gebhart/patrepeval huggingface dataset:
Immunophilin FK506 binding protein associated with inositol 1,4,5-trisphosphate receptor modulates calcium flux. (1995)

The immunophilin FK506 binding protein 12 (FKBP12) is associated with and modulates the ryanodine receptor calcium release channel of skeletal muscle. Ryanodine receptor has amino acid homology and functional similarity with another intracellular Ca2+ release channel, the inositol 1,4,5-trisphosphate receptor (IP3R). In the present study we show that highly purified preparations of IP3R contain FKBP12. The complex of these two proteins is disrupted by the immunosuppressants FK506 and rapamycin, both of which are known to bind FKBP12 with high affinity. Disrupting the IP3R-FKBP12 interaction increases Ca2+ flux through IP3R, an effect that is reversed by added FKBP12. FKBP12 appears to be physiologically linked to IP3R, regulating its Ca2+ conductance.
Hormonal, electrolyte, and renal responses to exercise are intensity dependent (1991)

Previous work indicates that the magnitude and direction of renal responses to exercise depend on the exercise intensity. To examine mechanisms responsible for these findings, renal and hormonal responses were studied in eight healthy male subjects (29.6 +/- 1.9 yr) before and immediately after four 20-min bouts of submaximal exercise (cycle ergometry) at work loads representing 25, 40, 60, and 80% of maximal oxygen consumption. Urine flow, osmotic clearance, glomerular filtration rate, and sodium excretion (UNa+V) all tended to rise at the 25% work load but were markedly reduced at the higher work intensities. Changes in urine flow paralleled changes in glomerular filtration rate (r = 0.91). Plasma vasopressin (ADH), aldosterone, and plasma renin activity tended to increase progressively with increases in work load, with the increases for all hormones reaching statistical significance when the level of exercise reached greater than or equal to 60% of maximal oxygen consumption. However, atrial natriuretic peptide was elevated (P less than 0.05) at all work loads from greater than 1.6-fold of control levels at the 25% work load to greater than 7-fold at the 80% work load. The increase in urine flow (6 of 8 subjects) and UNa+V (7 of 8 subjects) may be due to the increase in atrial natriuretic peptide and/or a 10% suppression (P less than 0.05) of ADH at the 25% work load.(ABSTRACT TRUNCATED AT 250 WORDS)
Double-ion-exchange process in glass for the fabrication of computer-generated waveguide holograms (1994)

We experimentally optimize double-ion-exchange process parameters to achieve a designed phase modulation for a wave front passing through a computer-generated waveguide hologram and numerically analyze the effects of fabrication errors. We also demonstrate a gradient-thickness waveguide hologram for ? beam splitting.
Activation of the Hematopoietic Progenitor Kinase-1 (HPK1)-dependent, Stress-activated c-Jun N-terminal Kinase (JNK) Pathway by Transforming Growth Factor β (TGF-β)-activated Kinase (TAK1), a Kinase Mediator of TGF β Signal Transduction (1997)

Transforming growth factor beta (TGF-beta)-activated kinase (TAK1) is known for its involvement in TGF-beta signaling and its ability to activate the p38-mitogen-activated protein kinase (MAPK) pathway. This report shows that TAK1 is also a strong activator of c-Jun N-terminal kinase (JNK). Both the wild-type and a constitutively active mutant of TAK1 stimulated JNK in transient transfection assays. Mitogen-activated protein kinase kinase 4 (MKK4)/stress-activated protein kinase/extracellular signal-regulated kinase (SEK1), a dual-specificity kinase that phosphorylates and activates JNK, synergized with TAK1 in activating JNK. Conversely, a dominant-negative (MKK4/SEK1 mutant inhibited TAK1-induced JNK activation. A kinasedefective mutant of TAK1 effectively suppressed hematopoietic progenitor kinase-1 (HPK1)-induced JNK activity but had little effect on germinal center kinase activation of JNK. There are two additional MAPK kinase kinases, MEKK1 and mixed lineage kinase 3 (MLK3), that are also downstream of HPK1 and upstream of MKK4/SEK mutant. However, because the dominant-negative mutants of MEKK1 and MLK3 did not inhibit TAK1-induced JNK activity, we conclude that activation of JNK1 by TAK1 is independent of MEKK1 and MLK3. In addition to TAK1, TGF-beta also stimulated JNK activity. Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. Our results also suggest the potential roles of TAK1 not only in the TGF-beta pathway but also in the other HPK1/JNK1-mediated pathways.
Human IL-2 Mutein with Higher Antitumor Efficacy Than Wild Type IL-2 (2013)

IL-2 has been used for the treatment of melanoma and renal cell carcinoma, but this therapy has limited efficacy and severe toxicity. Currently, it is assumed that part of the limited efficacy is due to the IL-2-driven preferential expansion of regulatory T cells, which dampen the antitumor immunity. In this study, we characterize a human IL-2 mutant with higher antitumor efficacy and lower toxicity than wild type human IL-2 (wtIL-2). The mutant differs from wtIL-2 by four mutations at the interface with the α subunit of IL-2R. The IL-2 mutant induces in vitro proliferation of CD8(+)CD44(hi) and NK1.1 cells as efficiently as does wtIL-2, but it shows a reduced capacity to induce proliferation of CD4(+)Foxp3(+) regulatory T cells. The IL-2 mutant shows a higher antimetastatic effect than does wtIL-2 in several transplantable tumor models: the experimental metastasis model of MB16F0 melanoma and the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222. Relevantly, the IL-2 mutant also exhibits lower lung and liver toxicity than does wtIL-2 when used at high doses in mice. In silico simulations, using a calibrated mathematical model, predict that the properties of IL-2 mutein are a consequence of the reduction, of at least two orders of magnitude, in its affinity for the α subunit of IL-2R (CD25). The human IL-2 mutant described in the present work could be a good candidate for improving cancer therapy based on IL-2.
Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation. (1995)

Bis-indolyl-(seco)-1,2,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e compounds are synthetic analogues of CC-1065 that are highly cytotoxic toward a broad spectrum of tumor cell lines. One of these compounds, called DC1, was conjugated to antibodies via novel cleavable disulfide linkers. Conjugates of DC1 with murine mAbs anti-B4 and N901 directed against tumor-associated antigens CD19 and CD56, respectively, proved to be extremely potent and antigen selective in killing target cells in culture. DC1 conjugates with humanized versions of anti-B4 and N901 antibodies were also constructed and demonstrated to be as cytotoxic and selective as the respective murine antibody conjugates. The anti-B4-DC1 conjugate showed antitumor efficacy in an aggressive metastatic human B-cell lymphoma survival model in SCID mice and completely cured animals hearing large tumors. Anti-B4-DC1 was considerably more effective in this tumor model than doxorubicin, cyclophosphamide, etoposide, or vincristine at their maximum tolerated doses.
2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity (2017)

2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.
Implementing Collaborative Process Management (2005)

Businesses often do not succeed with the implementation of collaborative processes, and research has not provided adequate help. The article provides a concept for services and standards to implement collaborative processes and describes experiences from a successful solution. The case of Net-Tech’s Elex analyzes how Net-Tech realized a collaborative process management for its manufacturing operations. The case study shows a concept for implementing collaborative processes as well as its implementation as a “proof by demonstration.” Even if the solution has proven to implement collaborative processes in a network of more than 50 partners in high-tech industry, more research is required toward generalization. Business managers might use the concept of the services and standards at Elex and the experiences of Net-Tech as guidelines when they are in a situation to decide on the implementation of collaborative processes.
The Child Affective Facial Expression (CAFE) set: validity and reliability from untrained adults (2015)

Emotional development is one of the largest and most productive areas of psychological research. For decades, researchers have been fascinated by how humans respond to, detect, and interpret emotional facial expressions. Much of the research in this area has relied on controlled stimulus sets of adults posing various facial expressions. Here we introduce a new stimulus set of emotional facial expressions into the domain of research on emotional development-The Child Affective Facial Expression set (CAFE). The CAFE set features photographs of a racially and ethnically diverse group of 2- to 8-year-old children posing for six emotional facial expressions-angry, fearful, sad, happy, surprised, and disgusted-and a neutral face. In the current work, we describe the set and report validity and reliability data on the set from 100 untrained adult participants.
The prevalence ofEscherichia coliO157.H7 in dairy and beef cattle in Washington State (1994)

Escherichia coli O157.H7 was found in 10 of 3570 (0.28%) faecal samples from dairy cattle in 5 of 60 herds (8.3%). Several tentative associations with manure handling and feeding management practices on dairy farms were identified. Faecal/urine slurry samples, bulk milk samples, and milk filters from dairy herds were negative for E. coli O157.H7. E. coli O157.H7 was also isolated from 10 of 1412 (0.71%) faecal samples from pastured beef cattle in 4 of 25 (16%) herds. The prevalence of E. coli O157.H7 excretion in feedlot beef cattle was 2 of 600 (0.33%). The identification of cattle management practices associated with colonization of cattle by E. coli O157.H7 suggests the possibility that human E. coli O157.H7 exposure may be reduced by cattle management procedures.
Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non–Small Cell Lung Cancer Cells (2016)

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.
Functional knockout of FUT8 in Chinese hamster ovary cells using CRISPR/Cas9 to produce a defucosylated antibody (2015)

We report the adaptation of the new CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR‐associated protein 9) system to disrupt the gene encoding fucosyltransferase 8 (FUT8), an α1,6‐fucosyltransferase that directs fucose addition to derived antibody Fc region asparagine 297, in Chinese hamster ovary (CHO) cells. Compared to previously reported homologous recombination or zinc‐finger nucleases (ZFNs) applications in CHO cells, CRISPR/Cas9 demonstrated higher targeting efficiency and easier customization. FUT8 disruptive clones (FUT8 −/− ) were obtained within 3 weeks at indel frequencies ranging from 9 to 25%, which could be enhanced to 52% with Lens culinaris agglutinin (LCA) selection. Based on the lectin blot method, the derived FUT8 −/− clone had the ability to produce defucosylated therapeutic mAb with no detrimental effects on cell growth, viability, or product quality. The clone had the potential of industrial application for therapeutic antibodies manufacturing. We have demonstrated functionally that a gene related to product synthesis could be mutated using CRISPR/Cas9 technology, and consequently the glycan profile of expressed mAb was alternated. We believe that with its robustness and effectiveness, CRISPR/Cas9 can be widely applicable in cell line development leading to higher productivity and better quality of mAbs and other biological therapeutics.
Interaural time delay personalisation using incomplete head scans (2017)

When using a set of generic head-related transfer functions (HRTFs) for spatial sound rendering, personalisation can be considered to minimise localisation errors. This typically involves tuning the characteristics of the HRTFs or a parametric model according to the listener's anthropometry. However, measuring anthropometric features directly remains a challenge in practical applications, and the mapping between anthropometric and acoustic features is an open research problem. Here we propose matching a face template to a listener's head scan or depth image to extract anthropometric information. The deformation of the template is used to personalise the interaural time differences (ITDs) of a generic HRTF set. The proposed method is shown to outperform reference methods when used with high-resolution 3-D scans. Experiments with single-frame depth images indicate that the method is applicable to lower resolution or partial scans which are quicker and easier to obtain than full 3-D scans. These results suggest that the proposed method may be a viable option for ITD personalisation in practical applications.
Nuclear localization of the protein encoded by the Wilms’ tumor gene WT1 in embryonic and adult tissues (1993)

The human Wilms' tumor gene WT1 encodes a putative transcription factor implicated in tumorigenesis and in specifying normal urogenital development. We have studied the distribution of WT1 protein and mRNA using immunohistochemistry and in situ hybridization. Monoclonal antibodies were raised against a peptide specific to the first alternative splice site of WT1. Two antibodies specifically reacted on Western blot to this WT1 isoform. Immunofluorescence localized WT1 protein to podocytes during mesonephric and metanephric development. In situ hybridization revealed a similar pattern of expression except that WT1 mRNA was also present in metanephric blastema and renal vesicles. Messenger RNA expression was most pronounced in the kidneys during early fetal development and declined thereafter. In contrast, WT1 protein was readily detectable in glomerular podocytes throughout adulthood. WT1 protein in Wilms' tumor was present in blastema and glomeruloid structures. Expression in the female gonad was linked to the different stages of granulosa cell development. In the male gonad, expression was restricted to Sertoli cells and their precursors, the embryonic tunica albuginea and the rete testis. The intracellular distribution of the WT1 protein was investigated by confocal laser microscopy and was demonstrated to be exclusively nuclear. The nuclear distribution and the selective pattern of expression support the proposed role of WT1 as a transcription factor active during urogenital development. The persistence of WT1 expression in the adult kidney suggests a role in homeostasis of the podocyte.
Perovskite as Light Harvester: A Game Changer in Photovoltaics (2014)

It is not often that the scientific community is blessed with a material, which brings enormous hopes and receives special attention. When it does, it expands at a rapid pace and its every dimension creates curiosity. One such material is perovskite, which has triggered the development of new device architectures in energy conversion. Perovskites are of great interest in photovoltaic devices due to their panchromatic light absorption and ambipolar behavior. Power conversion efficiencies have been doubled in less than a year and over 15% is being now measured in labs. Every digit increment in efficiency is being celebrated widely in the scientific community and is being discussed in industry. Here we provide a summary on the use of perovskite for inexpensive solar cells fabrication. It will not be unrealistic to speculate that one day perovskite-based solar cells can match the capability and capacity of existing technologies.
A space-efficient flash translation layer for CompactFlash systems (2002)

Flash memory is becoming increasingly important as nonvolatile storage for mobile consumer electronics due to its low power consumption and shock resistance. However, it imposes technical challenges in that a write should be preceded by an erase operation, and that this erase operation can be performed only in a unit much larger than the write unit. To address these technical hurdles, an intermediate software layer called a flash translation layer (FTL) is generally employed to redirect logical addresses from the host system to physical addresses in flash memory. Previous approaches have performed this address translation at the granularity of either a write unit (page) or an erase unit (block). We propose a novel FTL design that combines the two different granularities in address translation. This is motivated by the idea that coarse grain address translation lowers the resources required to maintain translation information, which is crucial in mobile consumer products for cost and power consumption reasons, while fine grain address translation is efficient in handling small size writes. Performance evaluation based on trace-driven simulation shows that the proposed scheme significantly outperforms previously proposed approaches.
An analysis on the effect of image activity on lossy coding performance (2002)

When we compress a variety of images of different types using a fixed wavelet filter, it is seen that the peak signal-to-noise ratio (PSNR) values vary widely from image to image. This large variation in PSNR by as much as 30 dB, can mainly be attributed to a characteristic of the image known as Image Activity Measure (IAM). In this paper, we analyze a set of textures and images to determine the best measure of image activity. We show that such IAM is very effective in capturing the activities differentiating between various images. This IAM also links well with the PSNR value of the image in the lossy coding context. We establish this linkage in the form of an IAM-PSNR equation.
The United Nations (1999)

A recurrent theme of these lectures is the mismatch between the inescapable realities of interdependence on the one hand and fierce enduring loyalty to national identity and sovereignty, and to the nation-state system which expresses them, on the other. For the reasons explained in Lecture 1, the mismatch has been growing since the Industrial Revolution in Europe 200 years ago.1 As long as there is such a mismatch, a wide variety of organisations and arrangements will be required to help manage interdependence. There are indeed thousands of such organisations already in existence, all reflecting in their different ways the need for sovereign nations to act together rather than on their own. At one end of the spectrum these organisations may be concerned solely with regulatory functions in some limited specialist sphere. At the other end of the spectrum stand grand alliances with vital responsibilities for the safeguarding of peace. The organisations may be bilateral, plurilateral or indeed omnilateral; local, sectoral, regional, intersectoral, 'macro' or 'micro'. They all represent a certain national readiness, albeit reluctant, to accord to international bodies a measure of control over national affairs involving some sacrifice of sovereignty.KeywordsSecurity CouncilInternational PeacePermanent MemberCollective SecurityMember GovernmentThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.