gebhart/patrepeval huggingface dataset:
Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts (1999)

Notch signal transduction regulates expression of downstream genes through the activation of the DNA-binding protein Su(H)/CBF1. In Drosophila most of Notch signaling requires Su(H); however, some Notch-dependent processes occur in the absence of Su(H) suggesting that Notch signaling does not always involve activation of this factor. Using constitutively active forms of Notch lacking CBF1-interacting sequences we identified a Notch signaling pathway that inhibits myogenic differentiation of C2C12 myoblasts in the absence of CBF1 activation. Here we show that ligand-induced Notch signaling suppresses myogenesis in C2C12 myoblasts that express a dominant negative form of CBF1, providing additional evidence for CBF1-independent Notch signal transduction. Surprisingly mutant forms of Notch deficient in CBF1 activation are unable to antagonize MyoD activity, despite the fact that they inhibit myogenesis. Moreover, Notch-induced antagonism of MyoD requires CBF1 suggesting that the CBF1-dependent pathway mediates a cell-type-specific block in the myogenic program. However, Notch signaling in the absence of CBF1 activation blocks both myogenesis and osteogenesis, indicative of a general block in cellular differentiation. Taken together our data provide evidence for two distinct Notch signaling pathways that function to block differentiation at separate steps during the process of myogenesis in C2C12 myoblasts.
Dynamic pH junction focusing and isoelectric focusing in capillary electrophoresis mass spectrometry (2021)

Capillary electrophoresis−mass spectrometry (CE−MS) is complementary to liquid chromatography−mass spectrometry (LC−MS) because of the orthogonal separation mechanism. An electrospray ionization (ESI) interface is the pivotal device in CE-MS and its emitter location relative to the MS inlet orifice has a significant influence on both ESI stability and detection sensitivity. A flow-through microvial interface provides a path for ion transmission between the CE and the MS systems. Based on the microvial interface with its small dilution volume and asymmetric emitter geometry, CE−MS concentration sensitivity can arrive at the nanomolar level with often-used mass spectrometers. To further improve the concentration sensitivity in CE–MS, dynamic pH junction focusing has been studied. By a focusing mechanism similar to isoelectric focusing (IEF), pH junction method can achieve a significant on-line preconcentration effect on weakly alkaline and zwitterionic analytes prior to the CE separation. Dynamic pH junction and its technical variant, dynamic pH barrage focusing have been investigated both theoretically and experimentally regarding peak symmetry, capturing efficiency, quantitative performance and compatibility to MS detection. Simulation-based optimization provided theoretical evidences that both configurations can capture targeted analyte with negligible or no loss during analyte focusing, giving adequate calibration curve linearity. Most theoretical predictions, alongside the capability of selective focusing in complex matrices, were verified by experimental evaluations with optical or MS detection. High resolution capillary isoelectric focusing mass spectrometry (cIEF−MS) enabled by the microvial interface is an attractive method for the charge heterogeneity characterization of biopolymers. Peptide and protein were used to demonstrate the feasibility of two online electrolyte configurations. pI resolution up to 0.02 pH in neutrally-coated capillaries demonstrated the high separation power. Isotopically resolved mass spectra collected by an Orbitrap MS instrument provided protein structural information. Analyses of intact monoclonal antibodies (mAb), including infliximab and adalimumab, an unidentified mAb and a reference mAb, showed the potential of cIEF–MS for charge variant separation and online identification in the biopharmaceutical industry. Automated cIEF–MS analysis shortened separation and identification process of mAb charge variants from days to approximately 2 h.
Solid-Phase Supports for Oligonucleotide Synthesis (2003)

The solid-phase strategy for oligonucleotide synthesis has been responsible for much of the widespread utilization of synthetic oligonucleotides. Indeed, without this approach, the chemical synthesis of oligonucleotides would have remained a difficult and tedious task suitable for only the most dedicated chemist. Now of course, as anyone owning an automated synthesizer knows, the solid-phase synthesis of oligonucleotides is as easy as pressing a few buttons. However, despite the obvious advantages of solid-phase synthesis, the development of satisfactory procedures for oligonucleotide synthesis required almost 20 years from the first introduction of this technique. This was primarily because of two obstacles that had to be overcome. The first was the need for rapid and highly efficient coupling reactions, and the second was the need for a suitable solid-phase support. This chapter is devoted to a treatment of the solid-phase supports and the important covalent linkage that binds the oligonucleotide to it.
The Volatility of the Pe Ratio and its Components: A Contrast of Japanese and U.S. Markets (1995)

This paper extends previous research by reexamining the difference in cross‐sectional variability of Japanese and U.S. price‐to‐earnings (PE) ratios. A simple model is developed to decompose the variance of the PE ratio into three components: the variance of the price‐to‐book (PB) ratio, the variance of the book‐to‐earnings (BE) ratio and the covariance of the PB and BE ratios. We analyze the behavior of the cross‐sectional variability of the PE ratio and its components and compare the behavior of these ratios across the U.S. and Japanese markets. We find that the cross‐sectional variability of the PE ratio in the Japanese market is consistently lower than that of the PB ratio and the converse is true for the U.S. market. The cross‐sectional variability of PE ratios in Japan is lower than that in the U.S. and the converse is true for the PB ratio. Our results are inconsistent with those reported by Bildersee et al. and indicate that the main factor causing the differences between the cross‐sectional variability of PE ratios and PB ratios is the high negative covariance of the PB and BE ratios.
Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor (2016)

The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
Novel Point Mutation in the Extracellular Domain of the Granulocyte Colony-Stimulating Factor (G-Csf) Receptor in a Case of Severe Congenital Neutropenia Hyporesponsive to G-Csf Treatment (1999)

Severe congenital neutropenia (SCN) is a heterogeneous condition characterized by a drastic reduction in circulating neutrophils and a maturation arrest of myeloid progenitor cells in the bone marrow. Usually this condition can be successfully treated with granulocyte colony-stimulating factor (G-CSF). Here we describe the identification of a novel point mutation in the extracellular domain of the G-CSF receptor (G-CSF-R) in an SCN patient who failed to respond to G-CSF treatment. When this mutant G-CSF-R was expressed in myeloid cells, it was defective in both proliferation and survival signaling. This correlated with diminished activation of the receptor complex as determined by signal transducer and activator of transcription (STAT) activation, although activation of STAT5 was more affected than STAT3. Interestingly, the mutant receptor showed normal affinity for ligand, but a reduced number of ligand binding sites compared with the wild-type receptor. This suggests that the mutation in the extracellular domain affects ligand-receptor complex formation with severe consequences for intracellular signal transduction. Together these data add to our understanding of the mechanisms of cytokine receptor signaling, emphasize the role of GCSFR mutations in the etiology of SCN, and implicate such mutations in G-CSF hyporesponsiveness.
Studies of theCis, Cis‐Cyclodeca‐1,6‐Diene System (1975)

Abstract In the course of attempting to synthesize cyclodeca‐1,6‐diyne (IIIa) from cis, cis ‐cyclodeca‐1,6‐diene (XIX) derivatives by a successive bromination and dehydrobromination, transannular addition of one mole of bromine to the diene system occurred. The reaction products were bicyclic decalin derivatives. New symmetric and unsymmetric derivatives of XIX were prepared. Various approaches towards obtaining [10]annulene‐quinone (XXIX) are reported.
Reverse phase protein microarrays advance to use in clinical trials (2010)

Individualizing cancer therapy for molecular targeted inhibitors requires a new class of molecular profiling technology that can map the functional state of the cancer cell signal pathways containing the drug targets. Reverse phase protein microarrays (RPMA) are a technology platform designed for quantitative, multiplexed analysis of specific phosphorylated, cleaved, or total (phosphorylated and non-phosphorylated) forms of cellular proteins from a limited amount of sample. This class of microarray can be used to interrogate tissue samples, cells, serum, or body fluids. RPMA were previously a research tool; now this technology has graduated to use in research clinical trials with clinical grade sensitivity and precision. In this review we describe the application of RPMA for multiplexed signal pathway analysis in therapeutic monitoring, biomarker discovery, and evaluation of pharmaceutical targets, and conclude with a summary of the technical aspects of RPMA construction and analysis.
Mutational Analysis of a Fatty Acyl-Coenzyme A Synthetase Signature Motif Identifies Seven Amino Acid Residues That Modulate Fatty Acid Substrate Specificity (1997)

Fatty acyl-CoA synthetase (fatty acid:CoA ligase, AMP-forming; EC 6.2.1.3) catalyzes the formation of fatty acyl-CoA by a two-step process that proceeds through the hydrolysis of pyrophosphate. In Escherichia coli this enzyme plays a pivotal role in the uptake of long chain fatty acids (C12-C18) and in the regulation of the global transcriptional regulator FadR. The E. coli fatty acyl-CoA synthetase has remarkable amino acid similarities and identities to the family of both prokaryotic and eukaryotic fatty acyl-CoA synthetases, indicating a common ancestry. Most notable in this regard is a 25-amino acid consensus sequence, DGWLHTGDIGXWXPXGXLKIIDRKK, common to all fatty acyl-CoA synthetases for which sequence information is available. Within this consensus are 8 invariant and 13 highly conserved amino acid residues in the 12 fatty acyl-CoA synthetases compared. We propose that this sequence represents the fatty acyl-CoA synthetase signature motif (FACS signature motif). This region of fatty acyl-CoA synthetase from E. coli, 431NGWLHTGDIAVMDEEGFLRIVDRKK455, contains 17 amino acid residues that are either identical or highly conserved to the FACS signature motif. Eighteen site-directed mutations within the fatty acyl-CoA synthetase structural gene (fadD) corresponding to this motif were constructed to evaluate the contribution of this region of the enzyme to catalytic activity. Three distinct classes of mutations were identified on the basis of growth characteristics on fatty acids, enzymatic activities using cell extracts, and studies using purified wild-type and mutant forms of the enzyme: 1) those that resulted in either wild-type or nearly wild-type fatty acyl-CoA synthetase activity profiles; 2) those that had little or no enzyme activity; and 3) those that resulted in lowering and altering fatty acid chain length specificity. Among the 18 mutants characterized, 7 fall in the third class. We propose that the FACS signature motif is essential for catalytic activity and functions in part to promote fatty acid chain length specificity and thus may compose part of the fatty acid binding site within the enzyme.
Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy (1997)

The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
Revenues of Pumped-Storage from Energy and Reserves Markets (2016)

This paper studies the revenues of pumped-storage doing price arbitrage on the day-ahead market (DAM) and providing frequency containment reserves (FCRs). To derive the DAM revenues, a perfectly forecasting price-taker framework is considered along with historic Belgian DAM prices. Based on a simple linear programming formulation, yearly revenues per megawatt of storage are derived in function of both the cycle efficiency and the number storage hours. It is then considered that the pumped-storage unit is operated at variable speed, and thus able to provide FCRs. Based on realistic operation ranges of such a unit, DAM implications of the FCRs provision are discussed, revenues are estimated and compared to those obtained in the case of DAM arbitrage only.
The isolation and culture of adult mouse colonic epithelium. (1995)

A technique is described for the reproducible primary culture of colonic epithelium from adult mice. A collagenase-dispase digestion technique (adapted form Evans et al. 1992) is used to release the epithelium, followed by differential sedimentation to produce a high purity crypt preparation with maintained structural integrity and minimal mesenchymal contamination. The crypt units attach to collagen coated plastic within 24 h and the epithelial cells quickly begin to migrate outwards producing a monolayer surrounding the attached crypts. Electron microscopy revealed that the migrating epithelial cells possessed both desmosomes and microvilli. Proliferation in the colony supports the outward migration of cells until the migratory cells of adjacent colonies connect and a confluent monolayer begins to form. Proliferation is routinely maintained for 10 days (although cultures have now been maintained without subculturing for 35 days) and is demonstrated by increased cell numbers in spite of continuous cell loss into the culture media. Culture growth is enhanced by increasing concentrations of fetal calf and mouse serum and EGF but does not appear to respond significantly to added transferrin. Growth is also stimulated by a murine small intestinal extract thought to contain a potentially novel growth factor or cocktail of factors. This culture model has considerable potential for studies on growth factor control of this carcinoma susceptible tissue and its differentiated function as well as studies into the mechanisms of carinogenesis.
Cross-reactivity of mouse IgG subclasses to human Fc gamma receptors: Antibody deglycosylation only eliminates IgG2b binding (2020)

Immunoglobulin G (IgG) antibodies are important for protection against pathogens and exert effector functions through binding to IgG-Fc receptors (FcγRs) on myeloid and natural killer cells, resulting in destruction of opsonized target cells. Despite interspecies differences, IgG subclasses and FcγRs show substantial similarities and functional conservation between mammals. Accordingly, binding of human IgG (hIgG) to mouse FcγRs (mFcγRs) has been utilized to study effector functions of hIgG in mice. In other applications, such as immunostaining with mouse IgG monoclonal antibodies (mAbs), these cross-reactivities are undesired and prone to misinterpretation. Despite this drawback, the binding of mouse IgG (mIgG) subclasses to human FcγR (hFcγR) classes has never been fully documented. Here, we report detailed and quantifiable characterization of binding affinities for all mIgG subclasses to hFcγRs, including functional polymorphic variants. mIgG subclasses show the strongest binding to hFcγRIa, with relative affinities mIgG2a = mIgG2c > mIgG3 >> mIgG2b, and no binding by mIgG1. hFcγRIIa/b showed general low reactivities to all mIgG (mIgG1> mIgG2a/c > mIgG2b), with no reactivity to mIgG3. A particularly high affinity was observed for mIgG1 to the hFcγRIIa-R131 polymorphic variant. hFcγRIIIa showed lower binding (mIgG2a/c > mIgG3), slightly favouring binding to the hFcγRIIIa-V158 over the F158 polymorphic variant. No binding was observed of mIgG to hFcγRIIIb. Deglycosylation of mIgG1 did not abrogate binding to hFcγRIIa-R131, nor did deglycosylation of mIgG2a/c and mIgG3 prevent hFcγRIa binding. Importantly, deglycosylation of the least cross-reactive mIgG subclass, mIgG2b, abrogated reactivity to all hFcγRs. Together, these data document for the first time the full spectrum of cross-reactivities of mouse IgG to human FcγRs.
Rectilinear Ion Trap:  Concepts, Calculations, and Analytical Performance of a New Mass Analyzer (2004)

A mass analyzer based on a rectilinear geometry ion trap (RIT) has been built, and its performance has been characterized. Design concepts for this type of ion trap are delineated with emphasis on the effects of electrode geometry on the calculated electric field. The Mathieu stability region was mapped experimentally. The instrument can be operated using mass-selective instability scans in both the boundary and resonance ejection versions. Comparisons of performance between different versions of the device having different dimensions allowed selection of an optimized geometry with an appropriate distribution of higher-order electric fields. Comparisons made under the same conditions between the performance of a conventional cylindrical ion trap and a RIT of 4 times greater volume show an improvement of 40 times in the signal-to-noise ratio resulting from the higher ion trapping capacity of the RIT. The demonstrated capabilities of the RIT include tandem mass spectrometry, a mass resolution in excess of 1000, and a mass/charge range of 650 Th, all in a simple structure that is only 3.5 cm(3) in internal volume.
Animal‐derived lipocalin allergens exhibit immunoglobulin E cross‐reactivity (2007)

Several lipocalins exhibited IgE cross-reactivity, probably due to the sequential identity of the proteins and also due to similarities in their three-dimensional structures. The clinical significance of the findings needs to be elucidated. Low-level IgE cross-reactivity can play a role in regulating immune response to lipocalin allergens.
Lipid peroxidation and antioxidant status in colorectal cancer (2005)

Colorectal carcinogenesis is associated with serious oxidative stress and confirms that gradual advancement of oxidative-antioxidative disorders is followed by progression of colorectal cancer.
IL-12 is a potent neonatal vaccine adjuvant (1999)

Neonatal animals show generally poor responsiveness to foreign antigens and are known to display polarized expression of Th2-like cytokines and antibody responses. We now report that newborn mice display a reduction in peripheral expression of the Th1-inducing cytokine, IL-12. Attempts to overcome this decrease by immunization and treatment with IL-12 within 24 h of birth resulted in elevated levels of IFN-gamma and IL-10 mRNA in the spleens of mice compared to animals exposed to antigen only. Moreover, such animals showed dramatic enhancement of IgG2a and IgG2b antibody levels upon adult challenge compared to mice primed with antigen alone. These effects appeared to be due to induction of neonatal B cell memory. IgG1 antibody levels, a measure of Th2 activity, were unaffected or even somewhat enhanced by neonatal IL-12 treatment. Taken together, these results provide evidence that IL-12 administration induces a Th1-like cytokine response in newborns and causes priming for heightened memory antibody responses in vivo. Our findings suggest the use of IL-12 as a vaccine adjuvant in neonates for inducing protection against common childhood pathogens.
United-residue force field for off-lattice protein-structure simulations: III. Origin of backbone hydrogen-bonding cooperativity in united-residue potentials (1998)

Based on the dipole model of peptide groups developed in our earlier work [Liwo et al., Prot. Sci., 2, 1697 (1993)], a cumulant expansion of the average free energy of the system of freely rotating peptide-group dipoles tethered to a fixed α-carbon trace is derived. A graphical approach is presented to find all nonvanishing terms in the cumulants. In particular, analytical expressions for three- and four-body (correlation) terms in the averaged interaction potential of united peptide groups are derived. These expressions are similar to the cooperative forces in hydrogen bonding introduced by Koliński and Skolnick [J. Chem. Phys., 97, 9412 (1992)]. The cooperativity arises here naturally from the higher order terms in the power-series expansion (in the inverse of the temperature) for the average energy. Test calculations have shown that addition of the derived four-body term to the statistical united-residue potential of our earlier work [Liwo et al., J. Comput. Chem., 18, 849, 874 (1997)] greatly improves its performance in folding poly-l-alanine into an α-helix. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 259–276, 1998