gebhart/patrepeval huggingface dataset:
Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors (2018)

Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.
MYC‐regulated genes involved in liver cell dysplasia identified in a transgenic model of liver cancer (2012)

Foci of liver cell dysplasia (LCD) are distinct morphological entities and may evolve into hepatocellular carcinomas (HCCs). While most HCCs overexpress c-Myc, its role in LCD remains uncertain. Therefore, a c-Myc transgenic model of HCC was investigated to understand the genetic events forcing liver cells into dysplasia and subsequent malignant transformation. Specifically, whole genome scans enabled fingerprinting of genes at different stages of disease, ie LCD and HCC, while laser microdissected LCD lesions were used to validate regulation of candidate genes by quantitative real-time RT-PCR, ie Mybbp1a, Rps7, Rps19, Rpl10a, Skp1a, Tfdp1, Nhp2, and Bola2. EMSA band shift assays confirmed c-Myc DNA binding at regulatory sequences of candidate gene-specific promoters. Additionally, published ChIP-seq data helped to define the candidate genes as c-Myc bona fide targets. Treatment of the human hepatoma cell line HepG2 with hepatic growth factor (Hgf) caused c-Myc protein induction and transcriptional up-regulation of candidate genes, albeit at different levels when individual genes were compared. A significant increase of HepG2 entering the G1-phase was associated with up-regulation of the candidate genes in an Hgf concentration-dependent matter. Finally, we confirmed regulation of candidate genes in patients' samples with low- and high-grade dysplasia and HCC staged T1 to T3, while their expression was unchanged in focal nodular hyperplasia and hepatic adenoma, therefore asserting the diagnostic value and clinical significance of these candidate genes. Overall, novel c-Myc targeted genes were identified and may contribute to hepatocyte transformation by altering cell cycle control, thereby contributing to c-Myc's oncogenic activity.
Diagnostic and prognostic value of RNA-proteolipid in sera of patients with malignant disorders following therapy: first clinical evaluation of a novel tumor marker. (1987)

The circulating level of a novel RNA-proteolipid complex associated with malignant diseases was critically evaluated as a tumor marker in clinical oncology. The complex, isolated from the sera of cancer patients, exhibited unvarying chemical composition regardless of the cell type and clinical staging. Clearance from blood was rapid with a half-life of approximately 2 days. Tumor mass could be correlated with the circulating level. After effective treatment the level fell and rose again 10 months prior to the conventional clinical diagnosis of relapse.
Anti-CD8 Antibodies Can Trigger CD8+ T Cell Effector Function in the Absence of TCR Engagement and Improve Peptide–MHCI Tetramer Staining (2011)

CD8(+) T cells recognize immunogenic peptides presented at the cell surface bound to MHCI molecules. Ag recognition involves the binding of both TCR and CD8 coreceptor to the same peptide-MHCI (pMHCI) ligand. Specificity is determined by the TCR, whereas CD8 mediates effects on Ag sensitivity. Anti-CD8 Abs have been used extensively to examine the role of CD8 in CD8(+) T cell activation. However, as previous studies have yielded conflicting results, it is unclear from the literature whether anti-CD8 Abs per se are capable of inducing effector function. In this article, we report on the ability of seven monoclonal anti-human CD8 Abs to activate six human CD8(+) T cell clones with a total of five different specificities. Six of seven anti-human CD8 Abs tested did not activate CD8(+) T cells. In contrast, one anti-human CD8 Ab, OKT8, induced effector function in all CD8(+) T cells examined. Moreover, OKT8 was found to enhance TCR/pMHCI on-rates and, as a consequence, could be used to improve pMHCI tetramer staining and the visualization of Ag-specific CD8(+) T cells. The anti-mouse CD8 Abs, CT-CD8a and CT-CD8b, also activated CD8(+) T cells despite opposing effects on pMHCI tetramer staining. The observed heterogeneity in the ability of anti-CD8 Abs to trigger T cell effector function provides an explanation for the apparent incongruity observed in previous studies and should be taken into consideration when interpreting results generated with these reagents. Furthermore, the ability of Ab-mediated CD8 engagement to deliver an activation signal underscores the importance of CD8 in CD8(+) T cell signaling.
Bacterial control of Agromyces ramosus in soil (1985)

Agromyces ramosus occurs in high numbers in many soils. It also is a known predator of various gram-positive and gram-negative soil bacteria, including Azotobacter vinelandii. Based on this, it would seem that, in natural soil, A. ramosus should control the population sizes of these soil bacteria. As a partial test of this assumption, we examined the possibility that soil might contain other bacterial predators that could hold A. ramosus in check. Three gram-negative bacterial predators of A. ramosus were isolated from soil. When one of these predators, strain N-1, was added to natural soil, it exhibited an attack – counter attack phenomenon in its interactions with A. ramosus. The indigenous A. ramosus cells in soil, or added A. ramosus cells, produced mycelium that approached, then lysed, approximately one-third of the N-1 cells. The surviving N-1 cells, however, then proceeded to lyse the A. ramosus mycelium, but not the rod-form cells that had fragmented from the mycelium. Strain N-1 then multiplied. This sequence also occurred if Azotobacter vinelandii was added with A. ramosus to soil, either with or without addition of N-1 cells. N-1 attacked the A. ramosus mycelium that was attacking Azotobacter vinelandii. In soil and with pure cultures in the laboratory, the dormant rod-form cells of A. ramosus that fragmented from the mycelium were not attacked. A growth initiation factor seemed to be involved in the attack – counter attack relationship of N-1 and A. ramosus. Strain N-1 and the other two gram-negative predators mentioned above could attack a variety of bacterial species in soil, in addition to A. ramosus which in itself is a predator. Thus, some sort of hierarchy of bacterial predation seems to exist in soil.
Comparison of Selective Polymerase Chain Reaction Primers and Differential Probe Hybridization of Polymerase Chain Reaction Products for Determination of Relative Amounts of Codon 215 Mutant and Wild-Type HIV-1 Populations (1995)

A mutation at codon 215 of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) gene results in decreased sensitivity to zidovudine (ZDV). In order to follow changes in codon 215 mutant (MUT) and wild-type (WT) populations in the plasma of patients during therapy, two polymerase chain reaction (PCR) procedures were investigated. The first was a nested, selective PCR, wherein a first round with viral-specific primers was followed by a second round with allele-specific primers. Although the procedure is relatively sensitive, some samples in the first round of PCR could not be amplified. In mixing experiments, mispriming of the MUT primer made relative determination of quantities subjective and difficult. Differential hybridization of PCR product with probes specific for codon 215 MUT or WT sequences was also investigated. A probe directed to a highly conserved region of the RT gene in the amplified PCR product was used to determine the total amount of PCR product analyzed. Differential hybridization was linear and reproducible over several logs of MUT:WT ratios, and determination of a 1:100 ratio of MUT:WT was readily achieved. When applied to longitudinal samples from three patients, dramatic changes in each population were readily apparent. These changes were evaluated with regard to viral load.
Sex, Sex Steroids, and Brain Injury (2009)

Biologic sex and sex steroids are important factors in clinical and experimental stroke and traumatic brain injury (TBI). Laboratory data strongly show that progesterone treatment after TBI reduces edema, improves outcomes, and restores blood-brain barrier function. Clinical studies to date agree with these data, and there are ongoing human trials for progesterone treatment after TBI. Estrogen has accumulated an impressive reputation as a neuroprotectant when evaluated at physiologically relevant doses in laboratory studies of stroke, but translation to patients remains to be shown. The role of androgens in male stroke or TBI is understudied and important to pursue given the epidemiology of stroke and trauma in men. To date, male sex steroids remain largely evaluated at the bench rather than the bedside. This review evaluates key evidence and highlights the importance of the platform on which brain injury occurs (i.e., genetic sex and hormonal modulators).
Synthesis and biological evaluation of some phosphate triester derivatives of the anti-viral drug AraA (1989)

A number of novel phosphate triester derivatives of the anti-cancer nucleoside analogue araC have been prepared by a rapid 2-step procedure, not necessitating prior sugar protection. Spectroscopic and lipophilicity data have been collected on these compounds. An in vitro assay indicated inhibition of thymidine incorporation by mammalian epithelial cells, by each of these compounds, in the range 3-300 microM. Moreover, the degree of inhibition showed a close correlation to chemical structure; in particular, there was a clear relationship between inhibition of thymidine incorporation and log(P). These results are consistent with cellular penetration by the intact phosphate triesters and intracellular action by an unspecified mechanism. Triethyl phosphate is inactive under the conditions of the test.
Molecular cloning of mRNA sequences encoding rat lens crystallins. (1981)

To provide access to crystallin-specific DNA sequences, we have constructed plasmid clones bearing duplex DNA sequences complementary to crystallin mRNAs isolated from rat lens. Optimization of the cDNA reaction conditions enabled us to fractionate three double-stranded (ds) cDNA groups. Molecular cloning of dC-tailed ds cDNAs into the Pst I site of dG-tailed pBR322 yielded crystallin-specific clones of each group. By means of positive hybridization selection and translation, recombinant plasmids containing cDNA sequences coding for rat lens polypeptides from alpha-, beta-, and gamma-crystallins could be identified. The established cDNA clones have been used for a blot-hybridization analysis to map the crystallin mRNAs from which they originated. Both procedures revealed a high degree of homology between the gamma-crystallin sequences. From the beta-crystallin class, the beta H-specific cDNA coding for the beta B1a polypeptide was obtained. The alpha A-chain clone did not show any cross-hybridization to the alpha B-chain mRNA despite the existence of 60% homology between the corresponding gene products. As this clone hybridized to both alpha A2 and alpha AIns mRNAs, sequence analysis was applied for further characterization. The results showed that the cloned cDNA corresponds to the alpha A2 sequence exclusively.
Endothelialized Microvasculature Based on a Biodegradable Elastomer (2005)

Vital organs maintain dense microvasculature to sustain the proper function of their cells. For tissue- engineered organs to function properly, artificial capillary networks must be developed. We have microfabricated capillary networks with a biodegradable and biocompatible elastomer, poly(glycerol sebacate) (PGS). We etched capillary patterns onto silicon wafers by standard micro-electromechanical systems (MEMS) techniques. The resultant silicon wafers served as micromolds for the devices. We bond the patterned PGS film with a flat film to create capillary networks that were perfused with a syringe pump at a physiological flow rate. The devices were endothelialized under flow conditions, and part of the lumens reached confluence within 14 days of culture. This approach may lead to tissue-engineered microvasculature that is critical in vital organs engineering.
Involvement of a Novel Chemokine Decoy Receptor CCX-CKR in Breast Cancer Growth, Metastasis and Patient Survival (2009)

We showed for the first time that CCX-CKR is a negative regulator of growth and metastasis in breast cancer mainly by sequestration of homeostatic chemokines and subsequent inhibition of intratumoral neovascularity. This finding may lead to a new therapeutic strategy against breast cancer.
Annelation of tricarbonyliron complexes of ortho-disubstituted [4]annulenes. Synthesis of tricarbonyliron complexes of derivatives of bicyclo[6.2.0]decapentaene via Wittig cycloolefination (1977)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAnnelation of tricarbonyliron complexes of ortho-disubstituted [4]annulenes. Synthesis of tricarbonyliron complexes of derivatives of bicyclo[6.2.0]decapentaene via Wittig cycloolefinationFred A. Kaplan and Bryan W. RobertsCite this: J. Am. Chem. Soc. 1977, 99, 2, 513–517Publication Date (Print):January 1, 1977Publication History Published online1 May 2002Published inissue 1 January 1977https://pubs.acs.org/doi/10.1021/ja00444a033https://doi.org/10.1021/ja00444a033research-articleACS PublicationsRequest reuse permissionsArticle Views56Altmetric-Citations19LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Appendix to the report by R. Thiebe et al. Characteristics of the immunoglobulin Vκ genes, pseudogenes, relics and orphons in the mouse genome (1999)

No abstracts
MEGA2: molecular evolutionary genetics analysis software (2001)

s.kumar@asu.edu
Learning visual landmarks for pose estimation (2003)

We present an approach to vision-based mobile robot localization, even without an a-priori pose estimate. This is accomplished by learning a set of visual features called image-domain landmarks. The landmark learning mechanism is designed to be applicable to a wide range of environments. Each landmark is detected as a focal extremum of a measure of uniqueness and represented by an appearance-based encoding. Localization is performed using a method that matches observed landmarks to learned prototypes and generates independent position estimates for each match. The independent estimates are then combined to obtain a final position estimate, with an associated uncertainty. Quantitative experimental evidence is presented that demonstrates that accurate pose estimates can be obtained, despite changes to the environment.
Antiretroviral Drug Resistance Testing in Adult HIV‐1 Infection: 2008 Recommendations of an International AIDS Society–USA Panel (2008)

Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care to review recently published data and presentations at scientific conferences and to provide updated recommendations. Whenever possible, resistance testing is recommended at the time of HIV infection diagnosis as part of the initial comprehensive patient assessment, as well as in all cases of virologic failure. Tropism testing is recommended whenever the use of chemokine receptor 5 antagonists is contemplated. As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non-subtype B strains of HIV will become increasingly important.
The protein tyrosine kinase inhibitor herbimycin A, but not genistein, specifically inhibits signal transduction by the T cell antigen receptor (1992)

Several lines of evidence implicate a regulatory tyrosine phosphorylation in the activation of phospholipase C (PLC) by the T cell antigen receptor (TCR). These include studies using inhibitors of protein tyrosine kinases (PTKs). In Jurkat T cells expressing the heterologous human muscarinic receptor (HM1), PLC activity can be induced by either the TCR or HM1. HM1 activates PLC via a guanine nucleotide binding protein. We have studied the selectivity of the effects of the PTK inhibitors, herbimycin A and genistein, in this system. The results indicate that these inhibitors have different mechanisms of action, and suggest that herbimycin A, but not genistein, is a specific inhibitor of PTKs in T cells. Herbimycin A markedly inhibited both the resting and induced levels of phosphotyrosine-containing proteins, including the gamma 1 isozyme of PLC and the zeta chain of the TCR, and prevented activation of PLC by anti-TCR mAb. Herbimycin A did not inhibit activation of PLC by HM1. Genistein had a much less pronounced effect than herbimycin A on the appearance of tyrosine phosphoproteins. Moreover, genistein inhibited activation of PLC by both the TCR and HM1, and inhibition was only partial. Genistein was cytotoxic and markedly inhibited protein synthesis in both Jurkat cells and human peripheral lymphocytes. Herbimycin A was not cytotoxic. These findings confirm the role of a regulatory tyrosine phosphorylation in activation of PLC by the TCR. Herbimycin A was a selective inhibitor of a subclass of PTKs in Jurkat cells. In contrast, inhibition of signal transduction and later events in T cells by genistein may be due to effects other than direct inhibition of PTK activity.
Structure and function in rhodopsin: A tetracycline-inducible system in stable mammalian cell lines for high-level expression of opsin mutants (2002)

Tetracycline-inducible HEK293S stable cell lines have been prepared that express high levels (up to 10 mg/liter) of WT opsin and its mutants only in response to the addition of tetracycline and sodium butyrate. The cell lines were prepared by stable transfection of HEK293S-TetR cells with expression plasmids that contained the opsin gene downstream of a cytomegalovirus promoter containing tetO sequences as well as the neomycin resistance gene under control of the weak H(2)L(d) promoter. The inducible system is particularly suited for overcoming problems with toxicity either due to the addition of toxic compounds, for example, tunicamycin, to the growth medium or due to the expressed protein products. By optimization of cell growth conditions in a bioreactor, WT opsin, a constitutively active opsin mutant, E113Q/E134Q/M257Y, presumed to be toxic to the cells, and nonglycosylated WT opsin obtained by growth in the presence of tunicamycin have been prepared in amounts of several milligrams per liter of culture medium.
Outcomes of subatmospheric pressure dressing therapy on wounds of the diabetic foot. (2002)

The purpose of this retrospective study was to evaluate outcomes of people with large diabetic foot wounds treated with subatmospheric pressure dressing therapy immediately following surgical wound debridement. Data were abstracted from the medical records of 31 consecutive patients with diabetes, 77.4% male (n = 24), aged 56.1 +/- 11.7 years, presenting for care at two large multidisciplinary wound care centers. All patients received surgical debridement for indolent diabetic foot wounds and were subsequently started on a regimen of subatmospheric pressure dressing therapy delivered using a vacuum-assisted closure device for a mean of 4.7 +/- 4.2 weeks (mode = 2 weeks) using a protocol that called for cessation of therapy when the wound bed approached 100% coverage with granulation tissue with no exposed tendon, joint capsule, or bone. Outcomes evaluated included time to complete wound closure, proportion of patients achieving wound healing at the level of initial debridement, and complications associated with use of the device. The mean duration of wounds before therapy was 25.4 +/- 23.8 weeks. In patients treated with subatmospheric pressure dressing therapy, 90.3% (n = 28) of wounds healed at the level of debridement without the need for further bony resection in a mean 8.1 +/- 5.5 weeks. The remaining 9.7% (n = 3) went on to higher level amputation (below knee amputation = 3.2%, [n = 1] and transmetatarsal amputation = 6.5% [n = 2]). Complications included periwound maceration (19.4% [n = 6]), periwound cellulitis (3.2% [n = 1]), and deep space infection (3.2% [n = 1]). The authors concluded that appropriate use of subatmospheric pressure dressing therapy to achieve a rapid granular bed in diabetic foot wounds may have promise in treatment of this population at high risk for amputation and that a large, randomized trial is now indicated.
Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans. (1993)

The lin-12 gene of Caenorhabditis elegans is thought to encode a receptor which mediates cell-cell interactions required to specify certain cell fates. Reversion of the egg-laying defective phenotype caused by a hypomorphic lin-12 allele identified rare extragenic suppressor mutations in five genes, sel-1, sel-9, sel-10, sel-11 and sel(ar40) (sel = suppressor and/or enhancer of lin-12). Mutations in each of these sel genes suppress defects associated with reduced lin-12 activity, and enhance at least one defect associated with elevated lin-12 activity. None of the sel mutations cause any obvious phenotype in a wild-type background. Gene dosage experiments suggest that sel-1 and sel(ar40) mutations are reduction-of-function mutations, while sel-9 and sel-11 mutations are gain-of-function mutations. sel-1, sel-9, sel-11 and sel(ar40) mutations do not suppress amorphic lin-12 alleles, while sel-10 mutations are able to bypass partially the requirement for lin-12 activity in at least one cell fate decision. sel-1, sel-9, sel-10, sel-11 and sel(ar40) mutations are also able to suppress the maternal-effect lethality caused by a partial loss-of-function allele of glp-1, a gene that is both structurally and functionally related to lin-12. These sel genes may therefore function in both lin-12 and glp-1 mediated cell fate decisions.