Menin promotes the commitment of pluripotent mesenchymal stem cells to the osteoblast lineage by interacting with the BMP-2 signaling molecules Smad1/5, and Runx2. However, the relationship between ...menin and the Wnt-β-catenin pathway in bone is unclear. Reduction of menin expression by transfection of a menin antisense construct did not alter the levels of β-catenin in mouse mesenchymal C2C12 and osteoblastic MC3T3-E1 cells. However, menin co-immunoprecipitated with β-catenin as well as LEF-1 in C2C12 and MC3T3-E1 cells. Reduction of menin expression by antisense menin transfection antagonized β-catenin-induced transcriptional activity of the pGL3-OT luciferase reporter construct in C2C12 and MC3T3-E1 cells. Antisense menin transfection antagonized the BMP-2 and β-catenin-stimulated increases in Runx2 and alkaline phosphatase levels in C2C12 cells. The data show that menin interacts with β-catenin in mouse mesenchymal and osteoblastic cells, and suggest that the interaction is important for osteoblast differentiation.
To compare blood flow response to arterial carbon dioxide tension change in the heart and brain of normal elderly men. Thirteen healthy elderly male volunteers were studied. Hypercapnea was induced ...by carbon dioxide inhalation and hypocapnea was induced by hyperventilation. Myocardial blood flow mL min⁻¹ x (100 g of perfusable tissue)⁻¹ and cerebral blood flow mL min⁻¹ x (100 g of perfusable tissue)⁻¹ were measured simultaneously at rest, under carbon dioxide gas inhalation and hyperventilation using the combination of two positron emission tomography scanners. Arterial carbon dioxide tension increased significantly during carbon dioxide inhalation (43.1 ± 2.7 mmHg, P < 0.05) and decreased significantly during hyperventilation (29.2 ± 3.4 mmHg, P < 0.01) from baseline (40.2 ± 2.4 mmHg). Myocardial blood flow increased significantly during hypercapnea (88.7 ± 22.4, P < 0.01) from baseline (78.2 ± 12.6), as did the cerebral blood flow (baseline: 39.8 ± 5.3 vs. hypercapnea: 48.4 ± 10.4, P < 0.05). During hypocapnea cerebral blood flow decreased significantly (27.0 ± 6.3, P < 0.01) from baseline as did the myocardial blood flow (55.1 ± 14.6, P < 0.01). However, normalized myocardial blood flow by cardiac workload 100 mL mmHg⁻¹ x (heart beat)⁻¹ x (gram of perfusable tissue)⁻¹ was not changed from baseline (93.4 ± 16.6) during hypercapnea (90.5 ± 14.3) but decreased significantly from baseline during hypocapnea (64.5 ± 18.3, P < 0.01). In normal elderly men, hypocapnea produces similar vasoconstriction both in the heart and brain. Mild hypercapnea increased cerebral blood flow but did not have an additional effect to dilate coronary arteries beyond the expected range in response to an increase in cardiac workload.
Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate ...diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.
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•A few genes differ on alteration frequencies in UTUC and UBC•UTUC comprises five molecular subtypes: hypermutated, TP53/MDM2, RAS, FGFR3, and TN•UTUC subtypes correlate with gene expression, histology, and clinical outcomes•Sequencing urinary sediment is a non-invasive diagnostic tool for UTUC
Based on an integrated genomic analysis of 199 upper urinary tract urothelial carcinomas (UTUCs), Fujii et al. identify five genetic subtypes with discrete profile of gene mutation, expression, histology, and clinical outcome and also demonstrate a high diagnostic value of sequencing urinary sediment-derived DNA for non-invasive detection of UTUCs.
Measurements of reflectance in visible and near-infrared spectral regions were made on detached leaves of two crop species of different leaf morphology, structure, and water content (peanut and ...wheat) troughout progressive desiccation. Relative water content (RWC) was well correlated with water index (WI) but even better with the ratio of WI and normalized difference vegetation index. RWC was also significantly correlatred with structural independent pigment index indicative of carotenoids/chlorophyll ratio. New indication is thus provided to assess leaf water content and apply simple and fast radiometric techniques for plant water stress management.
The possibility of using exhaled breath as a substitute for blood/plasma in areas of therapeutic drug monitoring was investigated. Theophylline was used as a model chemical of non-volatile drugs and ...the adsorbents suitable for drug capture from exhaled breath were studied. Two macro-porous adsorbents with different monomer compositions were prepared by suspension copolymerization. The capture properties of the synthesized adsorbents and two conventional gas adsorbents packed in a cartridge were evaluated by both aerosol generation and rat expiration. The efficiency of drug capture did not improve by decreasing the pore size and by increasing the specific surface area. A hydrophilic region was found to be necessary for holding the aerosol particles on the adsorbent surface, but a hydrophobic region is also necessary for the adsorption of theophylline. The materials were applied to the intravenous bolus experiment of rats. The amount of theophylline collected from exhaled breath was in the range of 0-0.02 ng min
−1
, and it varied similarly to the concentration in blood, which was in the range of 0-37 μg mL
−1
.
The possibility of using exhaled breath as a substitute for blood/plasma in areas of therapeutic drug monitoring was investigated.
Sample size determination is among the most commonly encountered tasks in statistical practice. A broad range of frequentist and Bayesian methods for sample size determination can be described as ...choosing the smallest sample that is sufficient to achieve some set of goals. An example for the frequentist is seeking the smallest sample size that is sufficient to achieve a desired power at a specified significance level. An example for the Bayesian is seeking the smallest sample size necessary to obtain, in expectation, a desired rate of correct classification of the hypothesis as true or false. This article explores parallels between Bayesian and frequentist methods for determining sample size. We provide a simple but general and pragmatic framework for investigating the relationship between the two approaches, based on identifying mappings to connect the Bayesian and frequentist inputs necessary to obtain the same sample size. We illustrate this mapping with examples, highlighting a somewhat surprising "approximate functional correspondence" between power-based and information-based optimal sample sizes.
Focal adhesion kinase (Fak) has been implicated as a signaling molecule involved in the early response of cardiac myocytes to mechanical stress. The mechanism of Fak activation by mechanical stimuli ...is not clear. In this study, we report the load-induced Fak activation and its association with myosin heavy chain in cardiac myocytes. Pressure overload lasting from 3 to 60 minutes was shown to induce Fak phosphorylation at Tyr-397, -576/7, -861, and -925 as detected by phosphospecific antibodies. This was paralleled by increases of Fak/Src association and Src activity (Tyr-418 phosphorylation). Yeast two-hybrid screening of an adult rat cDNA library revealed an interaction between Fak and C-terminal coiled-coil region of α-myosin heavy chain. This was confirmed by pulldown assay with GST-C-terminal myosin fragment and native Fak from rat left ventricle. Such interaction was confirmed by coimmunoprecipitation assay with anti-Fak and anti–heavy chain cardiac myosin antibodies, confocal microscopy of double-labeled isolated cardiac myocytes and immunoelectron microscopy with anti-Fak antibody. Fak activation by mechanical stress was accompanied by a reduction of Fak/myosin heavy chain association and its relocation at subcellular sites such as costameres, Z-discs, and nuclei. Thus, our present data identify Fak interaction with C-terminal region of myosin heavy chain adding comprehensive data on Fak activation by mechanical stress and mechanotransduction in cardiac myocytes.
This paper proposes a cascade-connected arrayed-waveguide grating (AWG) as a solution to the problem of crosstalk accumulation in a large-scale AWG multiplexer/demultiplexer (MUX/DEMUX) and ...demonstrates a 64-channel cascaded AWG module with a very low background crosstalk of less than -80 dB and a total crosstalk of about -34 dB. In this paper, the authors densely integrate 64 additional compactly designed crosstalk-suppressing AWGs whose bandwidths were carefully optimized and directly attach them to a conventional 64-channel AWG. Consequently, in addition to a very low crosstalk, a low insertion loss and a compact size without passband shape distortion are achieved with this module. Based on the performance of the cascaded AWG module, it is then estimated that it is possible to realize a 1000-channel AWG MUX/DEMUX that is free from the problem of crosstalk accumulation.
The immune response is regulated, in part, by effector cells whose activation requires multiple signals. For example, T cells require signals emanating from the T cell antigen receptor and ...co-stimulatory molecules for full activation. Here, we present evidence indicating that IgE-mediated hypersensitivity reactions in vivo also require cognate signals to activate mast cells. Immediate hypersensitivity reactions in the conjunctiva are ablated in mice deficient in eotaxin-1, despite normal numbers of tissue mast cells and levels of IgE. To further define the co-stimulatory signals mediated by chemokine receptor 3 (CCR3), an eotaxin-1 receptor, effects of CCR3 blockade were tested with an allergic conjunctivitis model and in ex vivo isolated connective tissue-type mast cells. Our results show that CCR3 blockade significantly suppresses allergen-mediated hypersensitivity reactions as well as IgE-mediated mast cell degranulation. We propose that a co-stimulatory axis by CCR3, mainly stimulated by eotaxin-1, is pivotal in mast cell-mediated hypersensitivity reactions.
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