gebhart/patrepeval huggingface dataset:
Irreversible Protein Kinase Inhibitors (2011)

Targeting cancer with small molecule irreversible inhibitors of kinases represents an emerging challenge in drug discovery. Irreversible inhibitors bind to kinase active site in a covalent and irreversible form, most frequently by reacting with a nucleophilic cysteine residue, located near the ATP binding pocket. The most common mechanism is the Michael reaction, that refers to the addition of a nucleophile, such as cysteine, to an α,β unsaturated carbonyl. The nucleophile reacts at the electrophilic β-position to form an adduct; as a result the inhibitor irreversibly blocks binding of ATP to the kinase, rendering the kinase inactive. Different cysteine-reactive groups have been evaluated, an acrylamide or a substituted acrylamide moiety are the Michael acceptors of choice. There are some advantages for the irreversible kinase inhibition. These compounds are highly selective because they target a specific cysteine and only a limited number of kinases has a cysteine at the corresponding position. Another advantage is that covalent bond formation can overcome competition with the high endogenous concentration of ATP. A further motivation for designing irreversible inhibitors is their longer duration of action respect to conventional inhibitors. In fact, once bound to enzyme, these compounds do not readily dissociate and the inhibition continues even after the inhibitor leaves the circulation. Moreover, these inhibitors have the potential to overcome and prevent the emergence of acquired resistance conferred by mutations. In this review examples of irreversible inhibitors are reported, focusing on chemical structures, SAR and biological activities. The great potential of these compounds could open new and promising perspectives for a broader application of this approach.
NEFL mRNA Expression Level Is a Prognostic Factor for Early-Stage Breast Cancer Patients (2012)

Neurofilament, light polypeptide (NEFL) was demonstrated to be ectopically expressed in breast cancer tissues and decreased in lymph node metastases compared to the paired primary breast cancers in our previous study. Moreover, in several studies, NEFL was regarded as a tumor suppressor gene, and its loss of heterozygosity (LOH) was related to carcinogenesis and metastasis in several types of cancer. To explore the role of NEFL in the progression of breast cancer and to evaluate its clinical significance, we detected the NEFL mRNA level in normal breast tissues, primary breast cancer samples and lymph node metastases, and then analyzed the association between the NEFL expression level and several clinicopathological parameters and disease-free survival (DFS). NEFL mRNA was found to be expressed in 92.3% of breast malignancies and down-regulated in lymph node metastases compared to the paired primary tumors. NEFL mRNA level was lower in primary breast cancers with positive lymph nodes than in cancers with negative lymph nodes. Moreover, a low expression level of NEFL mRNA indicated a poor five-year DFS for early-stage breast cancer patients. Thus, NEFL mRNA is ectopically expressed in breast malignancies and could be a potential prognostic factor for early-stage breast cancer patients.
Learning in High-Tech and Multimedia Environments (2006)

When do high-tech environments promote learning? The goal of this article is to offer one answer to this question by examining the classic distinction between media and method, in terms of their roles in promoting learning with technology. To this end, I first propose a cognitive theory of learning with media, from which a set of instructional design principles are derived. Then I review research in which the relative learning contributions of method and media are investigated, and I offer final reflections for future research.
Nuclear ribosomal internal transcribed spacer phylogeny and host diversity in the coelomycete Phomopsis (1994)

Species concepts in Phomopsis are based primarily on host association because morphological and cultural characters are generally insufficient for species diagnosis. Increasingly, there are reports that some species of Phomopsis are not host restricted but are capable of infecting several or more taxonomically unrelated host genera. Phylogenetic analysis of nuclear ribosomal DNA internal transcribed spacer sequences (ITS1 and ITS2) for 43 North American and Caribbean strains of Phomopsis isolated from diverse plant hosts and geographic origins resolved three clades, provisionally termed groups A, B, and C. Group A consists of isolates from shrubs and trees originating primarily from eastern North America. Group B includes isolates from woody and herbaceous plants that originate from tropical to subtropical regions and produce paraphyses among their conidiogenous cells. Group C occurs primarily on herbaceous plant hosts, including agricultural field crops, and is widely distributed throughout temperate to subtropical North America. Isolates from Europe and Asia may be significantly different in ITS sequences compared with North American isolates. The diversity of host taxa associated with terminal clades in the ITS phylogeny suggests that either Phomopsis species infect more than one host or host switching occurs frequently during speciation. Key words: Ascomycotina, coelomycetes, Diaporthe, ITS, molecular phylogeny, Phomopsis.
NMR-Based Discovery of Lead Inhibitors That Block DNA Binding of the Human Papillomavirus E2 Protein (1997)

The E2 protein is required for the replication of human papillomaviruses (HPVs), which are responsible for anogenital warts and cervical carcinomas. Using an NMR-based screen, we tested compounds for binding to the DNA-binding domain of the HPV-E2 protein. Three classes of compounds were identified which bound to two distinct sites on the protein. Biphenyl and biphenyl ether compounds containing a carboxylic acid bind to a site near the DNA recognition helix and inhibit the binding of E2 to DNA. Benzophenone-containing compounds which lack a carboxylic acid group bind to the beta-barrel formed by the dimer interface and exhibit negligible effects on the binding of E2 to DNA. Structure-activity relationships from the biphenyl and biphenyl ether compounds were combined to produce a compound [5-(3'-(3",5"-dichlorophenoxy)-phenyl)-2,4-pentadienoic acid] with an IC50 value of approximately 10 microM. This compound represents a useful lead for the development of antiviral agents that interfere with HPV replication and further illustrates the usefulness of the SAR by NMR method in the drug discovery process.
E‐cadherin as a tumor (invasion) suppressor gene (1995)

Diffuse-type gastric carcinomas show diminished cell-cell adhesion. A recent paper reports that 50% of these carcinomas contain mutations in the E-cadherin gene, resulting in the destruction of the calcium-binding sites of E-cadherin, and providing strong in vivo evidence that alterations in E-cadherin play a major role in the development of this particular type of cancer and the short survival of the patients.
Lineage specific treatment of adult patients with acute lymphoblastic leukemia in first remission with anti‐B4‐blocked ricin or high‐dose cytarabine (2003)

Intensification therapy with anti-B4-blocked ricin is feasible for patients with CD19 positive ALL, although there is little evidence of an additional clinical benefit from the anti-B4-blocked ricin. Cancer 2003;97:1471-80.
Functional Analysis of Isoforms of NADPH:Protochlorophyllide Oxidoreductase (POR), PORB and PORC, in Arabidopsis thaliana (2003)

NADPH:protochlorophyllide oxidoreductase (POR) catalyzes the light-dependent reduction of protochlorophyllide. To elucidate the physiological function of three differentially regulated POR isoforms (PORA, PORB and PORC) in Arabidopsis thaliana, we isolated T-DNA tagged null mutants of porB and porC. The mature seedlings of the mutants had normal photosynthetic competencies, showing that PORB and PORC are interchangeable and functionally redundant in developed plants. In etiolated seedlings, only porB showed a reduction in the photoactive protochlorophyllide and the size of prolamellar bodies (PLBs), indicating that PORB, as well as PORA, functioned in PLB assembly and photoactive protochlorophyllide formation in etiolated seedlings. When illuminated, the etiolated porB seedling was able to green to a similar extent as the wild type, whereas the greening was significantly reduced under low light conditions. During greening, high light irradiation increased the level of PORC protein, and the greening of porC was repressed under high light conditions. The porB, but not porC, etiolated seedling was more sensitive to the far-red block of greening than the wild type, which is caused by depletion of endogenous POR proteins resulting in photo-oxidative damage. These results suggest that, at the onset of greening, PLBs are important for efficient capture of light energy for photoconversion under various light conditions, and PORC, which is induced by high light irradiation, contributes to photoprotection during greening of the etiolated seedlings.
Zur Kenntnis des Dicyandiamids (1908)

Das aus Cyanamid durch Polymerisation leicht hervorgehende Dicyandiamid ist mehrfach Gegenstand eingehender Entersuchungen
A General Synthesis of Pyrroles and Fused Pyrrole Systems from Ketones and Amino Acids (1996)

The lithium enolates of ketones react with BOC-α-amino aldehydes and BOC-α-amino ketones to afford aldol intermediates that cyclize under acidic conditions to yield pyrroles. The BOC-amino aldehydes and ketones are readily available from α-amino acids. The method allows incorporation of a wide variety of substituents at any of the five atoms of the pyrrole ring and is also suitable for the preparation of fused pyrrole systems.
Hepoxilin A3 induces changes in cytosolic calcium, intracellular pH and membrane potential in human neutrophils (1990)

The effects of hepoxilin A3 (HxA3), a 12-lipoxygenase metabolite of arachidonic acid, on cytosolic calcium ([Ca2+]i), intracellular pH (pHi), transmembrane potential and right-angle light scattering in human neutrophils were investigated. A rapid, transient elevation of [Ca2+]i was observed with HxA3 which was dependent on the concentration used. The effect of HxA3 on [Ca2+]i was blocked by pertussis toxin, suggesting involvement of receptors coupled to GTP-binding proteins. Experiments in Ca2(+)-free medium and using intracellular Ca2+ chelators indicated that HxA3 mobilized Ca2+ from intracellular stores. At similar concentrations, HxA3 altered pHi, producing an initial acidification followed by an alkalinization. The initial acidification was decreased in cells loaded with a Ca2+ chelator. In the presence of N-ethyl-N-(1-methylethyl)amino amiloride, an inhibitor of the Na+/H+ antiport, HxA3 induced a greater acidification but failed to elicit the recovery phase, suggesting that the latter is due to activation of the antiport. HxA3 also depolarized the membrane potential, although this effect was small. A decrease in right-angle light scattering, qualitatively similar to that observed with chemotactic peptides, was seen with HxA3, indicating that the 12-lipoxygenase metabolite can induce shape changes in neutrophils. At the concentrations used for the above effects, HxA3 was unable to generate a respiratory burst. These findings suggest that hepoxilins, which are formed by stimulated neutrophils, may have a role as messengers in neutrophil activation.
Implementation of ternary phase amplitude filters using a magnetooptic spatial light modulator (1989)

Ternary modulation can be achieved with a single SLM and improvedc orrelationd iscriminationc an bee xperimentally realized.
Tissue distribution, immunoreactivity, and physical properties of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. (1986)

6-Phosphofructo-2-kinase (EC 2.7.1.105) and fructose-2,6-bisphosphatase (EC 3.1.3.46) activities were determined in various rat tissues, the latter by using a method based on the formation of a phosphorylated enzyme intermediate during the course of catalysis. Both activities from liver, skeletal muscle, lung, kidney, and testis copurified during polyethylene glycol fractionation, anion-exchange and blue Sepharose chromatography, and gel filtration. The Stokes radius of these enzymes and of the liver bifunctional enzyme was 45 A. Extrahepatic tissues had only 10% or less of the kinase activity found in liver. The results indicate that a liver-type bifunctional enzyme is present in most extrahepatic tissues but that it is minimally expressed. However, the ratio of kinase to bisphosphatase activity in most extrahepatic tissues was 4- to 6-fold higher than in liver, whereas heart 6-phosphofructo-2-kinase had no associated bisphosphatase activity, although its Stokes radius was also 45 A. The heart enzyme was not precipitated by an antiserum to the liver enzyme, whereas only a fraction of the kidney and testis activities was precipitated by this antiserum. The data support the existence of a distinct form of extrahepatic 6-phosphofructo-2-kinase, most readily demonstrated in heart, which may not be bifunctional.
Acyclic diastereoselective synthesis using tartrate ester-modified crotylboronates. Double asymmetric reactions with .alpha.-methyl chiral aldehydes and synthesis of the C(19)-C(29) segment of rifamycin S (1990)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAcyclic diastereoselective synthesis using tartrate ester-modified crotylboronates. Double asymmetric reactions with .alpha.-methyl chiral aldehydes and synthesis of the C(19)-C(29) segment of rifamycin SWilliam R. Roush, Alan D. Palkowitz, and Kaori AndoCite this: J. Am. Chem. Soc. 1990, 112, 17, 6348–6359Publication Date (Print):August 1, 1990Publication History Published online1 May 2002Published inissue 1 August 1990https://pubs.acs.org/doi/10.1021/ja00173a024https://doi.org/10.1021/ja00173a024research-articleACS PublicationsRequest reuse permissionsArticle Views2803Altmetric-Citations257LEARN 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
Phylogenetic Study of Hypoxylon and Related Genera Based on Ribosomal ITS Sequences (2000)

Hypoxylon, with at least 130 currently accepted species and varieties, is one of the largest genera of the Xylariaceae. Taxonomic aspects that define and delimit the genus have varied among mycologists. To obtain insight in the phylogenetic relationships of Hypoxylon and its allies, the complete DNA sequences of the internal transcribed spacer region (including the 5.8S rRNA gene) from 41 isolates were determined, aligned and processed for phylogenetic reconstruction, and critically compared with the available taxonomic information. The results generally agree with the current concepts and limits established for the genus. The molecular approach supported the recent segregation of some allied genera (Biscogniauxia, Camillea, Whalleya, Creosphaeria, Nemania, and Kretzschmaria) from Hypoxylon. The species and varieties of Hypoxylon in the sense of modern authors appeared as a monophyletic group within the Xylariaceae. However, the recent infrageneric division of Hypoxylon into sections Hypoxylon and Annulata was not supported by this limited molecular phylogenetic analysis. Likewise, this preliminary analysis did not reflect generic distinctions among species in genera with bipartite stromata (Camillea and Biscogniauxia). The importance of the anamorphs in the classification of this fungal group was evidenced by the correlation between the type of anamorph and the relative placement of the teleomorphs in the phylogenetic tree derived from sequence analysis.
Synthetic fuel production in prewar and world war II Japan: A case study in technological failure (1993)

Summary Japan is a country largely lacking supplies of many essential natural resources including petroleum, coal, and iron ore. As her industrial base and economy expanded during the 1920s and 1930s, Japan's dependence on imports of these resources became increasingly evident. The onset of the Depression in the 1930s further threatened Japan's lifeline, and, in an effort to become economically independent and self-sufficient in natural resources (autarky), Japan's militaristic government pursued a policy of territorial expansion. Beginning in 1937, Japan's military forces swept out of Manchuria into China and then into Southeast Asia in search of strategic materials such as petroleum, coal, copper, zinc, and rubber. To achieve independence in petroleum, the Japanese developed a dual approach: they would acquire natural petroleum sources in Southeast Asia and at the same time establish a synthetic fuel industry for the conversion of coal to oil. Actually, the Japanese had begun research on synthetic fuel in the 1920s, only a few years after other countries, such as Germany and Britain, that lacked sources of natural petroleum. They did excellent laboratory research on the coal hydrogenation and Fischer-Tropsch conversion processes, but in their haste to construct large synthetic fuel plants they bypassed the intermediated pilot-plant stage and failed to make a successful transition from small- to large-scale production. Unable to synthesize liquid fuels from coal, they instead derived significant quantities from the technologically simpler coal carbonization and shale oil distillation processes. In the last year of World War II, the Japanese attempted to revive their synthetic fuel industry and entered into an agreement with IG Farben for technical assistance. Germany's defeat ended this final effort. The Japanese synthetic fuel industry presents a good case study of technological failure. It shows that high-quality basic scientific research does not necessarily translate into large-scale technological success.
Thrombopoietin, kit Ligand, and flk2/flt3 Ligand Together Induce Increased Numbers of Primitive Hematopoietic Progenitors From Human CD34+Thy-1+Lin− Cells With Preserved Ability to Engraft SCID-hu Bone (1998)

CD34(+)Thy-1(+)Lin- cells are enriched for primitive hematopoietic progenitor cells (PHP), as defined by the cobblestone area-forming cell (CAFC) assay, and for bone marrow (BM) repopulating hematopoietic stem cells (HSC), as defined by the in vivo SCID-hu bone assay. We evaluated the effects of different cytokine combinations on BM-derived PKH26-labeled CD34(+)Thy-1(+)Lin- cells in 6-day stroma-free cultures. Nearly all (>95%) of the CD34(+)Thy-1(+)Lin- cells divided by day 6 when cultured in thrombopoietin (TPO), c-kit ligand (KL), and flk2/flt3 ligand (FL). The resulting CD34(hi) PKHlo (postdivision) cell population retained a high CAFC frequency, a mean 3.2-fold increase of CAFC numbers, as well as a capacity for in vivo marrow repopulation similar to freshly isolated CD34(+)Thy-1(+)Lin- cells. Initial cell division of the majority of cells occurred between day 2 and day 4, with minimal loss of CD34 and Thy-1 expression. In contrast, cultures containing interleukin-3 (IL-3), IL-6, and leukemia inhibitory factor contained a mean of 75% of undivided cells at day 6. These CD34(hi) PKHhi cells retained a high frequency of CAFC, whereas the small population of CD34(hi) PKHlo postdivision cells contained a decreased frequency of CAFC. These data suggest that use of a combination of TPO, KL, and FL for short-term culture of CD34(+)Thy-1(+)Lin- cells increases the number of postdivision PHP, measured as CAFC, while preserving the capacity for in vivo engraftment.
The p85 Regulatory Subunit Controls Sequential Activation of Phosphoinositide 3-Kinase by Tyr Kinases and Ras (2002)

Class IA phosphoinositide 3-kinase (PI3K) is a heterodimer composed of a p85 regulatory and a p110 catalytic subunit that regulates a variety of cell responses, including cell division and survival. PI3K is activated following Tyr kinase stimulation and by Ras. We found that the C-terminal region of p85, including the C-Src homology 2 (C-SH2) domain and part of the inter-SH2 region, protects the p110 catalytic subunit from Ras-induced activation. Although the p110 activity associated with a C-terminal p85 deletion mutant increased significantly in the presence of an active form of Ras, purified wild type p85-p110 was only slightly stimulated by active Ras. Nonetheless, incubation of purified p85-p110 with Tyr-phosphorylated peptides, which mimic the activated platelet-derived growth factor receptor, restored Ras-induced p85-p110 activation. In conclusion, p85 inhibits p110 activation by Ras; this blockage is released by Tyr kinase stimulation, showing that the classical mechanism of class IA PI3K stimulation mediated by Tyr kinases also regulates Ras-induced PI3K activation.
New simplified molecular design for functional T cell receptor (1993)

We have produced a chimeric single-chain T cell receptor (TcR) that combines the specific antibody recognition function and TcR/CD3 signaling properties within the same polypeptide chain. This hybrid molecule consisted of a single-chain antibody combining site that was connected over a short spacer to the transmembrane and cytoplasmic region of CD3 zeta. When expressed on TcR- or TcR+ T cell hybridomas it could mediate recognition of relevant target cells and subsequent production of lymphokines; i.e. it could functionally replace the TcR/CD3 complex. Therefore, the single-chain TcR model presented here represents an interesting and useful means for the creation of T cells with new specificities.
Amplified dihydrofolate reductase genes in unstably methotrexate-resistant cells are associated with double minute chromosomes. (1979)

Selection of mammalian cells in progressively increasing concentrations of methotrexate results in selective amplification of DNA sequences coding for dihydrofolate reductase (tetrahydrofolate dehydrogenase, 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3). In some cell variants the amplified genes are stable with growth in the absence of methotrexate, whereas in other variants the amplified genes are lost from the population. We have previously reported that in a stably amplified variant of Chinese hamster ovary cells, the genes are localized to a single chromosome. Herein we report that in mouse S-180 and L5178Y cell lines unstably amplified dihydrofolate reductase DNA sequences are associated with small, paired chromosomal elements denoted "double minute chromosomes," whereas in stably amplified cells of the same origin, the genes are associated with large chromosomes.