gebhart/patrepeval huggingface dataset:
Inactivation of the Human Papillomavirus E6 or E7 Gene in Cervical Carcinoma Cells by Using a Bacterial CRISPR/Cas RNA-Guided Endonuclease (2014)

High-risk human papillomaviruses (HPVs), including HPV-16 and HPV-18, are the causative agents of cervical carcinomas and are linked to several other tumors of the anogenital and oropharyngeal regions. The majority of HPV-induced tumors contain integrated copies of the normally episomal HPV genome that invariably retain intact forms of the two HPV oncogenes E6 and E7. E6 induces degradation of the cellular tumor suppressor p53, while E7 destabilizes the retinoblastoma (Rb) protein. Previous work has shown that loss of E6 function in cervical cancer cells induces p53 expression as well as downstream effectors that induce apoptosis and cell cycle arrest. Similarly, loss of E7 allows increased Rb expression, leading to cell cycle arrest and senescence. Here, we demonstrate that expression of a bacterial Cas9 RNA-guided endonuclease, together with single guide RNAs (sgRNAs) specific for E6 or E7, is able to induce cleavage of the HPV genome, resulting in the introduction of inactivating deletion and insertion mutations into the E6 or E7 gene. This results in the induction of p53 or Rb, leading to cell cycle arrest and eventual cell death. Both HPV-16- and HPV-18-transformed cells were found to be responsive to targeted HPV genome-specific DNA cleavage. These data provide a proof of principle for the idea that vector-delivered Cas9/sgRNA combinations could represent effective treatment modalities for HPV-induced cancers. Importance: Human papillomaviruses (HPVs) are the causative agents of almost all cervical carcinomas and many other tumors, including many head and neck cancers. In these cancer cells, the HPV DNA genome is integrated into the cellular genome, where it expresses high levels of two viral oncogenes, called E6 and E7, that are required for cancer cell growth and viability. Here, we demonstrate that the recently described bacterial CRISPR/Cas RNA-guided endonuclease can be reprogrammed to target and destroy the E6 or E7 gene in cervical carcinoma cells transformed by HPV, resulting in cell cycle arrest, leading to cancer cell death. We propose that viral vectors designed to deliver E6- and/or E7-specific CRISPR/Cas to tumor cells could represent a novel and highly effective tool to treat and eliminate HPV-induced cancers.
溶接後熱処理及び切欠き靭性が溶接継手及び516鋼の焼ならし母材特性に及ぼす影響 第1部 ASTM A516鋼の焼ならし母材特性に及ぼすPWHTの影響 (2003)

A 22-year-old man was admitted with complaints of dyspnea and hoarseness. Laryngoscopy and computed tomography of the neck revealed a 1.5 x 2-cm solid mass obstructing the trachea. The black, pedunculated mass was completely removed through a tracheal incision, and a paratracheal lymph node dissection was performed. Histopathologic examination revealed nodular-type mucosal malignant melanoma. Cranial and thoracic computed tomography, abdominal ultrasonography, and histopathologic examination of the paratracheal lymph nodes showed no metastases. No recurrence has been noted in more than 3 years of follow-up.
Down‐regulation of DR12, an auxin‐response‐factor homolog, in the tomato results in a pleiotropic phenotype including dark green and blotchy ripening fruit (2002)

Following differential screening of gene expression during tomato fruit development, we isolated developmentally regulated (DR) clones, including several putative transcription factors. Based on sequence homology, DR1, DR3, DR4 and DR8 are members of the Aux/IAA family, and DR12 belongs to the auxin response factor (ARF) family of transcription factors. Importantly, mRNA accumulation for the Aux/IAA-like genes was regulated by ethylene in tomato fruit but not in the leaves, indicating that these putative auxin response components also participate to the ethylene-dependent regulation of gene expression in a tissue-specific manner. The functional significance of DR12, the ARF-like gene, was investigated by cellular biology and reverse genetics approaches. Heterologous protein targeting studies, carried out using a DR12-GFP gene fusion construct, revealed specific nuclear localization of the DR12-encoded protein, in accordance with its putative function as a transcriptional regulator. Transgenic plants over- and under-expressing DR12 were generated in order to explore the physiological role of the gene. Both antisense and sense co-suppressed DR12-inhibited lines displayed a pleiotropic phenotype that included dark-green immature fruit, unusual cell division in the fruit pericarp, blotchy ripening, enhanced fruit firmness, upward curling leaves and increased hypocotyl and cotyledon growth. While a perturbation of the response to auxin may explain some of the phenotypes, surprisingly, the expression of members of four classes of early auxin-regulated genes was unaffected in the DR12-inhibited plants. The involvement of this ARF-like encoded protein in mediating the auxin response is discussed along with the possibility that it might affect responsiveness to other phytohormones in the tomato.
Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. (2003)

One theory of immune regulation involves homeostasis between T-helper 1 (Th1) and T-helper 2 (Th2) activity. The Th1/Th2 hypothesis arose from 1986 research suggesting mouse T-helper cells expressed differing cytokine patterns. This hypothesis was adapted to human immunity, with Th1- and Th2-helper cells directing different immune response pathways. Th1 cells drive the type-1 pathway ("cellular immunity") to fight viruses and other intracellular pathogens, eliminate cancerous cells, and stimulate delayed-type hypersensitivity (DTH) skin reactions. Th2 cells drive the type-2 pathway ("humoral immunity") and up-regulate antibody production to fight extracellular organisms; type 2 dominance is credited with tolerance of xenografts and of the fetus during pregnancy. Overactivation of either pattern can cause disease, and either pathway can down-regulate the other. But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive pro-Th1 or -Th2 patterns. The non-helper regulatory T cells, or the antigen-presenting cells (APC), likely influence immunity in a manner comparable to Th1 and Th2 cells. Many diseases previously classified as Th1 or Th2 dominant fail to meet the set criteria. Experimentally, Th1 polarization is readily transformed to Th2 dominance through depletion of intracellular glutathione, and vice versa. Mercury depletes glutathione and polarizes toward Th2 dominance. Several nutrients and hormones measurably influence Th1/Th2 balance, including plant sterols/sterolins, melatonin, probiotics, progesterone, and the minerals selenium and zinc. The long-chain omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) significantly benefit diverse inflammatory and autoimmune conditions without any specific Th1/Th2 effect. Th1/Th2-based immunotherapies, e.g., T-cell receptor (TCR) peptides and interleukin-4 (IL-4) injections, have produced mixed results to date.
Nucleoside Phosphonates. Development of Synthetic Methods and Reagents (1996)

Abstract In this paper a short account of our recent research concerning development of new synthetic methods and new reagents for the preparation of DNA and RNA fragments and their analogues is given. #Dedicated to Professor Yoshihisa Mizuno on the occasion of his 75th birthday. ¶Present address: Astra Production Chemicals, S-151 85 Södertälje, Sweden. Notes #Dedicated to Professor Yoshihisa Mizuno on the occasion of his 75th birthday. ¶Present address: Astra Production Chemicals, S-151 85 Södertälje, Sweden.
The prediction of human exons by oligonucleotide composition and discriminant analysis of spliceable open reading frames. (1994)

Discriminant analysis is applied to the problem of recognition 5'-, internal and 3'-exons in human DNA sequences. Specific recognition functions were developed for revealing exons of particular types. The method based on a splice site prediction algorithm that uses the linear Fisher discriminant to combine the information about significant triplet frequencies of various functional parts of splice site regions and preferences of oligonucleotides in protein coding and intron regions (Solovyev, Lawrence, 1994). The accuracy of our splice site recognition function is about 97%. A discriminant function for 5'-exon prediction includes hexanucleotide composition of upstream region, triplet composition around the ATG codon, ORF coding potential, donor splice site potential and composition of downstream intron region. For internal exon prediction, we combine in a discriminant function the characteristics describing the 5'-intron region, donor splice site, coding region, acceptor splice site and 3'-intron region for each open reading frame flanked by GT and AG base pairs. The accuracy of precise internal exon recognition on a test set of 451 exon and 246693 pseudoexon sequences is 77% with a specificity of 79% and a level of pseudoexon ORF prediction of 99.96%. The recognition quality computed at the level of individual nucleotides is 89% for exon sequences and 98% for intron sequences. A discriminant function for 3'-exon prediction includes octanucleotide composition of upstream intron region, triplet composition around the stop codon, ORF coding potential, acceptor splice site potential and hexanucleotide composition of downstream region.(ABSTRACT TRUNCATED AT 250 WORDS)
Quality of life in adults with congenital adrenal hyperplasia relates to glucocorticoid treatment, adiposity and insulin resistance: United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) (2013)

Increased adiposity, insulin resistance and use of prednisolone or dexamethasone are associated with impaired QoL in adults with CAH. Intervention trials are required to establish whether choice of glucocorticoid treatment and/or weight loss can improve QoL in CAH adults.
Microfluidic polymer multilayer adsorption on liquid crystal droplets for microcapsule synthesis (2008)

Exploiting microfluidic principles, the potential for chip-based multilayer assembly for the synthesis of polymer microcapsules was investigated. We demonstrate that continuous flow microfluidic multilayer synthesis is a fast, efficient, automated alternative to conventional batch synthesis. In this work, we dispersed liquid crystal (LC) molecules (organic phase) as monodisperse droplets in an aqueous continuous phase containing the primary polymer and a suitable surfactant. The primary polymer was coadsorbed with the surfactant at the organic/aqueous interface, stabilizing the LC droplets against coalescence and providing a template for subsequent polymer adsorption. As the droplet templates are transported through the microfluidic channel, the polymer-containing aqueous continuous phase is selectively withdrawn and replaced with rinse solution, and then with an alternative polymer solution. This selective withdrawal and infusion cycle was repeated to assemble polymer multilayers onto the emulsion droplets. The process was followed using fluorescence microscopy of the fluorescently-labelled polymers at the LC interface and of the flowing polymer solutions during the sequential rinse stages. Cross-linking of the multilayers and removal of the dispersed LC phase resulted in polymer capsules retaining the high monodispersity of the droplet templates. This microfluidic approach significantly reduces the multilayer formation time (to <2 min for 3-layer capsules) of well-defined capsules that are envisaged to have benefits in biomedical applications, including drug delivery and encapsulated biochemical reactions.
Disorders of the Mitochondria (1998)

Recent advances in our understanding of the structure and function of mitochondria have led to the recognition that inherited and acquired mitochondrial dysfunction may be responsible for diseases affecting the liver and other organ systems. Mitochondrial health may also determine hepatocyte survival in other hepatic disorders not directly related to the mitochondrion. Primary mitochondrial hepatopathies are conditions in which there are inherited defects in structure or function of the mitochondria, most of which involve the respiratory chain and oxidative phosphorylation, fatty acid oxidation, the urea cycle, and other pathways confined to mitochondria. Maternally inherited mutations or deletions of the mitochondrial genome, or putative nuclear gene mutations encoding electron transport proteins, cause defective electron transport, oxidative stress, impaired oxidative phosphorylation, and other metabolic derangements that lead to hepatic failure or chronic liver dysfunction in affected children. The mitochondrial DNA (mtDNA) depletion syndrome, which similarly leads to liver failure and neurologic abnormalities, is caused by a putative nuclear gene that controls mtDNA replication or stability. Other proven or suspected primary mitochondrial hepatopathies include Pearson's marrow-pancreas syndrome, Alpers disease, mitochondrial neurogastrointestinal encephalomyopathy syndrome, and Navajo neuropathy. Secondary mitochondrial hepatopathies are conditions in which the mitochondria are major targets during liver injury from another cause, such as metal overload, certain drugs and toxins, alcoholic liver injury, and conditions of oxidant stress. Diagnosis of mitochondrial dysfunction may be difficult with currently available tools, however, elevated blood lactate: pyruvate ratios or arterial ketone body ratios with characteristic liver histology are initial tests. Measuring respiratory chain enzyme activities, mtDNA levels, and searching for mtDNA mutations and deletions are more specific tests. Treatment of these disorders is currently empirical, involving agents that may improve the redox status of mitochondria, promote electron flow, or act as mitochondrial antioxidants. Liver transplantation has occasionally been successful in patients who lack other systemic involvement.
Clearance of lipoprotein remnant particles in adipose tissue and muscle in humans (1997)

A major proportion of triglycerides in plasma triglyceride-rich lipoproteins (TRL) are removed in peripheral tissues by lipoprotein lipase, and hypothetically a minor proportion can also be removed by whole-lipoprotein particle uptake. This second removal pathway has not previously been directly demonstrated in humans. Simultaneous blood samples were drawn from arterialized blood, a vein draining the subcutaneous abdominal adipose tissue, and a deep antecubital vein of the forearm to provide arterio-venous gradients from blood-draining adipose tissue and muscle in seven male subjects. The men were given a fat-rich mixed meal containing vitamin A and the triglyceride and retinyl palmitate (RP) concentrations were quantified in the plasma. Density gradient ultracentrifugation was used to isolate TRL fractions, in which triglycerides, RP, apoB-48, and apoB-100 were quantified. There was clearance of triglycerides in muscle and adipose tissue and, in addition, removal of RP. By analysis of the TRL subfractions, the RP removal was likely to be confined to the largest chylomicron remnant particles. For the Sf > 400 fraction, the area under curve (AUC) relative to arterial for triglycerides were 79% (66-91%) and 81% (72-89%) in adipose tissue and muscle venous outflow, respectively (each P < 0.02 versus arterial). The corresponding values for RP were 87% (73-101%) and 85% (69-100%), respectively, (each P < 0.05 versus arterial). In the Sf 60-400 fraction there was further uptake of triglycerides, but not of RP. We hypothesize that the periphery could be of importance for removal of the largest chylomicron remnants, as their size might partially exclude them penetrating the fenestrated hepatic sinusoidal endothelium to reach the hepatic chylomicron remnant receptors.
Effect of local DNA sequence on topoisomerase I cleavage in the presence or absence of camptothecin. (1991)

In order to investigate the mechanism of topoisomerase I inhibition by camptothecin, we studied the induction of DNA cleavage by purified mammalian DNA topoisomerase I in a series of oligonucleotides and analyzed the DNA sequence locations of preferred cleavage sites in the SV40 genome. The oligonucleotides were derived from the sequence of the major camptothecin-induced cleavage site in SV40 DNA (Jaxel, C., Kohn, K. W., and Pommier, Y. (1988) Nucleic Acids Res. 16, 11157 to 11170) with the cleaved bond in their center. DNA length was critical since cleavage was detectable only in 30 and 20 base pair-(bp) oligonucleotides, but not in a 12-bp oligonucleotide. Cleavage was at the same position in the oligonucleotides as in SV40 DNA. Its intensity was greater in the 30- than in the 20-bp oligonucleotide, indicating that sequences more than 10 bp away from the cleavage site may influence intensity. Camptothecin-induced DNA cleavage required duplex DNA since none of the single-stranded oligonucleotides were cleaved. Analysis of base preferences around topoisomerase I cleavage sites in SV40 DNA indicated that camptothecin stabilized topoisomerase I preferentially at sites having a G immediately 3' to the cleaved bond. Experiments with 30-bp oligonucleotides showed that camptothecin produced most intense cleavage in a complementary duplex having a G immediately 3' to the cleavage site. Weaker cleavage was observed in a complementary duplex in which the 3'G was replaced with a T. The identity of the 3' base, however, did not affect topoisomerase I-induced DNA cleavage in the absence of drug. These results indicate that camptothecin traps preferentially a subset of the enzyme cleavage sites, those having a G immediately 3' to the cleaved bond. This strong preference suggests that camptothecin binds reversibly to the DNA at topoisomerase I cleavage sites, in analogy to a model previously proposed for inhibitors of topoisomerase II (Capranico, G., Kohn, K.W., and Pommier, Y. (1990) Nucleic Acids Res. 18, 6611-6619).
Effect of tunicamycin, an inhibitor of protein glycosylation, on the biological properties of acetylcholine receptor in cultured muscle cells. (1983)

We have studied the effect of tunicamycin (TM), an antibiotic which inhibits the glycosylation of nascent proteins, on the properties of the acetylcholine receptor (AChR) at the surface of embryonic chick skeletal muscle cells. The use of two separate assays, specific binding of 125I-alpha-bungarotoxin and carbamylcholine-activated 22Na+ uptake, has allowed us to monitor the effects of impaired glycosylation on the metabolic and functional properties of AChR. A significant decrease in the amounts of surface AChR elaborated in the presence of TM is detected by both measurements. This decrease has been found to reflect an enhanced proteolytic degradation of the underglycosylated AChR. The underglycosylated AChR, expressed on the cell surface in the presence of TM, retains the capability of mediating agonist-activated ionic permeability changes, but displays quantitatively altered interactions with receptor ligands. We conclude that the carbohydrate moiety on AChR may play a role in determining the folding of newly synthesized polypeptides to form a conformation compatible with the metabolic properties and ligand interactions characteristic of glycosylated AChR.
Integrating association rule mining with relational database systems (1998)

Data mining on large data warehouses is becoming increasingly important. In support of this trend, we consider a spectrum of architectural alternatives for coupling mining with database systems. These alternatives include: loose-coupling through a SQL cursor interface; encapsulation of a mining algorithm in a stored procedure; caching the data to a file system on-the-fly and mining; tight-coupling using primarily user-defined functions; and SQL implementations for processing in the DBMS. We comprehensively study the option of expressing the mining algorithm in the form of SQL queries using Association rule mining as a case in point. We consider four options in SQL-92 and six options in SQL enhanced with object-relational extensions (SQL-OR). Our evaluation of the different architectural alternatives shows that from a performance perspective, the Cache-Mine option is superior, although the performance of the SQL-OR option is within a factor of two. Both the Cache-Mine and the SQL-OR approaches incur a higher storage penalty than the loose-coupling approach which performance-wise is a factor of 3 to 4 worse than Cache-Mine. The SQL-92 implementations were too slow to qualify as a competitive option. We also compare these alternatives on the basis of qualitative factors like automatic parallelization, development ease, portability and inter-operability.
Tumor Suppressor Genes (1991)

For the past decade, cellular oncogenes have attracted the attention of biologists intent on understanding the molecular origins of cancer. As the present decade unfolds, oncogenes are yielding their place at center stage to a second group of actors, the tumor suppressor genes, which promise to teach us equally important lessons about the molecular mechanisms of cancer pathogenesis.
Cooperative Self-Assembly of Double-Strand Conjugated Porphyrin Ladders (1999)

A series of conjugated zinc porphyrin oligomers, from the dimer through to the hexamer, form stable ladder complexes with linear bidentate ligands such as 1,4-diazabicyclo[2.2.2]octane (DABCO) and 4,4‘-bipyridyl (Bipy). The 1H NMR spectra of these ladders confirm their structures and show how they fray and dissociate in the presence of excess ligand. The thermodynamics of these equilibria were elucidated by spectrophotometric titration, using multivariate global factor analysis, in two different solvents (chloroform and toluene). Ladder formation and dissociation exhibit many indications of positive cooperativity, including all-or-nothing two-state assembly, sigmoidal isotherms, large Hill coefficients, and narcissistic self-sorting. Ladder formation increases the planarity and conjugation, resulting in a reduction in the gap between the highest occupied and lowest unoccupied molecular orbitals.
Novel general approach for the assay and inhibition of hydrolytic enzymes utilizing suicide-inhibitory bifunctionally linked substrates (SIBLINKS): exemplified by a phospholipase A2 assay (1990)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNovel general approach for the assay and inhibition of hydrolytic enzymes utilizing suicide-inhibitory bifunctionally linked substrates (SIBLINKS): exemplified by a phospholipase A2 assayWilliam N. Washburn and Edward A. DennisCite this: J. Am. Chem. Soc. 1990, 112, 5, 2040–2041Publication Date (Print):February 1, 1990Publication History Published online1 May 2002Published inissue 1 February 1990https://pubs.acs.org/doi/10.1021/ja00161a082https://doi.org/10.1021/ja00161a082research-articleACS PublicationsRequest reuse permissionsArticle Views181Altmetric-Citations21LEARN 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