gebhart/patrepeval huggingface dataset:
Targeting the Androgen Receptor with Steroid Conjugates (2014)

The androgen receptor (AR) is a major therapeutic target in prostate cancer pharmacology. Progression of prostate cancer has been linked to elevated expression of AR in malignant tissue, suggesting that AR plays a central role in prostate cancer cell biology. Potent therapeutic agents can be precisely crafted to specifically target AR, potentially averting systemic toxicities associated with nonspecific chemotherapies. In this review, we describe various strategies to generate steroid conjugates that can selectively engage AR with high potency. Analogies to recent developments in nonsteroidal conjugates targeting AR are also evaluated. Particular focus is placed on potential applications in AR pharmacology. The review culminates with a description of future prospects for targeting AR.
Induction of Ectopic Eyes by Targeted Expression of the eyeless Gene in Drosophila (1995)

The Drosophila gene eyeless (ey) encodes a transcription factor with both a paired domain and a homeodomain. It is homologous to the mouse Small eye (Pax-6) gene and to the Aniridia gene in humans. These genes share extensive sequence identity, the position of three intron splice sites is conserved, and these genes are expressed similarly in the developing nervous system and in the eye during morphogenesis. Loss-of-function mutations in both the insect and in the mammalian genes have been shown to lead to a reduction or absence of eye structures, which suggests that ey functions in eye morphogenesis. By targeted expression of the ey complementary DNA in various imaginal disc primordia of Drosophila, ectopic eye structures were induced on the wings, the legs, and on the antennae. The ectopic eyes appeared morphologically normal and consisted of groups of fully differentiated ommatidia with a complete set of photoreceptor cells. These results support the proposition that ey is the master control gene for eye morphogenesis. Because homologous genes are present in vertebrates, ascidians, insects, cephalopods, and nemerteans, ey may function as a master control gene throughout the metazoa.
Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome (2010)

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder associated with thrombocytopenia, eczema, and autoimmunity. We treated two patients who had this disorder with a transfusion of autologous, genetically modified hematopoietic stem cells (HSC). We found sustained expression of WAS protein expression in HSC, lymphoid and myeloid cells, and platelets after gene therapy. T and B cells, natural killer (NK) cells, and monocytes were functionally corrected. After treatment, the patients' clinical condition markedly improved, with resolution of hemorrhagic diathesis, eczema, autoimmunity, and predisposition to severe infection. Comprehensive insertion-site analysis showed vector integration that targeted multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis. (Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00000330.).
A Selective N-Type Calcium Channel Antagonist Reduces Extracellular Glutamate Release and Infarct Volume in Focal Cerebral Ischemia (1995)

Although a number of studies have demonstrated the neuroprotective effects of antagonists of postsynaptic N-methyl-D-aspartate (NMDA) and non-NMDA receptors in cerebral ischemia, little is known about the treatment of cerebral infarction through presynaptic blocking of extracellular glutamate release. We evaluated the effects of a presynaptic selective N-type calcium channel antagonist (SNX-111, given intravenously by continuous infusion at 5 mg/kg/h from 20 min prior to occlusion until 2 h postocclusion) on blood flow, extracellular glutamate, and infarct volume in rats with permanent occlusions of the right middle cerebral and right common carotid arteries plus 1-h transient occlusion of the left common carotid artery. There was no significant difference in CBF in the occluded cortex during the experiment between the treated and vehicle groups. SNX-111 significantly reduced total amount of extracellular glutamate during the experiment and the peak value of the glutamate after occlusion from 44.2 +/- 15.8 microM (mean +/- SD) to 21.4 +/- 11.4 microM (p < 0.01). Infusion of SNX-111 also significantly reduced the cortical volume of infarction from 47.2 +/- 5.8 to 19.9 +/- 7.3% (p < 0.0001). These results suggest that SNX-111 has a protective effect against focal ischemia through the inhibition of glutamate release from presynaptic sites, although SNX-111 may also affect the release of other neurotransmitters.
Linguistic Regularities in Continuous Space Word Representations (2013)

Continuous space language models have recently demonstrated outstanding results across a variety of tasks. In this paper, we examine the vector-space word representations that are implicitly learned by the input-layer weights. We find that these representations are surprisingly good at capturing syntactic and semantic regularities in language, and that each relationship is characterized by a relation-specific vector offset. This allows vector-oriented reasoning based on the offsets between words. For example, the male/female relationship is automatically learned, and with the induced vector representations, “King-Man + Woman ” results in a vector very close to “Queen. ” We demonstrate that the word vectors capture syntactic regularities by means of syntactic analogy questions (provided with this paper), and are able to correctly answer almost 40 % of the questions. We demonstrate that the word vectors capture semantic regularities by using the vector offset method to answer SemEval-2012 Task 2 questions. Remarkably, this method outperforms the best previous systems. 1
Organic transistors manufactured using inkjet technology with subfemtoliter accuracy (2008)

A major obstacle to the development of organic transistors for large-area sensor, display, and circuit applications is the fundamental compromise between manufacturing efficiency, transistor performance, and power consumption. In the past, improving the manufacturing efficiency through the use of printing techniques has inevitably resulted in significantly lower performance and increased power consumption, while attempts to improve performance or reduce power have led to higher process temperatures and increased manufacturing cost. Here, we lift this fundamental limitation by demonstrating subfemtoliter inkjet printing to define metal contacts with single-micrometer resolution on the surface of high-mobility organic semiconductors to create high-performance p-channel and n-channel transistors and low-power complementary circuits. The transistors employ an ultrathin low-temperature gate dielectric based on a self-assembled monolayer that allows transistors and circuits on rigid and flexible substrates to operate with very low voltages.
Configuration debugging as search: finding the needle in the haystack (2004)

This work addresses the problem of diagnosing configuration errors that cause a system to function incorrectly. For example, a change to the local firewall policy could cause a network-based application to malfunction. Our approach is based on searching across time for the instant the system transitioned into a failed state. Based on this information, a troubleshooter or administrator can deduce the cause of failure by comparing system state before and after the failure. We present the Chronus tool, which automates the task of searching for a failure-inducing state change. Chronus takes as input a user-provided software probe, which differentiates between working and non-working states. Chronus performs “time travel ” by booting a virtual machine off the system’s disk state as it existed at some point in the past. By using binary search, Chronus can find the fault point with effort that grows logarithmically with log size. We demonstrate that Chronus can diagnose a range of common configuration errors for both client-side and server-side applications, and that the performance overhead of the tool is not prohibitive. 1
Control of Hepatitis C: A Medicinal Chemistry Perspective (2005)

Abstract For Abstract see ChemInform Abstract in Full Text.
Up-Regulation of Anti-Inflammatory, STAT3-Activating Hepatocyte Growth Factor and Interleukin-11 In Polycythemia Vera Is Independent of JAK2V617F and Contributes to the Growth of Clonal Erythroblasts (2010)

Abstract Abstract 796 Context: The V617F activating mutation of JAK2, JAK2V617F, characterizes Polycythemia vera (PV). However, expression of JAK2V617F does not always result in clone expansion, implying that additional events are required for the growth of JAK2-mutated progenitors and development of the PV phenotype. In the present study, we provide evidence that anti-inflammatory cytokines are required for the growth of JAK2V617F-mutated erythroid progenitors. Methods: We searched for cytokines over-expressed in PV using cytokine antibody arrays and ELISAs for analyses of serum and bone marrow (BM) plasma, and quantitative RT-PCRs for analyses of cells purified from PV patients and controls. Transient transfection of JAK2V617F and invalidation of JAK2V617F with siRNA were used to study the effect of JAK2V617F on cytokine expression. Results: We found that PV patients over-expressed anti-inflammatory hepatocyte growth factor (HGF) and interleukin-11 (IL-11), BM stromal cells (BMSC) and erythroblasts being the main producers. HGF induced the production of IL-11 and both cytokines activate the STAT3 pathway. We used neutralizing antibodies specific for IL-11 or c-MET, the HGF receptor, to block autocrine/paracrine cytokine stimulation of erythroblasts in in vitro cultures. The growth of JAK2V617F-mutated PV erythroblasts and HEL cells was inhibited by at least 40%, indicating that JAK2V617F-mutated cells depend on HGF and IL-11 for their growth. Consistent with activation of HGF/IL-11 pathways, mRNA levels of gp130 (the receptor chain responsible for signalling common to cytokines of the IL-11/IL-6 family) and STAT3 were significantly elevated in PV erythroblasts. Moreover, mRNA levels of c-MET, HGF and IL-11 were correlated, a logical finding as c-MET, HGF and IL-11 act in cascade. No correlation was found with JAK2V617F mRNA levels. To the opposite, we provide evidence that the up-regulation of HGF and IL-11 in PV is not a consequence of JAK2V617F: transient expression of JAK2V617F in BaF-3/Epo-R cells and invalidation of JAK2V617F in HEL cells using anti-JAK2 siRNA had no effect on HGF and IL-11 expression. Conclusion: Anti-inflammatory, STAT3-activating HGF and IL-11 are up-regulated in PV independently of JAK2V617F. Both cytokines contribute to the proliferation of JAK2V617F-mutated erythroblasts, suggesting that drugs blocking the HGF/IL-11 pathways, such as c-MET antagonists, could be of interest as an additional therapeutic option in PV. Marjorie Boissinot and Cedric Cleyrat contibuted equally. Disclosures: No relevant conflicts of interest to declare.
Regulation of Epidermal Growth Factor Receptor Gene Expression (1989)

Synthesis and metabolism of the epidermal growth factor (EGF) receptor are extensively regulated to modulate cellular responses to ligand. To study regulation of EGF receptor gene expression, the 5' region of the gene was isolated from a human placental genomic library. A 5' proximal 1.1-kilobase fragment (-1100 to -19 relative to the ATG translation start site) and subfragments of this were subcloned in both forward and reverse orientations into the luciferase expression vector pSVOAL delta 5' and transfected into human cell lines. Luciferase activity was stimulated by treatment of transfected HeLa cells with EGF, 12-O-tetradecanoylphorbol 13-acetate (TPA), (Bu)2 cAMP, retinoic acid, and dexamethasone. Deletion analysis indicated full retention of activity after removal of the -1100 to -485 region (-485 to -19 fragment), but a 5-fold reduction in activity on removal of the -485 to -153 region (-153 to -19 fragment). Despite a reduction in basal activity, the proximal 134-basepair fragment retained responses to all inducers. Additivity was observed in response to maximal concentrations of TPA plus retinoic acid and of TPA plus (Bu)2 cAMP; the response to a combination of four inducers exceeded that to the RSV-LTR strong promoter. Differences in stimulated responses were observed in various recipients, with hepatoma HepG2 cells lacking responses to (Bu)2 cAMP and glioblastoma T98G cells lacking responses to EGF and TPA. These results indicate that a 134-basepair DNA fragment closely adjacent to the translation start site contains elements responsible for directing basal and stimulated expression of the EGF receptor gene.
Profiling protein expression and interactions: proximity ligation as a tool for personalized medicine (2010)

The ability to detect very low levels of expressed proteins has enormous potential for early diagnostics and intervention at curable stages of disease. An extended range of targets such as interacting or post-translationally modified proteins can further improve the potential for diagnostics and patient stratification, and for monitoring response to treatment. These are critical building blocks for personalized treatment strategies to manage disease. The past few decades have seen a remarkably improved understanding of the molecular basis of disease in general, and of tumour formation and progression in particular. This accumulated knowledge creates opportunities to develop drugs that specifically target molecules or molecular complexes critical for survival and expansion of tumour cells. However, tumours are highly variable between patients, necessitating the development of diagnostic tools to individualize treatment through parallel analysis of sets of biomarkers. The proximity ligation assay (PLA) can address many of the requirements for advanced molecular analysis. The method builds on the principle that recognition of target proteins by two, three or more antibodies can bring in proximity DNA strands attached to the antibodies. The DNA strands can then participate in ligation reactions, giving rise to molecules that are amplified for highly sensitive detection. PLA is particularly well suited for sensitive, specific and multiplexed analysis of protein expression, post-translational modifications and protein-protein interactions. The analysis of this extended range of biomarkers will prove critical for the development and implementation of personalized medicine.
Leucine attenuates skeletal muscle wasting via inhibition of ubiquitin ligases (2010)

The aim of this study was to assess the effect of leucine supplementation on elements of the ubiquitin-proteasome system (UPS) in rat skeletal muscle during immobilization. This effect was evaluated by submitting the animals to a leucine supplementation protocol during hindlimb immobilization, after which different parameters were determined, including: muscle mass; cross-sectional area (CSA); gene expression of E3 ligases/deubiquitinating enzymes; content of ubiquitinated proteins; and rate of protein synthesis. Our results show that leucine supplementation attenuates soleus muscle mass loss driven by immobilization. In addition, the marked decrease in the CSA in soleus muscle type I fibers, but not type II fibers, induced by immobilization was minimized by leucine feeding. Interestingly, leucine supplementation severely minimized the early transient increase in E3 ligase [muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1] gene expression observed during immobilization. The reduced peak of E3 ligase gene expression was paralleled by a decreased content of ubiquitinated proteins during leucine feeding. The protein synthesis rate decreased by immobilization and was not affected by leucine supplementation. Our results strongly suggest that leucine supplementation attenuates muscle wasting induced by immobilization via minimizing gene expression of E3 ligases, which consequently could downregulate UPS-driven protein degradation. It is notable that leucine supplementation does not restore decreased protein synthesis driven by immobilization.
Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo (2018)

Vitiligo is an autoimmune disease of the skin mediated by CD8<sup>+</sup> T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (T<sub>RM</sub>) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)-deficient mice reportedly have impaired T<sub>RM</sub> formation, and IL-15 promotes T<sub>RM</sub> function ex vivo. We found that both human and mouse T<sub>RM</sub> express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short-term treatment with anti-CD122 inhibits T<sub>RM</sub> production of interferon-γ (IFNγ), and long-term treatment depletes T<sub>RM</sub> from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving T<sub>RM</sub>.
Studies on Synthetic Polypeptide Antigens (1967)

Studies of systematically varied series of synthetic polypeptides lead to several generalizations about the chemical factors involved in antigenicity. Polymers containing aromatic amino acids generally elicit more antibody than those not containing aromatic amino acids. This is not an exclusive property, however, since the incorporation of alanine can enhance immunogenicity in some cases. Tyrosine and phenylalanine are equally effective in enhancing antibody formation, but there is no correlation between the amount of antibody elicited and the amount of the aromatic amino acid in the polypeptide. The charge of the antigen plays essentially a restrictive role: completely charged and highly charged polypeptides are very poor immunogens. The immunogenicity of d -amino acid polymers and the stereospecificity of the antibody response have been confirmed, and the reason for the difficulty in eliciting antibody formation has been established. Immunization with the relatively large doses of antigen used with l polymers (2 to 20 mg) does not generally elicit antibody formation with d antigens, but low doses (0.3 to 0.6 mg) of antigen administered over a long period of time induce antibody formation to a wide variety of d -polypeptides. The d polymers do not display a significant booster effect, and eventually the antibody response is abolished by continued injection of the antigen. Using this same low dosage schedule, polylysine and polyglutamic acid of both optical configurations also elicit antibody. Thus, the generalization can be made that small doses of poor immunogens stimulate antibody formation and larger doses induce immunological paralysis. The experiments described in this study suggest that the method needed to induce antibody formation is determined by quite general properties of the antigen (e.g. optical configuration, excessively high charge) and that the quantitative control of antibody production depends upon both the general properties and the detailed composition of the antigen (e.g. types of amino acids).
Comparative Antibody-Mediated Phagocytosis ofStaphylococcus epidermidisCells Grown in a Biofilm or in the Planktonic State (2006)

Staphylococcus epidermidis is an important cause of nosocomial infections. Virulence is attributable to elaboration of biofilms on medical surfaces that protect the organisms from immune system clearance. Even though leukocytes can penetrate biofilms, they fail to phagocytose and kill bacteria. The properties that make biofilm bacteria resistant to the immune system are not well characterized. In order to better understand the mechanisms of resistance of bacteria in biofilms to the immune system, we evaluated antibody penetration throughout the biofilm and antibody-mediated phagocytic killing of planktonic versus biofilm cells of S. epidermidis by using a rabbit antibody to poly-N-acetylglucosamine (PNAG). These antibodies are opsonic and protect against infection with planktonic cells of PNAG-positive Staphylococcus aureus and S. epidermidis. Antibody to PNAG readily penetrated the biofilm and bound to the same areas in the biofilm as did wheat germ agglutinin, a lectin known to bind to components of staphylococcal biofilms. However, biofilm cells were more resistant to opsonic killing than their planktonic counterparts in spite of producing more PNAG per cell than planktonic cells. Biofilm extracts inhibited opsonic killing mediated by antibody to PNAG, suggesting that the PNAG antigen within the biofilm matrix prevents antibody binding close to the bacterial cell surface, which is needed for efficient opsonic killing. Increased resistance of biofilm cells to opsonic killing mediated by an otherwise protective antibody was due not to a biofilm-specific phenotype but rather to high levels of antigen within the biofilm that prevented bacterial opsonization by the antibody.
Where do they go? “A day without a Mexican,” a perspective from south of the border (2006)

The author uses the film “A day without a Mexican” to explore Mexican-US migration and to examine current US policy on immigration and in particular, US attitudes toward undocumented Mexican migrant workers.
Chlamydomonas Kinesin-II–dependent Intraflagellar Transport (IFT): IFT Particles Contain Proteins Required for Ciliary Assembly in Caenorhabditis elegans Sensory Neurons (1998)

We previously described a kinesin-dependent movement of particles in the flagella of Chlamydomonas reinhardtii called intraflagellar transport (IFT) (Kozminski, K.G., K.A. Johnson, P. Forscher, and J.L. Rosenbaum. 1993. Proc. Natl. Acad. Sci. USA. 90:5519-5523). When IFT is inhibited by inactivation of a kinesin, FLA10, in the temperature-sensitive mutant, fla10, existing flagella resorb and new flagella cannot be assembled. We report here that: (a) the IFT-associated FLA10 protein is a subunit of a heterotrimeric kinesin; (b) IFT particles are composed of 15 polypeptides comprising two large complexes; (c) the FLA10 kinesin-II and IFT particle polypeptides, in addition to being found in flagella, are highly concentrated around the flagellar basal bodies; and, (d) mutations affecting homologs of two of the IFT particle polypeptides in Caenorhabditis elegans result in defects in the sensory cilia located on the dendritic processes of sensory neurons. In the accompanying report by Pazour, G.J., C.G. Wilkerson, and G.B. Witman (1998. J. Cell Biol. 141:979-992), a Chlamydomonas mutant (fla14) is described in which only the retrograde transport of IFT particles is disrupted, resulting in assembly-defective flagella filled with an excess of IFT particles. This microtubule- dependent transport process, IFT, defined by mutants in both the anterograde (fla10) and retrograde (fla14) transport of isolable particles, is probably essential for the maintenance and assembly of all eukaryotic motile flagella and nonmotile sensory cilia.