gebhart/patrepeval huggingface dataset:
Methylation hot spots in the 5' flanking region denote silencing of the O6-methylguanine-DNA methyltransferase gene. (1997)

The mechanism whereby the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is silenced in repair-deficient (Mer-) human tumor cells is unknown. The role of methylation of the 5' CpG island in MGMT gene suppression is controversial. Although we previously showed by restriction enzyme analysis that CpG methylation in this region was associated with gene suppression, methylation at such sites was generally incomplete, suggesting heterogeneity. To clarify this issue, we have unequivocally defined the methylation status of every CpG by genomic sequencing of individual cloned copies of bisulfite-modified DNA. The region from -249 to +259 at the transcription start site was virtually methylation free in HT29 cells (Mer+), whereas in BE or HeLa S3 cells (Mer-), this region was substantially methylated in every DNA copy, with "hot spots" from -249 to -103 and from +107 to +196. Up-regulation of MGMT in HeLa S3 cells induced by 5-azacytidine was accompanied by progressive demethylation and the appearance of totally unmethylated copies of DNA. We conclude that, in Mer- cells, the MGMT promoter contains specific CpG methylation hot spots that are tightly linked to and are potential markers of gene silencing.
Elucidation of an Alternate Isoleucine Biosynthesis Pathway in Geobacter sulfurreducens (2008)

The central metabolic model for Geobacter sulfurreducens included a single pathway for the biosynthesis of isoleucine that was analogous to that of Escherichia coli, in which the isoleucine precursor 2-oxobutanoate is generated from threonine. 13C labeling studies performed in G. sulfurreducens indicated that this pathway accounted for a minor fraction of isoleucine biosynthesis and that the majority of isoleucine was instead derived from acetyl-coenzyme A and pyruvate, possibly via the citramalate pathway. Genes encoding citramalate synthase (GSU1798), which catalyzes the first dedicated step in the citramalate pathway, and threonine ammonia-lyase (GSU0486), which catalyzes the conversion of threonine to 2-oxobutanoate, were identified and knocked out. Mutants lacking both of these enzymes were auxotrophs for isoleucine, whereas single mutants were capable of growth in the absence of isoleucine. Biochemical characterization of the single mutants revealed deficiencies in citramalate synthase and threonine ammonia-lyase activity. Thus, in G. sulfurreducens, 2-oxobutanoate can be synthesized either from citramalate or threonine, with the former being the main pathway for isoleucine biosynthesis. The citramalate synthase of G. sulfurreducens constitutes the first characterized member of a phylogenetically distinct clade of citramalate synthases, which contains representatives from a wide variety of microorganisms.
Domain Transfer SVM for video concept detection (2009)

Cross-domain learning methods have shown promising results by leveraging labeled patterns from auxiliary domains to learn a robust classifier for target domain, which has a limited number of labeled samples. To cope with the tremendous change of feature distribution between different domains in video concept detection, we propose a new cross-domain kernel learning method. Our method, referred to as Domain Transfer SVM (DTSVM), simultaneously learns a kernel function and a robust SVM classifier by minimizing both the structural risk functional of SVM and the distribution mismatch of labeled and unlabeled samples between the auxiliary and target domains. Comprehensive experiments on the challenging TRECVID corpus demonstrate that DTSVM outperforms existing cross-domain learning and multiple kernel learning methods.
Drug Transfer Across the Blood‐Brain Barrier: Correlation Between In Vitro and In Vivo Models (1992)

To assess the drug transport across the blood-brain barrier (BBB), we compared the maximal brain extraction values at time 0 [E(0) values] obtained using either in vitro or in vivo methods. The in vitro BBB model consisted of a coculture of brain capillary endothelial cells growing on one side of a filter and astrocytes on the other. The in vivo model used intracarotid injection in anesthetized rats. Eleven compounds were tested. They were selected because they exhibit quantitatively different brain extraction rates: very low for inulin and sucrose, low for oxicam-related nonsteroidal antiinflammatory drugs and diclofenac, and high for propranolol and diazepam. As these compounds are apparently transferred by a passive diffusion mechanism, two others, glucose and leucine, were added that cross the BBB by a known carrier-mediated process. The in vivo and in vitro E(0) values showed a strong correlation as indicated by the Spearman's correlation coefficient (r = 0.88, p less than 0.01). The relative ease with which such cocultures can be produced in large quantities could facilitate the screening of new centrally acting drugs.
Salicylaldimine-Based Metal–Organic Framework Enabling Highly Active Olefin Hydrogenation with Iron and Cobalt Catalysts (2014)

A robust and porous Zr metal-organic framework, sal-MOF, of UiO topology was synthesized using a salicylaldimine (sal)-derived dicarboxylate bridging ligand. Postsynthetic metalation of sal-MOF with iron(II) or cobalt(II) chloride followed by treatment with NaBEt3H in THF resulted in Fe- and Co-functionalized MOFs (sal-M-MOF, M = Fe, Co) which are highly active solid catalysts for alkene hydrogenation. Impressively, sal-Fe-MOF displayed very high turnover numbers of up to 145000 and was recycled and reused more than 15 times. This work highlights the unique opportunity of developing MOF-based earth-abundant catalysts for sustainable chemical synthesis.
A Unified Approach to Interpreting Model Predictions (2017)

Understanding why a model makes a certain prediction can be as crucial as the prediction's accuracy in many applications. However, the highest accuracy for large modern datasets is often achieved by complex models that even experts struggle to interpret, such as ensemble or deep learning models, creating a tension between accuracy and interpretability. In response, various methods have recently been proposed to help users interpret the predictions of complex models, but it is often unclear how these methods are related and when one method is preferable over another. To address this problem, we present a unified framework for interpreting predictions, SHAP (SHapley Additive exPlanations). SHAP assigns each feature an importance value for a particular prediction. Its novel components include: (1) the identification of a new class of additive feature importance measures, and (2) theoretical results showing there is a unique solution in this class with a set of desirable properties. The new class unifies six existing methods, notable because several recent methods in the class lack the proposed desirable properties. Based on insights from this unification, we present new methods that show improved computational performance and/or better consistency with human intuition than previous approaches.
High resolution and high sensitivity methods for oligosaccharide mapping and characterization by normal phase high performance liquid chromatography following derivatization with highly fluorescent anthranilic acid (1998)

Facile labeling of oligosaccharides (acidic and neutral) in a nonselective manner was achieved with highly fluorescent anthranilic acid (AA, 2-aminobenzoic acid) (more than twice the intensity of 2-aminobenzamide, AB) for specific detection at very high sensitivity. Quantitative labeling in acetate-borate buffered methanol (approximately pH 5.0) at 80 degreesC for 60 min resulted in negligible or no desialylation of the oligosaccharides. A high resolution high performance liquid chromatographic method was developed for quantitative oligosaccharide mapping on a polymeric-NH2bonded (Astec) column operating under normal phase and anion exchange (NP-HPAEC) conditions. For isolation of oligosaccharides from the map by simple evaporation, the chromatographic conditions developed use volatile acetic acid-triethylamine buffer (approximately pH 4.0) systems. The mapping and characterization technology was developed using well characterized standard glycoproteins. The fluorescent oligosaccharide maps were similar to the maps obtained by the high pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD), except that the fluorescent maps contained more defined peaks. In the map, the oligosaccharides separated into groups based on charge, size, linkage, and overall structure in a manner similar to HPAEC-PAD with contribution of -COOH function from the label, anthranilic acid. However, selectivity of the column for sialic acid linkages was different. A second dimension normal phase HPLC (NP-HPLC) method was developed on an amide column (TSK Gel amide-80) for separation of the AA labeled neutral complex type and isomeric structures of high mannose type oligosaccharides. The oligosaccharides labeled with AA are compatible with biochemical and biophysical techniques, and use of matrix assisted laser desorption mass spectrometry for rapid determination of oligosaccharide mass map of glycoproteins is demonstrated. High resolution of NP-HPAEC and NP-HPLC methods combined with mass spectrometry (MALDI-TOF) can provide an effective technology for analyzing a wide repertoire of oligosaccharide structures and for determining the action of both transferases and glycosidases.
Recent progress in oligonucleotide synthesis. (1996)

New blocking group combinations for the machine-aided oligoribonucleotide synthesis on solid phase material have been developed and tested regarding their general application. An acetal function for 2'-OH protection offers a series of advantages in the synthetic approach but special conditions have to be fulfilled in order to guarantee a selective cleavage of the temporary 5'-OH blocking group such as the dansylethoxycarbonyl or even the acid-labile dimethoxytrityl group in the chain elongation process. The final removal of the 2'-O-acetal function in the partially deblocked oligomer proceeds unexpectedly well under weak acidic conditions due to a supposed intramolecular acid catalysis.
Targeting of cancer neoantigens with donor-derived T cell receptor repertoires (2016)

Accumulating evidence suggests that clinically efficacious cancer immunotherapies are driven by T cell reactivity against DNA mutation-derived neoantigens. However, among the large number of predicted neoantigens, only a minority is recognized by autologous patient T cells, and strategies to broaden neoantigen-specific T cell responses are therefore attractive. We found that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11 of 57 predicted human leukocyte antigen (HLA)-A*02:01-binding epitopes from three patients. Many of the T cell reactivities involved epitopes that in vivo were neglected by patient autologous tumor-infiltrating lymphocytes. Finally, T cells redirected with T cell receptors identified from donor-derived T cells efficiently recognized patient-derived melanoma cells harboring the relevant mutations, providing a rationale for the use of such "outsourced" immune responses in cancer immunotherapy.
DNA hypomethylation and proliferative activity are increased in the rectal mucosa of patients with long-standing ulcerative colitis (1996)

DNA hypomethylation and proliferative activity are increased in this group of patients, supporting the concept that their colonic mucosa undergoes epigenetic and kinetic changes that might predispose these individuals to develop colorectal neoplasms. However, it cannot be ruled out that these markers solely reflect hyperproliferation associated with active inflammation.
Transport of solutes through cartilage: permeability to large molecules. (1976)

A review of the transport of solutes through articular cartilage is given, with special reference to the effect of variations in matrix composition. Some physiological implications of our findings are discussed. Also, results of an experimental study of the permeability of articular cartilage to large globular proteins are presented. Because of the very low partition coefficients of large solutes between cartilage and an external solution new experimental techniques had to be devised, particularly for the study of diffusion. The partition coefficients of solutes were found to decrease very steeply with increase in size, up to serum albumin. There was, however, no further decrease for IGG. The diffusion coefficient of serum albumin in cartilage was relatively high (one quarter of the value in aqueous solution). These two facts taken together suggest that there may be a very small fraction of relatively large pores in cartilage through which the transport of large molecules is taking place. The permeability of cartilage to large molecules is extremely sensitive to variations in the glycosaminoglycan content: for a threefold increase in the latter there is a hundredfold decrease in the partition coefficient. For cartilage of fixed charge density around 0-19 m-equiv/g, there is no penetration at all of globular proteins of size equal to or larger than serum albumin.
Age-related changes in the elastic properties and thickness of human facial skin (1994)

Using recently designed, commercially available, non-invasive instruments, we measured the thickness and elasticity of the skin of the face and ventral forearm in 170 women, and evaluated the effects of age and exposure to sunlight. Skin thickness decreased with age in ventral forearm skin, which has limited exposure to sunlight, but increased significantly in the skin of the forehead, corners of the eyes, and cheeks, which are markedly exposed to sunlight. Skin elasticity (Ur/Uf) decreased with age on both the face and forearm. The ratio of viscosity element to elasticity element (Uv/Ue) increased with age at all sites. However, delayed distension (Uv), immediate retraction (Ur), final distension (Uf), and immediate distention (Ue), as individual elements, decreased on the face and increased on the forearm with age. This tendency was more marked after correction for skin thickness. These results suggested the specificity of skin thickness and elasticity in the facial skin. Analysis using a four-element model showed no changes in the elasticity coefficient of Maxwell element on the forearm, but an increase on the face. This indicates quantitative or qualitative changes in elastic fibres in facial skin. Thus, sunlight appears to have a considerable effect on the thickness and physical properties of facial skin.
Conditional Disruption of the Peroxisome Proliferator-Activated Receptor γ Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux (2002)

Disruption of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene causes embryonic lethality due to placental dysfunction. To circumvent this, a PPAR gamma conditional gene knockout mouse was produced by using the Cre-loxP system. The targeted allele, containing loxP sites flanking exon 2 of the PPAR gamma gene, was crossed into a transgenic mouse line expressing Cre recombinase under the control of the alpha/beta interferon-inducible (MX) promoter. Induction of the MX promoter by pIpC resulted in nearly complete deletion of the targeted exon, a corresponding loss of full-length PPAR gamma mRNA transcript and protein, and marked reductions in basal and troglitazone-stimulated expression of the genes encoding lipoprotein lipase, CD36, LXR alpha, and ABCG1 in thioglycolate-elicited peritoneal macrophages. Reductions in the basal levels of apolipoprotein E (apoE) mRNA in macrophages and apoE protein in total plasma and high-density lipoprotein (HDL) were also observed in pIpC-treated PPAR gamma-MXCre(+) mice. Basal cholesterol efflux from cholesterol-loaded macrophages to HDL was significantly reduced after disruption of the PPAR gamma gene. Troglitazone selectively inhibited ABCA1 expression (while rosiglitazone, ciglitazone, and pioglitazone had little effect) and cholesterol efflux in both PPAR gamma-deficient and control macrophages, indicating that this drug can exert paradoxical effects on cholesterol homeostasis that are independent of PPAR gamma. Together, these data indicate that PPAR gamma plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.
Audiovisual localization of multiple speakers in a video teleconferencing setting (2003)

Abstract Attending to multiple speakers in a video teleconferencing setting is a complex task. From a visual point of view, multiple speakers can occur at different locations and present radically different appearances. From an audio point of view, multiple speakers may be speaking at the same time, and background noise may make it difficult to localize sound sources without some a priori estimate of the sound source locations. This article presents a novel sensor and corresponding sensing algorithms to address the task of attending, simultaneously, to multiple speakers for video teleconferencing. A panoramic visual sensor is used to capture a 360° view of the speakers in the environment and from this view potential speakers are identified via a color histogram approach. A directional audio system based on beamforming is then used to confirm potential speakers and attend to them. Experimental evaluation of the sensor and its algorithms are presented including sample performance of the entire system in a teleconferencing setting. © 2003 Wiley Periodicals, Inc. Int J Imaging Syst Technol 13: 95–105, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ima.10045
Acetylcholinesterase in murine erythroleukemia (Friend) cells: evidence for megakaryocyte-like expression and potential growth-regulatory role of enzyme activity (1992)

Features of true acetylcholinesterase (AChE) regulation during growth and differentiation of Friend murine erythroleukemia cells (MELC) have been investigated with respect to other erythroid and nonerythroid murine elements. Enzyme levels of uninduced MELC were in between the very low AChE contents of erythroid cells and the huge amounts of activity exhibited by megakaryocytes and platelets. After MELC commitment to terminal division, the enzyme-specific activity increased largely, approaching values that were much closer to those of thrombocytic than of normal erythroid elements. The bulk of AChE activity in MELC, megakaryocytes, and platelets was found to be located in the cytosol as a free-soluble form. Moreover, during incubation, MELC actively released large amounts of AChE into the medium, like it occurs in murine thrombocytes. Conversely, the enzyme of the erythroid elements was mainly associated with the membranes and was not released extracellularly. Experiments with inducers showed that changes in AChE- specific activity of MELC correlated directly with the arrest of cell proliferation rather than with the activation of differentiated erythroid functions. The inverse relationship existing between MELC growth rates and AChE levels was further supported by the relative enzyme activities of the slow- and fast-growing subclones. We conclude that uninduced MELC potentially share properties of both the erythroid and megakaryoblastic phenotype. The latter might be revealed by typical regulation of AChE activity according to a thrombocytic-like program activated upon MELC commitment to terminal division. Eventually, the inhibition of MELC growth by exogenous pure bovine AChE suggested that the secreted murine enzyme might serve as a potential negative signal of cellular replication.
Insights into the transcriptional control of adipocyte differentiation (1999)

The adipocyte is now known to play an active role in many physiological and pathological processes regarding energy metabolism. Consideration of adipose tissue as an endocrine organ that secretes a variety of unrelated bioactive molecules has broadened our appreciation of adipocyte function to exceed the once considered passive role in lipid metabolism. Growing interest in this tissue has lead to significant advances regarding the molecular basis for adipocyte differentiation. Several diverse families of transcription factors are currently under active investigation for their roles in mediating this complex process. Knowledge concerning the sequence of transcriptional events during adipogenesis and the interplay among adipogenic transcription factors provides a basis for understanding the physiological processes associated with adipose tissue as well as for the development of therapeutic intervention of adipocyte related diseases. J. Cell. Biochem. Suppls. 32/33:59-67, 1999.
TGF-β and αvβ6 Integrin Act in a Common Pathway to Suppress Pancreatic Cancer Progression (2012)

The TGF-β pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a protumorigenic microenvironment. However, the clinical application of TGF-β inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-β in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-β inhibition in pancreatic cancer in relation to tumor stage, genetic profile, and concurrent chemotherapy. We found that αvβ6 integrin acted as a key upstream activator of TGF-β in evolving pancreatic cancers. In addition, TGF-β or αvβ6 blockade increased tumor cell proliferation and accelerated both early and later disease stages. These effects were dependent on the presence of Smad4, a central mediator of TGF-β signaling. Therefore, our findings indicate that αvβ6 and TGF-β act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression.
Novel preparation of functional Sindbis virosomes (1986)

Lipid and protein factors important for the preparation and stability of reconstituted membranes prepared by the insertion of detergent-solubilized Sindbis virus glycoproteins into preformed lipid vesicles have been defined. It was found that both the state of aggregation of the membrane protein and the phase of the lipid are critical for the insertion of proteins into preformed lipid vesicles. The membranes prepared with the insertion technique were characterized in terms of residual detergent, protein orientation, and whether or not they were sealed. Binding and fusion experiments have been carried out with the insertion membranes and virus. It was found that BHK-21 cells at 4 degrees C bound one-fifth to one-tenth the number of insertion membranes as intact virus, and binding was saturable in both cases. Variation of the lipid/protein ratio did not result in significant differences in binding. The insertion membranes were found to fuse to a model lipid bilayer at least as well as the virus. These results are discussed in terms of structural factors important for the biological functionalities of the viral spike glycoproteins.