gebhart/patrepeval huggingface dataset:
Identification of a DNA binding site for the nuclear factor YY1 in the human GM-CSF core promoter (1994)

It has been well documented that the repeated CATT(A/T) sequence, localized between -64 and -35 in the human GM-CSF promoter, is required for the promoter activity, and this region likely serves as a core recognition sequence for a cellular transcription factor. However, the transcription factor that interacts with this site was not identified. Here, we report that this element contains a binding site for the nuclear factor YY1, which has not been reported to play a role in the regulation of cytokine gene transcription. Results from transient transfection assays of the Jurkat T cell line revealed that this repeated CATT(A/T) element exhibited enhancer activity when linked to both the human IFN-gamma promoter and the TK promoter. Mutation of the YY1 binding site eliminated about 60% of the enhancer activity of the element. We have found that the YY1 binding site could form two specific DNA-protein complexes, A and B, with Jurkat nuclear proteins in the electrophoretic mobility shift assay and that the binding of these complexes correlates with the enhancer activity. UV cross-linking analysis revealed that the A complex is a multi-protein complex and in addition to YY1, other proteins are required for formation of the protein complex. Cotransfection assays with a YY1 expression vector revealed that overexpression of YY1 resulted in an inhibitory effect on the repeated CATT(A/T) element, indicating that in addition to YY1, cofactors also are required for the activator function of the A complex.
Intracellular signalling by binding sites for the antipsoriatic agent monomethylfumarate on human granulocytes. (1997)

Monomethylfumarate (MMF), the most active metabolite of the new antipsoriasis drug Fumaderm, stimulates an anti-inflammatory mediator profile in human leucocytes and inhibits the proliferation of keratinocytes. These effects of MMF on cells in vitro may in part explain the beneficial action of Fumaderm in patients. In addition, we have reported that MMF stimulates an increase in the intracellular free Ca2+ concentration ([Ca2+]i) and the cyclic adenosine monophosphate (cAMP) concentration in granulocytes and keratinocytes. Because Ca2+ and cAMP control many physiological cellular responses, including cell proliferation and inflammatory mediator production, the present study focused on the intracellular signal transduction pathway which links interaction between MMF and granulocytes with increases in [Ca2+]i and the cAMP concentration. The increase in [Ca2+]i in granulocytes after MMF depended both on extracellular Ca2+ and Ca2+ from intracellular stores. Ca2+ is essential for the increase in the cAMP concentration after stimulation with MMF. The results found for pharmacological inhibitors of various protein kinases suggest that a staurosporine-sensitive protein kinase different from protein kinase C (PKC) and protein kinase A is involved in the MMF-induced increase in [Ca2+]i in granulocytes. As MMF activated protein tyrosine kinase (PTK), and inhibition of this protein kinase partially reduced the increase in [Ca2+]i in granulocytes, PTK activity most likely is involved. In addition, activation of protein kinase histone 4 (PKH4) probably plays a part in the MMF-stimulated increase in [Ca2+]i in granulocytes as well. As MMF stimulated an increase in the GTP-ase activity of membranes and pertussis toxin (PTX) inhibited the increase in the [Ca2+]i and PKH4 activity of granulocytes stimulated by this compound, it is concluded that MMF activates PTX-sensitive G proteins. Competition binding studies with radiolabelled dimethylfumarate (DMF) and unlabelled DMF and MMF revealed the presence of specific binding sites for methylated fumarates on granulocytes. In summary, MMF binds to specific sites on the plasma membrane of cells. This interaction activates pertussis toxin-sensitive G proteins which then stimulate an increase in PTK and PKH4 activity. These protein kinases may regulate the rise in [Ca2+]i and the intracellular cAMP concentration. Elevated [Ca2+]i and intracellular cAMP concentration stimulate protein kinases that regulate transcription factors. Activation of these factors results in induction of downstream gene expression and thus controls cell functions, e.g. cell proliferation and production of inflammatory mediators, as has been found for cells incubated with MMF.
Towards K-means-friendly Spaces: Simultaneous Deep Learning and Clustering (2016)

Most learning approaches treat dimensionality reduction (DR) and clustering separately (i.e., sequentially), but recent research has shown that optimizing the two tasks jointly can substantially improve the performance of both. The premise behind the latter genre is that the data samples are obtained via linear transformation of latent representations that are easy to cluster; but in practice, the transformation from the latent space to the data can be more complicated. In this work, we assume that this transformation is an unknown and possibly nonlinear function. To recover the `clustering-friendly' latent representations and to better cluster the data, we propose a joint DR and K-means clustering approach in which DR is accomplished via learning a deep neural network (DNN). The motivation is to keep the advantages of jointly optimizing the two tasks, while exploiting the deep neural network's ability to approximate any nonlinear function. This way, the proposed approach can work well for a broad class of generative models. Towards this end, we carefully design the DNN structure and the associated joint optimization criterion, and propose an effective and scalable algorithm to handle the formulated optimization problem. Experiments using different real datasets are employed to showcase the effectiveness of the proposed approach.
Long-Term Survivorship in Multiple Endocrine Neoplasia Type 2B Diagnosed Before and in the New Millennium (2017)

Patients with MEN2B developed MTC at an early age with wide ranging aggressiveness, but the outcome was generally better after 2000 than before 2000.
Biochemical differences among four inosinate dehydrogenase inhibitors, mycophenolic acid, ribavirin, tiazofurin, and selenazofurin, studied in mouse lymphoma cell culture. (1985)

The mechanism of the cellular toxicity of four inosinate dehydrogenase (IMP-DH) inhibitors with different antitumor and antiviral pharmacological profiles was investigated in mouse lymphoma (S-49) cell culture. Drug effects on cell growth, nucleotide pools, and DNA and RNA synthesis were measured in the presence and absence of guanine salvage supplies. Both guanine and guanosine were capable of bypassing the IMP-DH block, while they also demonstrated some growth-inhibitory effects when added alone in high concentrations. All four drugs reduced cellular guanosine triphosphate levels and caused secondary changes of the uridine, cytidine, and adenosine triphosphate pools that were similar among the four drugs. However, several drug effects in addition to IMP-DH inhibition were observed except with mycophenolic acid which may represent a pure IMP-DH inhibitor. Both tiazofurin and selenazofurin interfered with the uptake and/or metabolism of uridine and thymidine tracers; however, this effect appeared not to contribute to their cellular toxicity in vitro. Moreover, selenazofurin and tiazofurin impaired the utilization of exogenous guanine salvage supplies for DNA and RNA synthesis, and guanine was particularly ineffective in reversing the toxic effects of tiazofurin on cell growth. This finding is important in view of the available guanine salvage supplies in vivo. Since tiazofurin, selenazofurin, and their known metabolites failed to inhibit hypoxanthine-guanine-phosphoribosyl transferase, guanosine monophosphate kinase, and guanosine diphosphate kinase in cell extracts or permeabilized cells, these drugs may interfere with salvage transport across cellular membranes. The toxic effects of mycophenolic acid and ribavirin were similarly reversed by salvage supplies of up to 200 microM guanine, which suggests that ribavirin primarily acts as an IMP-DH inhibitor under these conditions. This result could explain the rather low antitumor efficacy of both mycophenolic acid and ribavirin in vivo. However, increasing the guanine salvage supply in the medium above 200 microM further reversed the toxic effects of mycophenolic acid to maximum rescue, while it increased the toxicity of ribavirin (300 microM). This finding suggests the presence of a toxic mechanism of ribavirin at higher concentrations that is dependent upon the presence of guanine supplies sufficient to fully overcome the IMP-DH inhibition. This study documents that each antimetabolite displays a unique spectrum of activities with multiple toxic targets.
Formation of functional peptide complexes of class II major histocompatibility complex proteins from subunits produced in Escherichia coli. (1993)

Class II major histocompatibility complex molecules play a major role in the immune response by binding peptide fragments of exogenous antigens and displaying them on the surfaces of antigen-presenting cells, where they can be recognized by T cells. To facilitate structural and functional studies of these molecules, we have produced truncated alpha and beta chains of the murine class II molecule I-Ek in Escherichia coli (Ec-I-Ek) and have developed conditions to fold them in the presence of specific peptides with yields of complex approaching 2%. Reconstitution is specific since only unlabeled peptide known to bind I-Ek compete with biotinylated peptide, as assessed by ELISA. Complexes of the refolded heterodimer (Ec-I-Ek) with either of two different peptide antigens remain associated during nonreducing SDS/PAGE. Immobilized Ec-I-Ek-peptide complexes stimulate lymphokine production by three T-cell clones in an antigen-specific manner with a dose-response relation comparable to previously described soluble I-Ek molecules produced in CHO cells. These results demonstrate that folding of Ek alpha and Ek beta polypeptides does not require any other protein to produce the biologically relevant conformation and that carbohydrate modification of this class II molecule is not necessary for alpha beta T-cell recognition.
Low temperature wafer direct bonding (1994)

A pronounced increase of interface energy of room temperature bonded hydrophilic Si/Si, Si/SiO/sub 2/, and SiO/sub 2//SiO/sub 2/ wafers after storage in air at room temperature, 150/spl deg/C for 10-400 h has been observed. The increased number of OH groups due to a reaction between water and the strained oxide and/or silicon at the interface at temperatures below 110/spl deg/C and the formation of stronger siloxane bonds above 110/spl deg/C appear to be the main mechanisms responsible for the increase in the interface energy. After prolonged storage, interface bubbles are detectable by an infrared camera at the Si/Si bonding seam. Desorbed hydrocarbons as well as hydrogen generated by a reaction of water with silicon appear to be the major contents in the bubbles. Design guidelines for low temperature wafer direct bonding technology are proposed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Successful Opacification of the Left Heart Chambers on Echocardiographic Examination after Intravenous Injection of a New Saccharide Based Contrast Agent (1990)

A new monosaccharide microparticle based echocardiographic contrast agent (SH U 508) was injected intravenously into five healthy male volunteers following which the heart was imaged in an apical four-chamber view. Volumes of 2, 4, 8, and 16 mL of SH U 508 were incrementally injected into each volunteer. Concentrations of 50, 100, 200, 300, and 400 mg microparticles per mL of suspension were used in five successive examinations. Left heart opacification of diagnostic value was obtained during the whole cardiac cycle with concentrations of 300 and 400 mg/mL. There was no interference in imaging of the left ventricular walls due to increased attenuation. SH U 508 showed a good tolerance. No side effect was observed and no clinical relevant changes were observed in the heart rate, blood pressure, ECG, blood chemistry, hematology or urinalysis findings. This new agent may greatly extend the role of cardiac ultrasound and may also permit the examination of the arterial circulation in other organs.
Topical corticosteroid therapy in psoriasis vulgaris: update and new strategies. (1999)

This is an update of a previous report on the use of topical steroids in the management of psoriasis vulgaris. The current focus is on new combination therapies that enhance the efficacy of corticosteroids while diminishing their potential side effects.
3D-Stacked Many-Core Architecture for Biological Sequence Analysis Problems (2017)

Sequence analysis plays extremely important role in bioinformatics, and most applications of which have compute intensive kernels consuming over 70% of total execution time. By exploiting the compute intensive execution stages of popular sequence analysis applications, we present and evaluate a VLSI architecture with a focus on those that target at biological sequences directly, including pairwise sequence alignment, multiple sequence alignment, database search, and short read sequence mappings. Based on coarse grained reconfigurable array we propose the use of many-core and 3D-stacked technologies to gain further improvement over memory subsystem, which gives another order of magnitude speedup from high bandwidth and low access latency. We analyze our approach in terms of its throughput and efficiency for different application mappings. Initial experimental results are evaluated from a stripped down implementation in a commodity FPGA, and then we scale the results to estimate the performance of our architecture with 9 layers of $$70 \hbox { mm}^{2}$$ stacked wafers in 45-nm process. We demonstrate numerous estimated speedups better than corresponding existed hardware accelerator platforms for at least 40 times for the entire range of applications and datasets of interest. In comparison, the alternative FPGA based accelerators deliver only improvement for single application, while GPGPUs perform not well enough on accelerating program kernel with random memory access and integer addition/comparison operations.
Re-emergence of interferon-α in the treatment of chronic myeloid leukemia (2012)

Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-α (IFNα), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNα, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNα in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNα were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNα exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical studies have demonstrated that the combination of imatinib and IFNα is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNα often impede its administration, especially in combination therapy. Here, we review the role of IFNα in CML treatment and the recent developments that have renewed interest in this once standard therapy for patients with CML.
Biochemical, functional and potency characteristics of type A botulinum toxin in clinical use (2008)

Dysport? (botulinum type A toxin; BoNT-A) 500 LD50 unit vial was first licensed for clinical use in 1990. Inter-batch reproducibility and comparability of the Dysport toxin?haemagglutinin complex must ensure the consistency of clinical material. The specific potency (potency per unit weight of toxin protein) provides the level of protein administered per injection. We report a high degree of batch-to-batch consistency for the long-term specific potency of Dysport, with a mean toxin protein content of 4.35 ng per 500 LD50 unit vial, based upon consistent bulk toxin data. Additional biochemical and functional data demonstrate the consistency and reliability of Dysport. [Received 4 November 2007; Accepted 12 December 2007]
Pancreas islets in metabolic signaling - focus on the beta-cell (2008)

The Islets of Langerhans form a nutrient sensing network spread throughout the pancreas. They are tightly connected to the source organ, the intestine, and the target organs--liver, muscle, and fat cells. The expression of a unique set of proteins enables beta cells, the most frequent islet cell type, to detect elevated blood glucose levels and secrete insulin accordingly. Clustered beta-cells achieve tighter regulation of glucose-induced insulin secretion by coordination through cell surface proteins. They also adjust their secretory capacity and flow to avoid being damaged. The immediate reaction of the beta cell to nutrients is regulated by translational mechanisms, while longer term adaptations involve changes in transcription. Glucose increases overall protein synthesis in beta-cells but selectively boosts translation of some secretory proteins including insulin. This may be mediated through recognition of RNA motifs in the untranslated regions of those messengers. If essential molecular components of this nutrient sensing system are broken or fail due to repeated stress, beta cells malfunction, which on a larger scale manifest as diseases like diabetes mellitus.
Photoluminescence of CdSe Nanoparticles in the Presence of a Hole Acceptor:  n-Butylamine (2001)

Addition of butylamine to a solution of colloidal CdSe nanoparticles (NPs) caused a decrease in fluorescence intensity, with no effect on the picosecond bleach recovery of the exciton formation or on the luminescence dynamics. The relative fluorescence quantum yield was found to decrease with increasing butylamine concentration and to level off at high concentrations, but the fluorescence lifetimes were not influenced. The nonlinear concentration dependence of the fluorescence quantum yield did not follow the Stern−Volmer equation. This is in agreement with the observation that the CdSe luminescence lifetime was not affected by the addition of butylamine. A mechanism is proposed in which the emission observed in CdSe is assumed to result from the combination of surface-trapped electrons and holes. n-Butylamine occupies hole sites, thus blocking the recombination process, which results in decreasing the density of luminescent centers. These results will be discussed in terms of the nature of the binding sites of the amine on the nanoparticle surface.
Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects (2010)

Adoptive transfer of viral antigen-specific memory T cells can reconstitute antiviral immunity, but in a recent report a majority of virus-specific cytotoxic T-lymphocyte (CTL) lines showed in vitro cross-reactivity against allo-human leukocyte antigen (HLA) molecules as measured by interferon-γ secretion. We therefore reviewed our clinical experience with adoptive transfer of allogeneic hematopoietic stem cell transplantation donor-derived virus-specific CTLs in 153 recipients, including 73 instances where there was an HLA mismatch. There was no de novo acute graft-versus-host disease after infusion, and incidence of graft-versus-host disease reactivation was low and not significantly different in recipients of matched or mismatched CTL. However, we found that virus-specific T cell lines recognized up to 10% of a panel of 44 HLA disparate targets, indicating that virus-specific T cells can have cross-reactivity with HLA-mismatched targets in vitro. These data indicate that the adoptive transfer of partially HLA-mismatched virus-specific CTL is safe despite in vitro recognition of recipient HLA molecules.
Activation of the GLP-1 Receptor Signalling Pathway: A Relevant Strategy to Repair a Deficient Beta-Cell Mass (2011)

Recent preclinical studies in rodent models of diabetes suggest that exogenous GLP-1R agonists and DPP-4 inhibitors have the ability to increase islet mass and preserve beta-cell function, by immediate reactivation of beta-cell glucose competence, as well as enhanced beta-cell proliferation and neogenesis and promotion of beta-cell survival. These effects have tremendous implication in the treatment of T2D because they directly address one of the basic defects in T2D, that is, beta-cell failure. In human diabetes, however, evidence that the GLP-1-based drugs alter the course of beta-cell function remains to be found. Several questions surrounding the risks and benefits of GLP-1-based therapy for the diabetic beta-cell mass are discussed in this review and require further investigation.
Cutting Edge: Epigenetic Regulation of Foxp3 Defines a Stable Population of CD4+ Regulatory T Cells in Tumors from Mice and Humans (2014)

CD4(+) regulatory T cells (Tregs) are critical for maintaining self-tolerance and function to prevent autoimmune disease. High densities of intratumoral Tregs are generally associated with poor patient prognosis, a correlation attributed to their broad immune-suppressive features. Two major populations of Tregs have been defined, thymically derived natural Tregs (nTregs) and peripherally induced Tregs (iTregs). However, the relative contribution of nTregs versus iTregs to the intratumoral Treg compartment remains controversial. Demarcating the proportion of nTregs versus iTregs has important implications in the design of therapeutic strategies to overcome their antagonistic effects on antitumor immune responses. We used epigenetic, phenotypic, and functional parameters to evaluate the composition of nTregs versus iTregs isolated from mouse tumor models and primary human tumors. Our findings failed to find evidence for extensive intratumoral iTreg induction. Rather, we identified a population of Foxp3-stable nTregs in tumors from mice and humans.
Messenger RNA for FOXP3 in the Urine of Renal-Allograft Recipients (2005)

Measurement of FOXP3 mRNA in urine may offer a noninvasive means of improving the prediction of outcome of acute rejection of renal transplants.