gebhart/patrepeval huggingface dataset:
Insulin regulates the activity of forkhead transcription factor Hnf-3β/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization (2003)

Hepatocyte nuclear factors 3 alpha, beta, and gamma (Foxa-1, -2, and -3) are transcriptional activators of important metabolic genes in the liver that are suppressed by the actions of insulin. Here, we show that the activation of phosphatidylinositol 3-kinase-Akt by insulin induces Foxa-2 phosphorylation, nuclear exclusion, and inhibition of Foxa-2-dependent transcriptional activity. Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. These results implicate an evolutionarily conserved mechanism in the regulation of Foxa-2-dependent transcriptional control by extracellular signals such as insulin.
T cell responses to human malignant tumours. (1992)

The immunological and molecular mechanisms that govern T cell responses to human malignant tumours are just starting to be understood within a more complex framework of humoral, cellular and molecular interactions. The definition of multiple antigens simultaneously expressed on human melanoma, as detected with cytolytic T cells in immunoselection experiments, is a first step towards the molecular characterization of these antigens. Observations on the influence of expression of restriction elements of the major histocompatibility complex on the recognition of these tumour associated antigens have advanced our understanding of how the immune system responds to cancer cells in vivo. It is specificity that is tuning the immune system, not only in cancer. The molecular characterization of the first human cancer antigen recognized by CTL is now under way as outlined by Boon et al in this issue.
Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo (2013)

Recent basic and clinical studies have shown that the programmed death ligand (PD-L)/PD-1 pathway has a significant role in tumour immunity, and its blockade has a therapeutic potential against several human cancers. We hypothesized that anti-angiogeneic treatment might augment the efficacy of PD-1 blockade. To this end, we evaluated combining the blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2) in a murine cancer model using Colon-26 adenocarcinoma. Interestingly, simultaneous treatment with anti-PD-1 and anti-VEGFR2 monoclonal antibodies (mAbs) inhibited tumour growth synergistically in vivo without overt toxicity. Blocking VEGFR2 inhibited tumour neovascularization significantly, as demonstrated by the reduced number of microvessels, while PD-1 blockade had no impact on tumour angiogenesis. PD-1 blockade might promote T cell infiltration into tumours and significantly enhanced local immune activation, as shown by the up-regulation of several proinflammatory cytokine expressions. Importantly, VEGFR2 blockade did not interfere with T cell infiltration and immunological activation induced by PD-1 blockade. In conclusion, simultaneous blockade of PD-1 and VEGFR2 induced a synergistic in-vivo anti-tumour effect, possibly through different mechanisms that might not be mutually exclusive. This unique therapeutic strategy may hold significant promise for future clinical application.
Further study on the 1,4-.ALPHA.-transglucosylation of rubusoside, a sweet steviol-bisglucoside from Rubus suavissimus. (1991)

Rubusoside (the beta-D-glucosyl ester of 13-O-beta-D-glucosyl-steviol), which is the major sweet principle of leaves of Rubus suavissimus S. Lee, was subjected to 1,4-alpha-transglucosylation by the cyclodextringlucanotransferase-starch system (the CGTase system). The tri- and tetra-glucosylated products were isolated together with the mono- and di-glucosylated products, which had already been isolated. A prominent increase in intensity of the sweetness was observed for the compounds which were di- and tri-glucosylated at the 13-O-glucosyl moiety. This result further substantiated the structure-sweetness relationship for 1,4-alpha-glucosylated compounds of steviol-glycosides reported previously. For protection of the 19-COO-glucosyl moiety against glucosylation by the CGTase system, the 4-hydroxyl group of the 19-COO-glucosyl moiety was beta-galactosylated by the beta-galactosidase-lactose system. This galactosylated compound was subjected to a regio-selective glucosylation of the 13-O-glucosyl moiety by the CGTase system, which was followed by enzymic elimination of the galactosyl group to furnish an exclusive preparation of the improved sweeteners just mentioned.
Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. (2003)

Notch signaling plays a critical role in maintaining the balance between cell proliferation, differentiation, and apoptosis; hence, perturbed Notch signaling may contribute to tumorigenesis. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in Africa and Asia. The mechanisms that orchestrate the multiple oncogenic insults required for initiation and progression of HCC are not clear. We constitutively overexpressed active Notch1 in human HCC to explore the effects of Notch1 signaling on HCC cell growth and to investigate the underlying molecular mechanisms. We show here that overexpression of Notch1 was able to inhibit the growth of HCC cells in vitro and in vivo. Biochemical analysis revealed the involvement of cell cycle regulated proteins in Notch1-mediated G(0)/G(1) arrest of HCC cells. Compared with green fluorescent protein (GFP) control, transient transfection of Notch1 ICN decreased expression of cyclin A (3.5-fold), cyclin D1 (2-fold), cyclin E (4.5-fold), CDK2 (2.8-fold), and the phosphorylated form of retinoblastoma protein (3-fold). Up-regulation of p21(waf/cip1) protein expression was observed in SMMC7721-ICN cells stably expressing active Notch1 but not in SMMC7721-GFP cells, which only express GFP. Furthermore, a 12-fold increase in p53 expression and an increase (4.8-fold) in Jun-NH(2)-terminal kinase activation were induced in SMMC7721-ICN cells compared with SMMC7721-GFP cells. In contrast, expression of the antiapoptotic Bcl-2 protein could not be detected in SMMC7721-ICN cells. These findings suggest that Notch1 signaling may participate in the development of HCC cells, affecting multiple pathways that control both cell proliferation and apoptosis.
Coordinate Interaction between IL-13 and Epithelial Differentiation Cluster Genes in Eosinophilic Esophagitis (2010)

We have previously proposed that the pathogenesis of eosinophilic esophagitis (EE) is mediated by an IL-13-driven epithelial cell response associated with marked gene dysregulation including eotaxin-3 overproduction. In this study, we compared epithelial responses between healthy patients and those with EE, aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained for up to five passages, with 67% and 62% of cell lines reaching confluence in healthy controls and EE cases, respectively. Both sets of epithelial cells avidly responded to IL-13 at similar levels as assessed by eotaxin-3 production. Acidic pH increased cellular release of eotaxin-3 (4.6 +/- 1.98 ng/ml versus 12.46 +/- 2.90 ng/ml at pH 7.4 and 4, respectively; p < 0.05). Numerous epidermal differentiation complex (EDC) genes, such as filaggrin and SPRR3, were downregulated both in IL-13-stimulated esophageal epithelial cells and in EE biopsies specimens compared with healthy controls. Whereas the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared with control individuals (6.1% versus 1.3% respectively; p = 0.0172), the decreased filaggrin expression was uniformly seen in all EE cases in vivo. Indeed, expression of the EDC genes filaggrin and involucrin was strongly decreased directly by IL-13. These results establish that the epithelial response in EE involves a cooperative interaction between IL-13 and expression of EDC genes.
Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects (2003)

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior side-effect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.
Formation of High-Speed Motion Pattern of a Mechanical Arm by Trial (1978)

High-speed motion of a mechanical arm is necessary to speed up a job done by the arm. In high speed, however, the desired trajectory of motion of the arm cannot be obtained simply by applying the trajectory function to the servo system as the reference function because the time lag in the servo system is not negligible.A solution to this problem is to apply dynamically compensating computed torques to the servo system. By this method, however, for increasing the accuracy of the mathematical model of the arm necessary to compute the compensating torques, a very large effort would be required. To avoid this difficulty, an alternative method of correcting the reference function by trial will be useful. Repeating a proper process of trial and correction, the reference function which realizes the desired pattern of trajectory may be obtained.In this paper, correcting algorithm of a reference function for this method is investigated theoretically from the standpoint of stability or convergency of the process of trial and correction, and a stable correcting algorithm is obtained. Through the experiment using a mechanical arm of six degrees of freedom controlled by a digital computer, it is confirmed that the process of trial and correction by this algorithm is stable and the response of the servo system converges rapidly to the desired pattern of trajectory.
Generation of a Recombinant Cytomegalovirus for Expression of a Hantavirus Glycoprotein (2003)

A cytomegalovirus (CMV) was isolated from its natural host, Peromyscus maniculatus, and was designated Peromyscus CMV (PCMV). A recombinant PCMV was constructed that contained Sin Nombre virus glycoprotein G1 (SNV-G1) fused in frame to the enhanced green fluorescent protein (EGFP) gene inserted into a site homologous to the human CMV UL33 (P33) gene. The recombinant CMV was used for expression and immunization of deer mice against SNV-G1. The results of the study indicate that P. maniculatus could be infected with as few as 10 virus particles of recombinant virus. Challenge of P. maniculatus with either recombinant or wild-type PCMV produced no overt pathology in infected animals. P. maniculatus immunized with recombinant virus developed an antibody response to SNV and EGFP. When rechallenged with recombinant virus, animals exhibited an anamnestic response against SNV. Interestingly, a preexisting immune response against PCMV did not prevent reinfection with recombinant PCMV.
Body-contacted SOI MOSFET structure with fully bulk CMOS compatible layout and process (1997)

A new SOI MOSFET structure to reduce the floating body effect is proposed and successfully demonstrated. The key idea of the proposed structure is that the field oxide does not consume the silicon film completely, so that the well contact can suppress the body potential increase in SOI MOSFET through the remaining silicon film between the field oxide and buried oxide. The measured results show the suppressed floating body effect as expected. This new structure retains most of the advantages in the propagation delay of the conventional SOI MOSFET without body potential instability. An additional advantage of the proposed structure is that the layout and process are the same as those of bulk CMOS.
Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntington's disease (2013)

Psychiatric symptoms such as depression and anxiety are important clinical features of Huntington's disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST and EPM. The behavioral manifestations occurred in the absence of reduced hippocampal cell proliferation/neurogenesis or upregulation of the hypothalamic-pituitary-adrenal axis. However, alterations in anxiety- and depression-regulating genes were present in the hypothalamus of BACHD mice including reduced mRNA expression of neuropeptide Y, tachykinin receptor 3 and vesicular monoamine transporter type 2 as well as increased expression of cocaine and amphetamine regulated transcript. Interestingly, the orexin neuronal population in the hypothalamus was increased and showed cellular atrophy in old BACHD mice. Furthermore, inactivation of mutant huntingtin in a subset of the hypothalamic neurons prevented the development of the depressive features. Taken together, our data demonstrate that the BACHD mouse recapitulates clinical HD with early psychiatric aspects and point to the role of hypothalamic dysfunction in the development of depression and anxiety in the disease.
Bacterial oxidation of propane (1994)

The bacterial metabolism of propane and the pathway(s) involved are poorly understood, as the relative importance of terminal versus subterminal oxidation of propane, via propan-1-ol and propan-2-ol, respectively, is still unclear. In the case of bacteria, the ability to oxidize propane appears to be confined mainly to the Gram-positive Corynebacterium - Nocardia - Mycobacterium - Rhodococcus complex. Studies on propane oxidation have been hampered by a lack of firm enzymological data; for example, to date there are no reports of a purified propane oxygenase system. However, oxygenase activity has been confirmed by the production of propan-1-ol and/or propan-2-ol, and more recently by the co-oxidation of propene to 1,2-epoxypropane in cell extracts of propane-grown cells. Here, we review the use of genetic, biochemical and immunological techniques to assess the role(s) of terminal and subterminal oxidation in the metabolism of propane by Rhodococcus rhodochrous PNKb1 and present a general overview of the topic.
SPARKLING: variable‐density k‐space filling curves for accelerated T2*‐weighted MRI (2019)

The proposed optimization-driven design of k-space trajectories is a versatile framework that is able to enhance MR sampling performance in the context of compressed sensing.
Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease (2015)

To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer's disease. These findings have translational relevance to multiple neurodegenerative conditions.
Fluorinated Boron‐Dipyrromethene (BODIPY) Dyes: Bright and Versatile Probes for Surface Analysis (2013)

A family of bright boron-dipyrromethene-type fluorophores with a high number of fluorine atoms (F-BODIPYs) has been developed and characterized by X-ray crystallography and optical spectroscopy. The introduction of 3,5-bis(trifluoromethyl)phenyl and pentafluorophenyl moieties significantly enhances the photostability of such dyes, yielding for instance photostable near-infrared (NIR) fluorophores that show emission maxima>750 nm, when the BODIPY's π system is extended with two (dimethylamino)styryl and (dimethylamino)naphthastyryl moieties, or green-emitting BODIPYs with fluorescence quantum yields of unity. When equipped with a suitable group that selectively reacts for instance with amines, F-BODIPYs can be used as potent dual labels for the quantification of primary amino groups on surfaces by X-ray photoelectron spectroscopy (XPS) and fluorescence, two powerful yet complementary tools for the analysis of organic surface functional groups. The advantage of reactive F-BODIPYs is that they allow a fast and non-destructive mapping of the labelled supports with conventional fluorescence scanners and a subsequent quantification of selected areas of the same sample by the potentially traceable XPS technique. The performance is exemplarily shown here for the assessment of the amino group density on SiO2 supports, one of the most common reactive silica supports, in particular, for standard microarray applications.
Yeast KEX1 protease cleaves a prohormone processing intermediate in mammalian cells. (1990)

A vaccinia virus vector was used to express the yeast KEX1 gene, which encodes a prohormone carboxypeptidase specific for the removal of basic amino acids from prohormone processing intermediates, in mammalian cells. When produced in BSC-40 cells, Kex1p was localized to the perinuclear region and conferred a large increase in enzymatic activity characteristic of this carboxypeptidase. Expression of the KEX1 gene together with the yeast KEX2 gene, which encodes a prohormone endopeptidase specific for cleavage at pairs of basic amino acids, and the mouse proopiomelanocortin (mPOMC) cDNA in BSC-40 cells resulted in the full conversion of mPOMC to mature peptides including gamma-lipotropin. This in vivo processing of mPOMC to mature peptides by the KEX2/KEX1 gene products demonstrates a significant functional homology of the basic prohormone processing machinery in yeast and neuroendocrine cells.
Kinetic isotope effects on metaphosphate generation from fragmentation of 2,3‐oxaphosphabicyclo[2.2.2]octene derivatives (1996)

Kinetic isotope effects of deuterium and oxygen-18 were measured on fragmentation of syn-3-ethoxy (1a) and syn-3-(N,N-diethylamino) (1b) 2,3-oxaphosphabicyclo[2.2.2]octene derivatives in 1,2-dichloroethane at 100°C. The secondary deuterium isotope effect on hydrogen adjacent to the P(SINGLE BOND)C bond was found to be 1.060 ± 0.008 for 1a and 1.081 ± 0.009 for 1b. The kinetic oxygen isotope effect on the bridge P(SINGLE BOND)O(SINGLE BOND)C is 0.9901 ± 0.0016 for 1a. The data indicate an unsymmetrical transition state for retrocycloaddition extrusion of the metaphosphate moiety, with the breakage of the C(SINGLE BOND)P bond and formation of the P (DOUBLE BOND) O bond more advanced than the C(SINGLE BOND)O breakage. A synthesis of 1a and 1b labeled with deuterium is described. © 1996 John Wiley & Sons, Inc.
1.3 μm InAs/GaAs quantum‐dot laser monolithically grown on Si substrates operating over 100°C (2014)

A high‐performance 1.3 μm InAs/GaAs quantum‐dot laser directly grown on Si substrates has been achieved by using InAlAs/GaAs strained‐layer superlattice serving as dislocation filter layers (DFLs). The Si‐based laser achieves lasing operation up to 111°C with a threshold current density of 200 A/cm 2 and an output power exceeding 100 mW at room temperature.