gebhart/patrepeval huggingface dataset:
Stress, alcohol and drug interaction: an update of human research (2008)

A challenging question that continues unanswered in the field of addiction is why some individuals are more vulnerable to substance use disorders than others. Numerous risk factors for alcohol and other drugs of abuse, including exposure to various forms of stress, have been identified in clinical studies. However, the neurobiological mechanisms that underlie this relationship remain unclear. Critical neurotransmitters, hormones and neurobiological sites have been recognized, which may provide the substrates that convey individual differences in vulnerability to addiction. With the advent of more sophisticated measures of brain function in humans, such as functional imaging technology, the mechanisms and neural pathways involved in the interactions between drugs of abuse, the mesocorticolimbic dopamine system and stress systems are beginning to be characterized. This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from occasional drug use to drug dependence. We also review factors that contribute to different levels of hormonal/brain stress activation, which has implications for understanding individual vulnerability to drug dependence. Ultimately, these efforts may improve our chances of designing treatment strategies that target addiction at the core of the disorder.
IP Traffic Engineering Architecture with Network Programming (2019)

This document describes a control plane based IP Traffic Engineering
Architecture where path information is kept in the control plane by
selected nodes instead of being inserted into each packet on ingress
of an administrative domain. The described proposal is also fully
compatible with the concept of network programming. It is positioned
as a complimentary technique to native SRv6 and can be used when there
are concerns with increased packet size due to depth of SID stack,
possible concerns regarding exceeding MTU or more strict simplicity
requirements typically seen in number of enterprise networks. The
proposed solution is applicable to both IPv4 or IPv6 based networks.
As an additional added value, detection of end to end path liveness as
well as dynamic path selection based on real time path quality is
integrated from day one in the design.
Null mutant analysis of responses to nicotine: Deletion of β2 nicotinic acetylcholine receptor subunit but not α7 subunit reduces sensitivity to nicotine-induced locomotor depression and hypothermia (2004)

The nicotinic acetylcholine receptor (nAChR) subtypes alpha4beta2 and alpha7 comprise the majority of brain nicotine-binding sites. Classical genetic strategies using inbred mice and their hybrids suggest that nicotine's effects on locomotor activity and body temperature are influenced by alpha4beta2 but not alpha7 receptors. To evaluate directly the role of these nicotinic subtypes on responses to nicotine, beta2 and alpha7 null mutant (-/-) mice, as well as wild-type (+/+) and heterozygous (+/-) mice, were tested for baseline body temperature and locomotion and nicotine (0-1.5 mg/kg)-induced changes in these responses. Basal responses for these measures were similar for all beta2 genotypes, but baseline Y-maze activity was higher in alpha7-/- mice compared with alpha7+/+ mice. Following nicotine injection, dose-dependent decreases in body temperature and locomotor activity were observed for all three genotypes of both beta2 and alpha7 mice. Although responses in alpha7 mice did not differ among genotypes, beta2 gene deletion was found to have a gene-dependent effect on nicotine's effects. beta2-/- mice were less sensitive to nicotine-induced locomotor depression and hypothermia at low nicotine doses (.25-.5 mg/kg) but were no different from beta2+/+ mice at the highest doses tested (1.0-1.5 mg/kg). Residual responses at high nicotine doses in beta2-/- mice as well as responses in all alpha7 and beta2 mouse genotypes were mediated by nicotinic receptors, since mecamylamine (1.0 mg/kg) blocked all responses following 1.0 mg/kg nicotine. This finding suggests receptors that include the beta2 nAChR subunit partially mediate nicotine's effects on locomotor activity and body temperature.
SOX2 Expression Associates with Stem Cell State in Human Ovarian Carcinoma (2013)

The SRY-related HMG-box family of transcription factors member SOX2 regulates stemness and pluripotency in embryonic stem cells and plays important roles during early embryogenesis. More recently, SOX2 expression was documented in several tumor types including ovarian carcinoma, suggesting an involvement of SOX2 in regulation of cancer stem cells (CSC). Intriguingly, however, studies exploring the predictive value of SOX2 protein expression with respect to histopathologic and clinical parameters report contradictory results in individual tumors, indicating that SOX2 may play tumor-specific roles. In this report, we analyze the functional relevance of SOX2 expression in human ovarian carcinoma. We report that in human serous ovarian carcinoma (SOC) cells, SOX2 expression increases the expression of CSC markers, the potential to form tumor spheres, and the in vivo tumor-initiating capacity, while leaving cellular proliferation unaltered. Moreover, SOX2-expressing cells display enhanced apoptosis resistance in response to conventional chemotherapies and TRAIL. Hence, our data show that SOX2 associates with stem cell state in ovarian carcinoma and induction of SOX2 imposes CSC properties on SOC cells. We propose the existence of SOX2-expressing ovarian CSCs as a mechanism of tumor aggressiveness and therapy resistance in human SOC.
Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components (2013)

Exosomes are small extracellular 40-100 nm diameter membrane vesicles of late endosomal origin that can mediate intercellular transfer of RNAs and proteins to assist premetastatic niche formation. Using primary (SW480) and metastatic (SW620) human isogenic colorectal cancer cell lines we compared exosome protein profiles to yield valuable insights into metastatic factors and signaling molecules fundamental to tumor progression. Exosomes purified using OptiPrep™ density gradient fractionation were 40-100 nm in diameter, were of a buoyant density ~1.09 g/mL, and displayed stereotypic exosomal markers TSG101, Alix, and CD63. A major finding was the selective enrichment of metastatic factors (MET, S100A8, S100A9, TNC), signal transduction molecules (EFNB2, JAG1, SRC, TNIK), and lipid raft and lipid raft-associated components (CAV1, FLOT1, FLOT2, PROM1) in exosomes derived from metastatic SW620 cells. Additionally, using cryo-electron microscopy, ultrastructural components in exosomes were identified. A key finding of this study was the detection and colocalization of protein complexes EPCAM-CLDN7 and TNIK-RAP2A in colorectal cancer cell exosomes. The selective enrichment of metastatic factors and signaling pathway components in metastatic colon cancer cell-derived exosomes contributes to our understanding of the cross-talk between tumor and stromal cells in the tumor microenvironment.
IMG: the integrated microbial genomes database and comparative analysis system (2011)

The Integrated Microbial Genomes (IMG) system serves as a community resource for comparative analysis of publicly available genomes in a comprehensive integrated context. IMG integrates publicly available draft and complete genomes from all three domains of life with a large number of plasmids and viruses. IMG provides tools and viewers for analyzing and reviewing the annotations of genes and genomes in a comparative context. IMG's data content and analytical capabilities have been continuously extended through regular updates since its first release in March 2005. IMG is available at http://img.jgi.doe.gov. Companion IMG systems provide support for expert review of genome annotations (IMG/ER: http://img.jgi.doe.gov/er), teaching courses and training in microbial genome analysis (IMG/EDU: http://img.jgi.doe.gov/edu) and analysis of genomes related to the Human Microbiome Project (IMG/HMP: http://www.hmpdacc-resources.org/img_hmp).
A virion-specific inhibitory molecule with therapeutic potential for human immunodeficiency virus type 1. (1993)

A potential new approach for gene therapy against human immunodeficiency virus type 1 (HIV-1) infection is the design of a nonstructural gene-based virion-specific inhibitory molecule that is packaged with virus to destroy its infectivity. We tested this approach for HIV-1 by using Vpx, a virion-associated protein of HIV-2 and simian immunodeficiency virus. Vpx was incorporated into HIV-1 virions and the resulting cell-free virus lost infectivity in CD4+ human T cells. This demonstrates the therapeutic potential of an accessory gene-based virion-specific inhibitory molecule. Vpx and its derivatives can be regarded as a new class of anti-HIV-1 molecule.
Functional Epitope Mapping of Insulin-Like Growth Factor I (IGF-I) by Anti-IGF-I Monoclonal Antibodies* (1997)

Based on a collection of monoclonal antibodies (mAb) against insulin-like growth factor I (IGF-I), we have defined the IGF-I epitopes involved in the interaction with IGF-binding proteins (IGFBP) and IGF-I receptors. We have also characterized the ability of these antibodies to block IGF-I-induced survival of the IL-3-dependent Ba/F3 cell line. More than 140 hybridomas secreting IGF-I-specific mAb were characterized, of which 28 were studied in detail. They display apparent affinity constants ranging from less than 10(6) to 10(10) M-1 and varying crossreactivity with IGF-II, including 2 mAb with higher affinity for IGF-II than for IGF-I. None crossreact with insulin or any other growth factor tested. Using both enzyme immunoassays and real-time biospecific interaction analysis, we have identified 8 epitopic clusters related to the primary structure of IGF-I, according to mAb reactivity to synthetic peptides, proteolytic fragments of IGF-I, and various IGF-I mutants. The mAb panel also was used to map the IGF domains implicated in the interaction with IGFBP and IGF-I receptors. An IGF-I domain has been identified that remains exposed after IGF-I binding to IGFBP-1 or to IGFBP-3, which is recognized by 6 different mAb. The mAb in this group also bind IGF-I, when complexed to the type-1 IGF receptor on the murine pro-B cell line Ba/F3, and BALB/c 3T3 fibroblasts overexpressing the human receptor. Finally, IGF-I-promoted survival can be blocked with mAb specific for target epitopes, and their potential use in tumor cell growth control is discussed.
Metabolism and Physiology of Abscisic Acid (1988)

INTRODUCTION 440 TECHNIQUES 440 Quantification of ABA . ...... . . ...... . 440 Separation of Sand R-Abscisic Acid 441 Stable Isotopes and Mass Spectrometry 442 Extraction and Quantification of Xanthoxin 442 METABOLISM 443 Biosynthesis in Fungi 443 Biosynthesis in Higher Plants 444 Catabolism . . . . . . . . . .. . .... . . . . . . . . . . . . . . .. . . ..... . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ..... . . . . . . . 453 Compartmentation 454 EFFECTS OF ABSCISIC ACID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456 Physiological Responses 456 Biochemical Responses..... . ...... . 461 CONCLUDING REMARKS 463
Monomeric site-specific nucleases for genome editing (2012)

Targeted manipulation of complex genomes often requires the introduction of a double-strand break at defined locations by site-specific DNA endonucleases. Here, we describe a monomeric nuclease domain derived from GIY-YIG homing endonucleases for genome-editing applications. Fusion of the GIY-YIG nuclease domain to three-member zinc-finger DNA binding domains generated chimeric GIY-zinc finger endonucleases (GIY-ZFEs). Significantly, the I-TevI-derived fusions (Tev-ZFEs) function in vitro as monomers to introduce a double-strand break, and discriminate in vitro and in bacterial and yeast assays against substrates lacking a preferred 5'-CNNNG-3' cleavage motif. The Tev-ZFEs function to induce recombination in a yeast-based assay with activity on par with a homodimeric Zif268 zinc-finger nuclease. We also fused the I-TevI nuclease domain to a catalytically inactive LADGLIDADG homing endonuclease (LHE) scaffold. The monomeric Tev-LHEs are active in vivo and similarly discriminate against substrates lacking the 5'-CNNNG-3' motif. The monomeric Tev-ZFEs and Tev-LHEs are distinct from the FokI-derived zinc-finger nuclease and TAL effector nuclease platforms as the GIY-YIG domain alleviates the requirement to design two nuclease fusions to target a given sequence, highlighting the diversity of nuclease domains with distinctive biochemical properties suitable for genome-editing applications.
Modulation of human alveolar macrophage tumoricidal activity by recombinant macrophage colony-stimulating factor. (1990)

Recombinant macrophage colony-stimulating factor (M-CSF) is a hemopoietic growth factor capable of modulating activities of both immature and mature monocytes. The effect of M-CSF on tumoricidal activity of alveolar macrophages and monocytes from nonsmoking normal volunteers was compared using [3H]thymidine-labeled human tumor cells (SK-MEL-28, melanoma) as targets. A dose-response study (500-5,000 U/ml) of recombinant M-CSF indicated that both alveolar macrophages and blood monocytes demonstrated peak cytotoxicity at 1,000 U/ml. Maximal activity occurred 72-96 h after exposure to 1,000 U/ml of M-CSF. To investigate the mechanisms involved in this cytotoxicity, tumor necrosis factor-alpha (TNF) and interleukin-1-beta (IL-1) were measured in supernatant fluids of 24 h M-CSF-treated cells. No significant increase in either cytokine was detected after M-CSF treatment of alveolar macrophages or monocytes. Superoxide anion production of alveolar macrophages was not enhanced by M-CSF. These data suggest that alveolar macrophages tumoricidal activity is induced by M-CSF and is not dependent on oxidative metabolism or secreted forms of IL-1 or TNF.
Quasistatic and continuous dynamic characterization of the mechanical properties of silk from the cobweb of the black widow spiderLatrodectus hesperus (2005)

Spider silks are among the strongest and toughest known materials, but investigation of these remarkable properties has been confined largely to orb-weaving spiders. We investigated the mechanical performance of silk from the cobweb-weaving spider Latrodectus hesperus. Both silk from the scaffolding region of the web and sticky gumfooted capture lines had material properties similar to the major ampullate silk that orb weavers use as the framework for their orb webs. Major ampullate fibers obtained from anaesthetized Latrodectus spiders were similar, but exhibited increased stiffness and reduced extensibility. Novel continuous dynamic analysis of the silks revealed that the loss tangent (tandelta) increased rapidly during the first 2-3% of extension and reached a maximum near the yield point of fibers. The loss tangent then rapidly declined at an ever-decreasing rate until failure. We suggest that these data support molecular models for the mechanics of spider silk. We also demonstrate that the addition of sticky aggregate glue to the ends of the gumfooted lines modulates their mechanical performance--reducing stiffness and increasing extensibility. The storage modulus of viscid regions of the gumfooted lines was much lower than dry regions. This may be explained by disruption of hydrogen bonding within the amorphous regions of the fibers due to hydration from the glue.
Sacral neuromodulation for treatment of lower urinary tract dysfunction (2000)

Despite initial reservations, sacral neuromodulation has begun to develop as a new therapeutic tool for the treatment of lower urinary tract dysfunction. It bridges the gap between conservative treatment options and highly invasive procedures, such as urinary diversion. At present, there are no clinical variables that can reliably predict the efficacy of neuromodulation in an individual patient. All patients, regardless of indication, must therefore undergo a test stimulation before they can be offered chronic sacral neuromodulation with an implanted system. Evaluations in various clinical trials have confirmed that sacral neuromodulation, based on unilateral sacral foramen electrode implantation, has statistically significant therapeutic effects compared to controls, in patients with urge syndromes and failure to empty. The patients most likely to benefit from this treatment are those with detrusor hyperactivity or detrusor hypo-activity. Those with pain syndromes are less likely to respond and to benefit from treatment. Acute and subchronic sacral neuromodulation are associated with very low rates of complications. Complications of chronic sacral neuromodulation are caused either by surgery-related morbidity or hardware problems. Conservative treatment options should be exhausted before neuromodulation is considered. This rule has two purposes: First, it postpones surgery, with its potential morbidity, for as long as possible; second, the long-term efficacy of neuromodulation is still unclear and may be limited in some patients. A fully exploited conservative therapy, in combination with subsequent sacral neuromodulation, may therefore be the optimum way to pursue therapeutic options of relatively low invasiveness.
Complex Regional Pain Syndrome Type 2 (Causalgia) After Automated Laser Discectomy (1997)

Complex regional pain syndrome Type 2 with sympathetically maintained pain is a condition that can result in serious disability and can be associated with a number of spinal procedures, including automated laser percutaneous discectomy. Early intervention is recommended to provide long-term resolution of the condition.
585. Trypanocides of the phenanthridine series. Part I. The effect of changing the quaternary grouping in dimidium bromide (1952)

T. I. Watkins, J. Chem. Soc., 1952, 3059 DOI: 10.1039/JR9520003059
Clinical pharmacology and toxicity of 4'-O-tetrahydropyranyladriamycin. (1987)

The clinical pharmacology and toxicity of a novel anthracycline derivative, 4'-O-tetrahydropyranyladriamycin (THP-adriamycin), was investigated in patients with advanced malignant diseases. The starting dose was 30 mg/m2 which was escalated by increments of 10 mg/m2. Twelve patients with a median age of 42 (range, 19-69) years and a median Eastern Cooperative Oncology Group performance score of 2 (range, 1-2) were entered into the study. The diagnoses included four testicular cancers, two breast cancers, two small cell lung cancers, two acute myeloid leukemias, one colon cancer, and one hemangiosarcoma. THP-adriamycin was given as an i.v. bolus injection every 3 weeks. Evaluable were 18 courses for general toxicity, 16 courses for hematological toxicity, and 16 courses for pharmacokinetics. THP-adriamycin had a short initial half-life of 1.4 +/- 0.3 min (mean +/- SD) due to rapid cellular uptake. Peak concentrations in unseparated blood cells were reached 5 min after drug injection and remained higher than in plasma throughout the observation period of 72 h. The half-lives of THP-adriamycin in plasma were 19 +/- 2.8 min in an intermediate and 13 +/- 1.6 h in the terminal phase. A linear correlation was observed between the dose and the areas under the concentration curves for THP-adriamycin in plasma (r2 = 0.97) and blood cells (r2 = 0.99). The volume of distribution was 2124 +/- 221 liters/m2 and the total clearance rate 115 +/- 11 liters/m2h. THP-adriamycin was metabolized to Adriamycin, THP-adriamycinol, and adriamycinol. The major metabolite was Adriamycin with a terminal half-life in plasma of 33 +/- 10 h. The area under the curve of Adriamycin was also correlated to the administered dose (r2 = 0.96). Since excessive peak concentrations of Adriamycin were avoided, the treatment with THP-adriamycin might be an alternative to continuous infusions or weekly administrations. The maximum tolerated dose was 70 mg/m2, and the dose-limiting toxicities were leukopenia and thrombocytopenia. Anemia, nausea, and vomiting were mild to moderate, and no other toxicity was observed. All side effects were dose dependent and reversible. In a patient with breast cancer, a disease stabilization was achieved lasting for 9 weeks. No objective remission was observed. We suggest 60 mg/m2 in pretreated or poor risk and 70 mg/m2 in untreated or good risk patients every 3 weeks for further clinical trials.
Overexpression of SMYD2 contributes to malignant outcome in gastric cancer (2014)

These findings suggest that SMYD2 has a crucial role in tumor cell proliferation by its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in gastric cancer.
The potential for isoenzyme‐selective modulation of protein kinase C (1997)

Protein kinase C (PKC) is a phospholipid-dependent serine/threonine kinase family consisting of at least 11 closely related isoenzymes. The different PKC isoenzymes play important roles in signal transduction pathways. The exact significance of each isoenzyme is not known at present; therefore, the elucidation of the roles of the various PKC isoenzymes is important. To explain the function of distinct PKC isoenzymes, the availability of isoenzyme-specific inhibibitors or activators would be an advantage. PKC inhibitors have been known for some time, but these compounds are not isoenzyme-specific and also inhibit other kinases. Recently, an inhibitor selective for PKC alpha and another one selective for PKCbetaI and betaII were described. Both compounds compete with the ATP binding sites that exhibit high homologies among the different PKC isoenzymes. Among others, the phosporyl transfer region, the pseudosubstrate domain, the phorbolester binding sequences, and the phosphorylation sites may also be targets for modulation of isoenzyme-specific PKC activity. The question is whether the differences in these domains and the substrate specificity of the PKC isoenzymes will allow isoenzyme-specific inhibition. In this review the human sequences of these sites, isoenzyme-specific substrates, inhibitory compounds, and inhibitory peptides are summarized.