gebhart/patrepeval huggingface dataset:
The anticodon and discriminator base are major determinants of cysteine tRNA identity in vivo. (1992)

Mutants of the Escherichia coli initiator tRNA (tRNA(fMet)) have been used to examine the role of the anticodon and discriminator base in in vivo aminoacylation of tRNAs by cysteinyl-tRNA synthetase. Substitution of the methionine anticodon CAU with the cysteine anticodon GCA was found to allow initiation of protein synthesis by the mutant tRNA from a complementary initiation codon in a reporter protein. Sequencing of the protein revealed that cysteine comprised about half of the amino acid at the N terminus. An additional mutation, converting the discriminator base of tRNA(GCAfMet) from A73 to the base present in tRNA(Cys) (U73), resulted in a 6-fold increase in the amount of protein produced and insertion of greater than or equal to 90% cysteine in response to the complementary initiation codon. Substitution of C73 or G73 at the discriminator position led to insertion of little or no cysteine, indicating the importance of U73 for recognition of the tRNA by cysteinyl-tRNA synthetase. Single base changes in the anticodon of tRNA(GCAfMet) containing U73 from GCA to UCA, GUA, GCC, and GCG (changes underlined) eliminated or dramatically reduced cysteine insertion by the mutant initiator tRNA indicating that all three cysteine anticodon bases are essential for specific aminoacylation of the tRNA with cysteine in vivo.
Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). (2002)

Imatinib mesylate, a selective inhibitor of the Abl tyrosine kinase, is effective as a single-agent therapy for chronic myelogenous leukemia. However, resistance has been reported, particularly in patients with advanced-stage disease. Mutations within the Abl kinase domain are a major cause of resistance, demonstrating that Bcr-Abl remains a critical drug target. Recently, a novel pyrido[2,3-d]pyrimidine derivative, PD180970, has been shown to potently inhibit Bcr-Abl and induce apoptosis in Bcr-Abl-expressing leukemic cells. We analyzed the inhibitory activity of PD180970 against Abl kinase domain mutations and cells expressing clinically relevant mutations. Our data indicate that PD180970 is active against several Bcr-Abl mutations that are resistant to imatinib and support the notion that developing additional Abl kinase inhibitors would be useful as a treatment strategy for chronic myelogenous leukemia.
Synergistic effect of desferrioxamine and recombinant erythropoietin on erythroid precursor proliferation in chronic renal failure (1999)

DFO increases erythroid precursor proliferation and has a synergistic in vivo effect with r-HuEpo in patients with chronic renal failure. Further investigations are needed to evaluate whether such an effect may have clinical application.
Omega-6 and omega-3 polyunsaturated fatty acids and inflammatory processes (2012)

Despite improvements reported in diagnosis and treatments in recent decades, pancreatic cancer is still characterized by poor prognosis and low survival rate among solid tumors. Intensive interests have grown in exploring novel predictive biomarkers, aiming to enhance the efficiency in early detection and treatment prognosis. In this study, we identified the differentially expressed genes (DEGs) in pancreatic cancer by analyzing five gene expression profiles and established the functional modules according to the functional interaction (FI) network between the DEGs. A significant upregulation of the selected DEG, interferon (IFN)-induced transmembrane protein 1 (IFITM1), was evaluated in several bioinformatics online tools and verified with immunohistochemistry staining from samples of 90 patients with pancreatic cancer. Prognostic data showed that high expression of IFITM1 associated with poor survival, and multivariate Cox regression analysis showed IFITM1 was one of the independent prognostic factors for overall survival. Meanwhile, significant correlations of the expression of IFITM1 and the infiltration of immune cells were found by TIMER. Furthermore, a higher level of IFITM1 was assessed in pancreatic cancer cell lines compared to normal human pancreatic duct epithelial cells, and silencing IFITM1 in tumor cells remarkedly inhibited cancer tumorigenicity. Collectively, our findings suggested that IFITM1 might have promising utility for pancreatic cancer.
Hypermedia on the Web (1999)

Abstract: Researchers in the hypermedia field often lament that the World Wide Web does not support many of hypermedia&amp;apos;s rich structuring, navigation and annotation features. What would it take for everyday Web applications to be fully hypermedia compliant, now that the basic hypermedia building blocks exist on the Web? The following four capabilities are the most critical for integrating hypermedia support in the Web environment: edit-capable browsers, storing document content and link anchors separately, external linkbases, and displaying link spans, node and link attributes. Individual developers cannot decide autonomously on how to resolve many of the outstanding issues. Developers need agreed-upon conventions and tools built upon today&amp;apos;s Web standards to fully incorporate hypermedia functionality into everyday applications. Categories and Subject Descriptors: H.5.4. [Information interfaces and presentation]
Phase 3 Randomized Double-Masked Study of Efficacy and Safety of Once-Daily 0.77% Olopatadine Hydrochloride Ophthalmic Solution in Subjects With Allergic Conjunctivitis Using the Conjunctival Allergen Challenge Model (2015)

Olopatadine 0.77% demonstrated a rapid onset and prolonged duration of action. It was superior to all comparators in alleviating AC-associated ocular itching with a favorable safety profile.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01743027.
Addressing substrate coupling in mixed-mode ICs: simulation and power distribution synthesis (1994)

This paper describes new techniques for the simulation and power distribution synthesis of mixed analog/digital integrated circuits considering the parasitic coupling of noise through the common substrate. By spatially discretizing a simplified form of Maxwell's equations, a three-dimensional linear mesh model of the substrate is developed. For simulation, a macromodel of the fine substrate mesh is formulated and a modified version of SPICE3 is used to simulate the electrical circuit coupled with the macromodel. For synthesis, a coarse substrate mesh, and interconnect models are used to couple linear macromodels of circuit functional blocks. Asymptotic Waveform Evaluation (AWE) is used to evaluate the electrical behavior of the network at every iteration in the synthesis process. Macromodel simulations are significantly faster than device level simulations and compare accurately to measured results. Synthesis results demonstrate the critical need to constrain substrate noise and simultaneously optimize power bus geometry and pad assignment to meet performance targets.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Limitations of Green Fluorescent Protein as a Cell Lineage Marker (2007)

The enhanced green fluorescent protein (GFP) reporter has been widely adopted for tracking cell lineage. Here, we compare three transgenic mouse strains in which GFP is considered "ubiquitously expressed," with the GFP transgene under control of the chicken beta-actin (CBA) or human ubiquitin C (UBC) promoter. We compared the expression of GFP using flow cytometry, direct tissue fluorescence, and immunostaining with multiple commercially available anti-GFP antibodies. Mice of CBA-GFP strain 1Osb have strong but variegated expression of GFP in adult liver, kidney, small intestine, and blood. Mice of CBA-GFP strain Y01 have the highest proportion of GFP-positive peripheral blood cells yet limited GFP expression in liver, intestine, and kidney. UBC-GFP mice express GFP only weakly in solid organs and variably in blood. Direct fluorescent detection of GFP in formalin-fixed, paraffin-embedded tissue sections was the simplest approach, but it was useful only in high-expressing strains and potentially subject to artifact because of tissue autofluorescence. Immunofluorescence using either primary goat or primary rabbit antibodies was much more sensitive and allowed better discrimination of authentic signal from autofluorescence. Immunohistochemical staining was less sensitive than direct fluorescence or immunofluorescence and was subject to false-positive signal in the small intestine. In conclusion, there is considerable variability of expression within and between GFP transgenic strains. None of the tested strains gave truly ubiquitous GFP expression. A detailed analysis of GFP expression in one's tissues of interest must guide the choice of reporter mouse strain when GFP is used as a marker of cell lineage or donor origin. Disclosure of potential conflicts of interest is found at the end of this article.
Targeting NF-κB in Waldenstrom macroglobulinemia (2008)

The nuclear factor-kappaB (NF-kappaB) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-kappaB pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-kappaB activity. We demonstrated that perifosine and bortezomib both targeted NF-kappaB through its recruitment to the promoter of its target gene IkappaB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-kappaB pathway.
Mechanism-derived gene expression signatures and predictive biomarkers in clinical oncology (2005)

Medical scientists have always sought to uncover fundamental mechanistic explanations for human disease and to use this information to predict patient outcome and devise specific therapeutics. Although monogenetic diseases have been elucidated, the more common disorders often have complex or heterogeneous origins and involve the failure of multiple systems before disease is manifested. Breast cancer is an example. Many factors and genes have been implicated in the initiation of the disease (e.g., BRCA1, PTEN, P53, hormone exposure, irradiation, free radicals, etc.), but mortality is due to metastatic disease that requires invasion, evasion of immune surveillance, implantation in ectopic sites, continuous replication, cell migration, and angiogenesis (1). Capturing all of the genetic components that support these cellular processes has been a challenge for cancer cell biology.

The article by Chang et al. (2) in this issue of PNAS is interesting and novel on several fronts. First, it takes a mechanism-driven approach to prognostic biomarker discovery on a genome scale. Second, by focusing on biological mechanisms in the discovery process, Chang et al. have uncovered the catalog of genes involved in a potentially new cellular process that defines the clinical biology of breast cancer. Third, they have rendered these findings applicable for clinical decision making.

Mechanistically derived candidate biomarkers have been identified in the past, and the approach is not new. Rather than seeking biomolecules simply associated or correlated with a clinical outcome, the discovery process starts with a specific biological process and then asks whether perturbations of its components could predict cancer phenotype. The identification of the collection of mismatch repair enzymes involved in hereditary nonpolyposis colon cancer (HNPCC) is an example of a successful genomic discovery of evolutionarily related mismatch repair genes that were later confirmed as important in carcinogenesis (3, 4).

The application of microarray platforms to …
Ribosomal Synthesis of Bicyclic Peptides via Two Orthogonal Inter-Side-Chain Reactions (2008)

Here we report a new methodology for the synthesis of bicyclic peptides by using a reconstituted cell-free translation system under the reprogrammed genetic code. Cysteine (Cys) and three different nonproteinogenic amino acids, Cab, Aha, and Pgl, were simultaneously incorporated into a peptide chain. The first cyclization occurred between the chloroacetyl group of Cab and the sulfhydryl group in Cys in situ of translation, and the second cyclization on the side chains of Aha-Pgl via Cu(I)-catalyzed azide-alkyne cycloaddition was performed. This offers us a powerful means of mRNA-programmed synthesis of various peptides with uniform bicyclic scaffolds.
Structure of human monoamine oxidase A at 2.2-Å resolution: The control of opening the entry for substrates/inhibitors (2008)

The mitochondrial outer membrane-anchored monoamine oxidase (MAO) is a biochemically important flavoenzyme that catalyzes the deamination of biogenic and xenobiotic amines. Its two subtypes, MAOA and MAOB, are linked to several psychiatric disorders and therefore are interesting targets for drug design. To understand the relationship between structure and function of this enzyme, we extended our previous low-resolution rat MAOA structure to the high-resolution wild-type and G110A mutant human MAOA structures at 2.2 and 2.17 A, respectively. The high-resolution MAOA structures are similar to those of rat MAOA and human MAOB, but different from the known structure of human MAOA [De Colibus L, et al. (2005) Proc Natl Acad Sci USA 102:12684-12689], specifically regarding residues 108-118 and 210-216, which surround the substrate/inhibitor cavity. The results confirm that the inhibitor selectivity of MAOA and MAOB is caused by the structural differences arising from Ile-335 in MAOA vs. Tyr-326 in MAOB. The structures exhibit a C-terminal transmembrane helix with clear electron density, as is also seen in rat MAOA. Mutations on one residue of loop 108-118, G110, which is far from the active center but close to the membrane surface, cause the solubilized enzyme to undergo a dramatic drop in activity, but have less effect when the enzyme is anchored in the membrane. These results suggest that the flexibility of loop 108-118, facilitated by anchoring the enzyme into the membrane, is essential for controlling substrate access to the active site. We report on the observation of the structure-function relationship between a transmembrane helical anchor and an extra-membrane domain.
Synthesis of Polyanhydrides (1962)

ポリスルホンポリアンハイドライドの合成原料を得る目的で, 文献記載のない新しいスルホンジカルボン酸6種を合成し, 赤外吸収スペクトルについて検討した。すなわちメルカプトジカルボン酸からチオエーテルジカルボン酸を合成し, 過酸化水素による酸化反応により次の一般式で表わされる構造の芳香族, 脂肪族α, ω-ジカルボキシスルホンを合成した.
In vitro antiproliferative activity of a medium-chain triglyceride solution of 1,25-dihydroxyvitamin D3 in HepG2 cells. (2001)

These results indicate that, 1,25-D3 dissolved in MCT probably accumulates and then acts as a sustained release drug depot formulation, in which case it may have potential for the regional treatment of liver tumors.
Managing low cardiac output syndrome after congenital heart surgery (2001)

From Cardiac Intensive Care, Children's Hospital, and Harvard Medical School, Boston, MA. Aggressive identification and treatment of low cardiac output conditions after cardiac surgery is central to the critical care of children with congenital heart disease. Address requests for reprints to: David L. Wessel, MD, Director, CICU Office, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. E-mail: [email protected]
Familial hypercholesterolemia in a rhesus monkey pedigree: molecular basis of low density lipoprotein receptor deficiency. (1990)

We have recently identified a family of rhesus monkeys with members exhibiting a spontaneous hypercholesterolemia associated with a low density lipoprotein receptor (LDLR) deficiency. By using the polymerase chain reaction, we now show that the affected monkeys are heterozygous for a nonsense mutation in exon 6 of the LDLR gene. This mutation changes the sequence of the codon for amino acid 284 (tryptophan) from TGG to TAG, thereby generating a nonsense codon potentially resulting in a truncated 283-amino acid protein, which needs documentation, however. This G----A mutation also creates a site for the restriction endonuclease Spe I. Using this site as a marker for this nonsense mutation, we have shown that the mutation is present in all of the affected members of the pedigree and absent in unaffected members and that the mutation segregates with the phenotype of spontaneous hypercholesterolemia through three generations. Quantitative analyses of RNA obtained from liver biopsies show that the abundance of the LDLR RNA is also reduced by about 50%. Thus, we have identified a primate model for human familial hypercholesterolemia which will be useful for studying the relationship between the LDLR and lipoprotein metabolism and for assessing the efficacy of diets and drugs in the treatment of human familial hypercholesterolemia.
BindingDB Entry 50010578: Discovery of 4-((2 (2021)

The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (<b>41</b>), which is currently being evaluated clinically in several diverse AP mediated indications.
Immunohistochemical Detection of the Wilms' Tumor Gene (WT1) in Epithelial Ovarian Tumors (2000)

The Wilms' tumor gene WT1 plays multiple roles in the development of the genitourinary organs and Wilms' tumors. The aims of this study were to immunohistochemically evaluate WT1 expression in normal female genital tissues and in epithelial ovarian tumors and to look for correlations between WT1 expression and histologic subtypes and cell proliferation in epithelial ovarian tumors. In normal female genital organs, WT1 expression was recognized in ovarian surface epithelium, the lining of inclusion cysts, and tubal epithelium, but not in the cervical or endometrial epithelium. In epithelial ovarian tumors, serous tumors generally revealed a high WT1 expression. Among adenocarcinomas, serous carcinoma revealed a significantly higher WT1 expression than the other histologic subtypes. There were no significant correlations between the WT1 labeling index and the Ki-67 labeling index, and no significant difference in survival between those showing high and low WT1 expression among the malignant cases. These results suggest that WT1 expression may be related to cell differentiation, and that the histologic subtypes of epithelial ovarian carcinomas may differ considerably in their biological characteristics.
Pharmacokinetics and metabolism of amitraz in ponies and sheep (1995)

Amitraz and its active metabolite BTS27271 were given intravenously to ponies and sheep at equimolar doses of 1 mg/kg and 0.68 mg/kg, respectively, and the plasma concentrations of amitraz and BTS27271 estimated at various times thereafter. Amitraz was hydrolysed to BTS27271 in both species. Amitraz was undetectable in sheep plasma after approximately 5 min but persisted in the plasma of ponies for at least 90 min. The persistence of unmetabolized amitraz in ponies may have implications for the toxicity of amitraz in that species. The primary and secondary disposition half-lives of amitraz in ponies were 2 and 39 min, respectively. BTS27271 was distributed rapidly outside the plasma in both species with a primary disposition half-life of 4.4 min in sheep and 5.9 min in ponies. The secondary disposition half-lives were 51 and 55 min, respectively. The secondary phase of the disposition of BTS27271 was similar whether BTS27271 was given directly or derived by hydrolysis from amitraz. However, significant differences were evident in the primary phase of the disposition of BTS27271. Sheep demonstrated a larger apparent volume of distribution of BTS27271 than ponies and more rapid body clearance.
111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer (2007)

NLS-peptides routed (111)In-trastuzumab to the nucleus of HER2/neu-positive human BC cells, rendering the radiopharmaceutical lethal to the cells through the emission of nanometer-micrometer range Auger electrons. The greater cytotoxic potency of (111)In-NLS-trastuzumab compared with unlabeled trastuzumab in vitro and its favorable tumor-targeting properties in vivo suggest that it could be an effective targeted radiotherapeutic agent for HER2/neu-amplified BC in humans.
Evolutionary Network Analysis (2014)

Evolutionary network analysis has found an increasing interest in the literature because of the importance of different kinds of dynamic social networks, email networks, biological networks, and social streams. When a network evolves, the results of data mining algorithms such as community detection need to be correspondingly updated. Furthermore, the specific kinds of changes to the structure of the network, such as the impact on community structure or the impact on network structural parameters, such as node degrees, also needs to be analyzed. Some dynamic networks have a much faster rate of edge arrival and are referred to as network streams or graph streams. The analysis of such networks is especially challenging, because it needs to be performed with an online approach, under the one-pass constraint of data streams. The incorporation of content can add further complexity to the evolution analysis process. This survey provides an overview of the vast literature on graph evolution analysis and the numerous applications that arise in different contexts.