 12 derivatives of N-phenyl-N'-aryl- or alkylthiourea, inhibitors of human enteroviruses and foot-and-mouth disease virus, on reproduction of some rhinoviruses (H-17, B-632) in HeLa Bristol cells was studied. As screening methods both the multicylce growth test in roller tube cultures and two variants of plaque inhibition tests were employed. The compounds selected were tested in one-step growth cycle set-up. We established that N-phenyl-N'-4-hydroxyphenylthiourea (V-24) and N-phenyl-N'-2-carboxyphenylthiourea (V-17) have a distinct inhibitory effect on the growth of rhinovirus H-17, and N-phenyl-N'-2-hydroxy-5-nitrophenylthiourea (V-25) inhibited strongly the multiplication of rhinovirus B-632.
Saponin adjuvant induction of ovalbumin-specific CD8+ cytotoxic T lymphocyte responses (1992)

The ability of a saponin adjuvant, QS-21, to induce OVA-specific, class I MHC Ag-restricted CTL was investigated using different forms of soluble OVA and OVA adsorbed onto alum as immunogens. C57BL/6 mice were immunized with soluble native or denatured OVA in formulations that contained increasing quantities of QS-21, and CTL responses were measured using EL4 and E.G7-OVA cells as targets and splenic mononuclear cells as effectors. Ag-specific CTL responses were produced but only if the QS-21 adjuvant was used. Similar responses were induced using alum-adsorbed OVA when mixed with the QS-21 adjuvant but not when used alone. The CTL were specific for an epitope present on the OVA258-276 synthetic peptide, which contains the dominant CTL epitope recognized by C57BL/6 mice. The CD8+ subpopulation of lymphocytes in immune mice was not increased in spleens but increased significantly in vitro after culture with soluble OVA. The CTL activity of splenic mononuclear cell preparations was totally destroyed by treatment with mAb specific to the CD8 Ag plus complement. The ability of the QS-21 adjuvant to induce class I MHC Ag-restricted CTL after immunization with soluble proteins is a characteristic unique to saponin adjuvants.
Very low-refractive-index optical thin films consisting of an array of SiO_2 nanorods (2006)

The refractive-index contrast in dielectric multilayer structures, optical resonators, and photonic crystals is an important figure of merit that creates a strong demand for high-quality thin films with a low refractive index. A SiO2 nanorod layer with low refractive index of n = 1.08, to our knowledge the lowest ever reported in thin-film materials, is grown by oblique-angle electron-beam deposition of SiO2. A single-pair distributed Bragg reflector employing a SiO2 nanorod layer is demonstrated to have enhanced reflectivity, showing the great potential of low-refractive-index films for applications in photonic structures and devices.
Human mb-1 gene: complete cDNA sequence and its expression in B cells bearing membrane Ig of various isotypes (1992)

The transmembrane protein, IgM-alpha, a product of mb-1 gene, has been shown to be specifically associated with membrane-bound IgM on the plasma membrane of B lymphocytes. Recent studies have suggested that IgM-alpha may play a role in transducing signals from the Ag receptors during the activation of B cells. A large amount of information has been obtained in the mouse system regarding IgM-alpha and other components of the newly conceived B cell Ag receptor complex. Here we report the cloning and the nucleotide sequencing of cDNA clones of human mb-1, covering the entire length of the mRNA. At the amino acid sequence level, human and murine mb-1 share a high homology in their transmembrane and intracytoplasmic segments, suggesting an important biologic function for these regions of mb-1. A major difference, mainly in the 3' untranslated part, exists between our cDNA sequence and the published partial human mb-1 cDNA sequence. It has also been observed that human mb-1 is expressed not only by B cell lines expressing membrane-bound Ig of mu and delta isotypes but also those expressing membrane-bound Ig of alpha and gamma isotypes.
Large-Conductance Ca2+-Activated K+ Channels:Physiological Role and Pharmacology (2003)

Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels differ from most of other K(+) channels in that their activation is under dual control, i.e., activated by either increase in intracellular Ca(2+) or membrane depolarization. These channels, which are widely distributed in a variety of cells, can control Ca(2+) influx as well as a number of Ca(2+)-dependent physiological processes. In neurons or neuroendocrine cells, BK(Ca) channels are believed to play an important role in controlling hormonal secretion by altering the duration and frequency of action potentials. The activity of BK(Ca) channels functionally expressed in vascular endothelial cells can control K(+) efflux and affect intracellular Ca(2+) concentration. Experimental observations have revealed that a variety of compounds can directly modulate BK(Ca) channel activity. Epoxyeicosatrienoic acids, a metabolite of arachidonic acid, and the increase in intracellular cyclic GMP with vinpocetine or YC-1 can stimulate BK(Ca) channel activity. The increased activity of BK(Ca) channels thus serves as a negative feedback mechanism to limit Ca(2+) influx in excitable cells. Clotrimazole, an imidazole P-450 inhibitor used for the management of sickle cell anemia, can directly suppress BK(Ca) channel activity. Riluzole, a drug used for the treatment of amyotrophic lateral sclerosis, can directly enhance channel activity in neuroendocrine cells. This effect may explain its inhibitory action on excitatory neurotransmission. 2-Methoxyestradil, an endogenous metabolite of 17beta-estradiol, suppresses BK(Ca) channel activity, whereas resveratrol, a natural phytoalexin present in grapes and wine, directly stimulates BK(Ca) channel activity in vascular endothelial cells. These effects may be responsible for their actions on functional activities of endothelial cells. The fenamates, a family of nonsteroidal anti-inflammatory drugs, are also openers of BK(Ca) channels. Therefore, the modulation of BK(Ca) channel activity in excitable and non-excitable cells can be important for therapeutic interventions.
ClinGen Cancer Somatic Working Group – standardizing and democratizing access to cancer molecular diagnostic data to drive translational research (2017)

A growing number of academic and community clinics are conducting genomic testing to inform treatment decisions for cancer patients (1). In the last 3–5 years, there has been a rapid increase in clinical use of next generation sequencing (NGS) based cancer molecular diagnostic (MolDx) testing (2). The increasing availability and decreasing cost of tumor genomic profiling means that physicians can now make treatment decisions armed with patient-specific genetic information. Accumulating research in the cancer biology field indicates that there is significant potential to improve cancer patient outcomes by effectively leveraging this rich source of genomic data in treatment planning (3). To achieve truly personalized medicine in oncology, it is critical to catalog cancer sequence variants from MolDx testing for their clinical relevance along with treatment information and patient outcomes, and to do so in a way that supports large-scale data aggregation and new hypothesis generation. One critical challenge to encoding variant data is adopting a standard of annotation of those variants that are clinically actionable. Through the NIH-funded Clinical Genome Resource (ClinGen) (4), in collaboration with NLM’s ClinVar database and >50 academic and industry based cancer research organizations, we developed the Minimal Variant Level Data (MVLD) framework to standardize reporting and interpretation of drug associated alterations (5). We are currently involved in collaborative efforts to align the MVLD framework with parallel, complementary sequence variants interpretation clinical guidelines from the Association of Molecular Pathologists (AMP) for clinical labs (6). In order to truly democratize access to MolDx data for care and research needs, these standards must be harmonized to support sharing of clinical cancer variants. Here we describe the processes and methods developed within the ClinGen’s Somatic WG in collaboration with over 60 cancer care and research organizations as well as CLIA-certified, CAP-accredited clinical testing labs to develop standards for cancer variant interpretation and sharing.