Coherent coupling of metamaterial resonators with dipole transitions of boron acceptors in Si.

We investigate the coherent coupling of metamaterial resonators with hydrogen-like boron acceptors in Si at cryogenic temperatures. When the resonance frequency of the metamaterial, chosen to be in the range 7-9 THz, superimposes the transition frequency from the ground state of the acceptor to an excited state, Rabi splitting as large as 0.4 THz is observed. The coherent coupling shows a feature of cooperative interaction, where the Rabi splitting is proportional to the square root of the density of the acceptors. Our experiments may help to open a possible route for the investigation of quantum information processes employing strong coupling of dopants in cavities.

Point mutations that inactivate MGAT4D-L, an inhibitor of MGAT1 and complex N-glycan synthesis.

The membrane-bound, long form of MGAT4D, termed MGAT4D-L, inhibits MGAT1 activity in transfected cells and reduces the generation of complex N-glycans. MGAT1 is the GlcNAc-transferase that initiates complex and hybrid N-glycan synthesis. We show here that Drosophila MGAT1 was also inhibited by MGAT4D-L in S2 cells. In mammalian cells, expression of MGAT4D-L causes the substrate of MGAT1 (Man5GlcNAc2Asn) to accumulate on glycoproteins, a change that is detected by the lectin Galanthus nivalis agglutinin (GNA). Using GNA binding as an assay for the inhibition of MGAT1 in MGAT4D-L transfectants, we performed site-directed mutagenesis to determine requirements for MGAT1 inhibition. Deletion of 25 amino acids (aa) from the C terminus inactivated MGAT4D-L, but deletion of 20 aa did not. Conversion of the five key amino acids (PSLFQ) to Ala, or deletion of PSLFQ in the context of full-length MGAT4D-L, also inactivated MGAT1 inhibitory activity. Nevertheless, mutant, inactive MGAT4D-L interacted with MGAT1 in co-immuno-precipitation experiments. The PSLFQ sequence also occurs in MGAT4A and MGAT4B GlcNAc-transferases. However, neither inhibited MGAT1 in transfected CHO cells. MGAT4D-L inhibitory activity could be partially transferred by attaching PSLFQ or the 25-aa C terminus of MGAT4D-L to the C terminus of MGAT1. Mutation of each amino acid in PSLFQ to Ala identified both Leu and Phe as independently essential for MGAT4D-L activity. Thus, replacement of either Leu-395 or Phe-396 with Ala led to inactivation of MGAT4D-L inhibitory activity. These findings provide new insights into the mechanism of inhibition of MGAT1 by MGAT4D-L, and for the development of small molecule inhibitors of MGAT1.

Quantitative structural analysis of glycans expressed within tumors derived from pancreatic cancer patient-derived xenograft mouse models.

Pancreatic ductal adenocarcinoma (PDAC) is an intractable malignancy for which novel therapeutic targets are in high demand. To uncover glycans expressed within PDAC, we previously performed glycome profiling of PDAC cell lines using lectin microarray and found that the lectin rBC2LCN with specificity to a Fucα1-2Galß1-3 motif exhibited strong binding to a PDAC cell line (Capan-1) and to all tumor tissues derived from 69 pancreatic cancer patients. Nevertheless, no information was available as to whether glycans containing the Fucα1-2Galß1-3 motif are expressed within PDAC. Here we used HPLC combined with MALDI-TOFMS to perform a structural and quantitative glycome analysis targeting both N- and O-glycans derived from two types of patient-derived PDAC xenograft mouse models, PC3 (well-differentiated) and PC42 (poorly-differentiated). A higher percentage of highly branched and sialylated complex-type N-glycans was detected in PC42 relative to PC3. The percentage of core 1 O-glycans was higher in PC42 relative to PC3, whereas that of core 3 O-glycans was higher in PC3. Cancer-related glycan epitopes such as Lewis A and Lewis Y were detected in core 3 O-glycans of both PC3 and PC42. H-type3 containing the Fucα1-2Galß1-3 motif was detected in Core 2 O-glycans in both models, explaining the molecular mechanism of the binding of rBC2LCN to PDAC.

Hybrid optical imaging with near-infrared, mid-infrared, and terahertz wavelengths for nondestructive inspection [Invited].

Optical imaging is a powerful tool for nondestructive inspection, with high spatial resolution and low invasiveness. As light-material interactions vary a great deal depending on the wavelength, it is difficult to select the best imaging wavelength without prior knowledge of the optical properties of the material. To overcome this difficulty, we constructed a hybrid optical imaging system using three different wavelengths: near-infrared (NIR), mid-infrared (MIR), and terahertz (THz) regions. The same imaging optics were integrated with different light sources and detectors. Depending on the light-material interaction and detection sensitivity, NIR and THz imaging indicated some potential for nondestructive inspection, but MIR imaging showed difficulty. A combination of NIR and THz imaging will be a powerful tool for optical nondestructive inspection.

Terahertz Emitter Using Resonant-Tunneling Diode and Applications.

A compact source is important for various applications utilizing terahertz (THz) waves. In this paper, the recent progress in resonant-tunneling diode (RTD) THz oscillators, which are compact semiconductor THz sources, is reviewed, including principles and characteristics of oscillation, studies addressing high-frequency and high output power, a structure which can easily be fabricated, frequency tuning, spectral narrowing, different polarizations, and select applications. At present, fundamental oscillation up to 1.98 THz and output power of 0.7 mW at 1 THz by a large-scale array have been reported. For high-frequency and high output power, structures integrated with cylindrical and rectangular cavities have been proposed. Using oscillators integrated with varactor diodes and their arrays, wide electrical tuning of 400-900 GHz has been demonstrated. For spectral narrowing, a line width as narrow as 1 Hz has been obtained, through use of a phase-locked loop system with a frequency-tunable oscillator. Basic research for various applications-including imaging, spectroscopy, high-capacity wireless communication, and radar systems-of RTD oscillators has been carried out. Some recent results relating to these applications are discussed.

Discrete Fourier Transform Radar in the Terahertz-Wave Range Based on a Resonant-Tunneling-Diode Oscillator.

We used a resonant-tunneling-diode (RTD) oscillator as the source of a terahertz-wave radar based on the principle of the swept-source optical coherence tomography (SS-OCT). Unlike similar reports in the terahertz range, we apply the stepwise frequency modulation to a subcarrier obtained by amplitude modulation instead of tuning the terahertz carrier frequency. Additionally, we replace the usual optical interference with electrical mixing and, by using a quadrature mixer, we can discriminate between negative and positive optical path differences, which doubles the measurement range without increasing the measurement time. To measure the distance to multiple targets simultaneously, the terahertz wave is modulated in amplitude at a series of frequencies; the signal returning from the target is detected and homodyne mixed with the original modulation signal. A series of voltages is obtained; by Fourier transformation the distance to each target is retrieved. Experimental results on one and two targets are shown.

Subcarrier Frequency-Modulated Continuous-Wave Radar in the Terahertz Range Based on a Resonant-Tunneling-Diode Oscillator.

We introduce a new principle for distance measurement in the terahertz-wave range using a resonant-tunneling-diode (RTD) oscillator as a source at 511 GHz and relying on the frequency-modulated continuous-wave (FMCW) radar technique. Unlike the usual FMCW radar, where the sawtooth frequency modulation is applied to the carrier, we propose applying it to a subcarrier obtained by amplitude modulation; this is advantageous when the source cannot be controlled precisely in oscillation frequency, but can easily be modulated in amplitude, as is the case of the RTD oscillator. The detailed principle and a series of proof-of-concept experimental results are presented.

Nonlinear optical detection of terahertz-wave radiation from resonant tunneling diodes.

The sensitive detection of terahertz (THz)-wave radiation from compact sources at room temperature is crucial for real-world THz-wave applications. Here, we demonstrate the nonlinear optical detection of THz-wave radiation from continuous-wave (CW) resonant tunneling diodes (RTDs) at 0.58, 0.78, and 1.14 THz. The up-conversion process in a MgO:LiNbO3 crystal under the noncollinear phase-matching condition offers efficient wavelength conversion from a THz wave to a near-infrared (NIR) wave that is detected using a commercial NIR photodetector. The minimum detection limit of CW THz-wave power is as low as 5 nW at 1.14 THz, corresponding to 2-aJ energy and 2.7 × 103 photons within the time window of a 0.31-ns pump pulse. Our results show that the input frequency and power of RTD devices can be calibrated by measuring the output wavelength and energy of up-converted waves, respectively. This optical detection technique for compact electronic THz-wave sources will open up a new opportunity for the realization of real-world THz-wave applications.

Influence of microwaves on the water surface tension.

In this study, microwave irradiation was applied to hanging droplets of both water and ethylene glycol. Once the irradiation had ceased and the droplet was allowed to return to its original temperature, it was found that the surface tension of ethylene glycol returned to its original value. In contrast, the water surface tension remained well below its original value for an extended period of time. Similar observations have been reported for magnetically treated water, but this is the first time that such a lasting effect has been reported for microwave irradiation. The effect can be attributed to the unique hydrogen bonds of interfacial water molecules. While the irradiation intensities used in this study are well above those in household devices, there is certainly the potential to apply the methodology to industrial applications where the manipulation of surface tension is required without the use of chemical addition.

Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho.

Secreted from intestine, human fibroblast growth factor 19 (hFGF19) is an endocrine metabolic regulator that controls bile acid synthesis in the liver. Earlier studies have suggested that hFGF19 at 10-100 nM levels signals through FGF receptor 4 (FGFR4) in the presence of a co-receptor, betaKlotho, but its activity and receptor specificity at physiological concentrations (picomolar levels) remain unclear. Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. Importantly, sGAGs isolated from liver are highly active in enhancing the picomolar hFGF19 signaling. At nanomolar levels, in contrast, hFGF19 activates all types of human FGFRs, i.e. FGFR1c, FGFR2c, FGFR3c, and FGFR4 in the co-presence of betaKlotho and heparin and activates FGFR4 even in the absence of betaKlotho. These results show that sGAGs play crucial roles in specific and sensitive hFGF19 signaling via FGF receptors and suggest that hepatic sGAGs are involved in the highly potent and specific signaling of picomolar hFGF19 through FGFR4 and betaKlotho. The results further suggest that hFGF19 at pathological concentrations may evoke aberrant signaling through various FGF receptors.

Fibroblast growth factor-12 (FGF12) translocation into intestinal epithelial cells is dependent on a novel cell-penetrating peptide domain: involvement of internalization in the in vivo role of exogenous FGF12.

The extracellular effect of fibroblast growth factor-12 (FGF12) remains unknown because FGF12 cannot activate any fibroblast growth factor receptors (FGFRs), and FGF12 is not currently thought to be released from cells. We reported previously that FGF12 plays an intracellular role in the inhibition of radiation-induced apoptosis. In this study, we demonstrated that recombinant FGF12 was able to be internalized into the cytoplasm of a rat intestinal epithelial cell line, IEC6, and this process was dependent on two novel cell-penetrating peptide (CPP) domains (CPP-M and CPP-C). In particular, CPP-C, composed of ∼10 amino acids, was identified as a specific domain of FGF12 and its subfamily in the C-terminal region (residues 140-149), although CPP-M was a common domain in the internal region of the FGF family. The absence of CPP-C from FGF12 or a mutation (E142L) in the CPP-C domain drastically reduced the internalization of FGF12 into cells. Therefore, CPP-C played an essential role in the internalization of FGF12. In addition, CPP-C was able to deliver other polypeptides into cells as a CPP because an FGF1/CPP-C chimeric protein was internalized into IEC6 cells more efficiently than wild-type FGF1. Finally, intraperitoneally added FGF12 inhibited radiation-induced apoptosis in the intestinal epithelial cells of BALB/c mice, and deletion of the CPP-C domain decreased the inhibition of the apoptosis. These findings suggest that exogenous FGF12 can play a role in tissues by translocating into cells through the plasma membrane, and the availability of this novel CPP provides a new tool for the intracellular delivery of bioactive molecules.

Glycosaminoglycan affinity of the complete fibroblast growth factor family.

BACKGROUND: Many fibroblast growth factor family proteins (FGFs) bind to the heparan sulfate/heparin (HP) subtypes of sulfated glycosaminoglycans (GAGs), and a few have recently been reported to also interact with chondroitin sulfate (CS), another sulfated GAG subtype. METHODS: To gain additional insight into this interaction, we prepared all currently known FGFs (i.e., FGF1-FGF23) and assessed their affinity for HP, CS-B, CS-D and CS-E. In addition, midkine, hepatocyte growth factor and pleiotrophin were studied as other known HP-binding proteins. RESULTS: We found that members of the FGF19 subfamily (i.e., FGF15, 19, 21 and 23) had little or no affinity for HP; all of the other secretable growth factors tested had strong affinities for HP, as was indicated by the finding that their elution from HP-Sepharose columns required 1.0-1.5 M NaCl. We also found that FGF3, 6, 8 and 22 had strong affinities for CS-E, while FGF5 had a moderate affinity for CS-D. The interactions between FGFs and GAGs thus appear to be more diverse than previously understood. GENERAL SIGNIFICANCE: This is noteworthy, as the differential interactions of these growth factors with GAGs may be key determinants of their specific biological activities.

An FGF1:FGF2 chimeric growth factor exhibits universal FGF receptor specificity, enhanced stability and augmented activity useful for epithelial proliferation and radioprotection.

Structural instability of wild-type fibroblast growth factor (FGF)-1 and its dependence on exogenous heparin for optimal activity diminishes its potential utility as a therapeutic agent. Here we evaluated FGFC, an FGF1:FGF2 chimeric protein, for its receptor affinity, absolute heparin-dependence, stability and potential clinical applicability. Using BaF3 transfectants overexpressing each FGF receptor (FGFR) subtype, we found that, like FGF1, FGFC activates all of the FGFR subtypes (i.e., FGFR1c, FGFR1b, FGFR2c, FGFR2b, FGFR3c, FGFR3b and FGFR4) in the presence of heparin. Moreover, FGFC activates FGFRs even in the absence of heparin. FGFC stimulated keratinocytes proliferation much more strongly than FGF2, as would be expected from its ability to activate FGFR2b. FGFC showed greater structural stability, biological activity and resistance to trypsinization, and less loss in solution than FGF1 or FGF2. When FGFC was intraperitoneally administered to BALB/c mice prior to whole body gamma-irradiation, survival of small intestine crypts was significantly enhanced, as compared to control mice. These results suggest that FGFC could be useful in a variety of clinical applications, including promotion of wound healing and protection against radiation-induced damage.

Comparison of expression profiles of several fibroblast growth factor receptors in the mouse jejunum: suggestive evidence for a differential radioprotective effect among major FGF family members and the potency of FGF1.

Several members of the fibroblast growth factor (FGF) family have the potential to protect the intestine against the side effects of radiation therapy. FGF1 is capable of signaling through all subtypes of FGF receptors (FGFRs), whereas FGF7 and FGF10 activate only the epithelial-specific subtype, FGFR2IIIb (FGFR2b). The present study compared the protective activity of FGF1, FGF7 and FGF10 and examined the profiles of FGFR expression in the jejunum of BALB/c mice given total-body irradiation (TBI) with gamma rays. TBI caused drastic increases in FGFR1-4 transcript levels in the jejunum. However, FGFR2b protein temporarily decreased at 12 and 24 h after irradiation. FGF1 pretreatment minimized the number of apoptotic cells in jejunal crypts at 16 and 24 h after irradiation and increased crypt survival most effectively. In addition, pretreatment with FGF7 or FGF10 decreased FGFR1 transcript levels. The greater effectiveness of FGF1 to enhance crypt survival was also observed even when each FGF was administered 1 h after irradiation. These findings indicate that FGF1 is more potent than FGF7 or FGF10 for protection of the intestine against radiation exposure and suggest that the profiles of FGFR expression in the intestine favor the FGF1 signaling pathway before and during the initial period after irradiation.

betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c.

Fibroblast growth factor (FGF) 21, a structural relative of FGF23 that regulates phosphate homeostasis, is a regulator of insulin-independent glucose transport in adipocytes and plays a role in the regulation of body weight. It also regulates ketogenesis and adaptive responses to starvation. We report that in a reconstituted receptor activation assay system using BaF3 cells, which do not endogenously express any type of FGF receptor (FGFR) or heparan sulfate proteoglycan, FGF21 alone does not activate FGFRs and that betaKlotho is required for FGF21 to activate two specific FGFR subtypes: FGFR1c and FGFR3c. Coexpression of betaKlotho and FGFR1c on BaF3 cells enabled FGF21, but not FGF23, to activate receptor signaling. Conversely, coexpression of FGFR1c and Klotho, a protein related to betaKlotho, enabled FGF23 but not FGF21 to activate receptor signaling, indicating that expression of betaKlotho/Klotho confers target cell specificity on FGF21/FGF23. In all of these cases, heparin enhanced the activation but was not essential. In 3T3-L1 adipocytes, up-regulation of glucose transporter (GLUT) expression by FGF21 was associated with expression of betaKlotho, which was absent in undifferentiated 3T3-L1 fibroblasts. It is thus suggested that betaKlotho expression is a crucial determinant of the FGF21 specificity of the target cells upon which it acts in an endocrine fashion.

[A case of lymphocytic hypophysitis successfully treated with steroid pulse therapy].

Lymphocytic hypophysitis is an autoimmune disorder of the pituitary gland. We report a case of lymphocytic hypophysitis managed by high dose methylprednisolone pulse therapy and review the literature. A 61-year-old woman presented with severe headache. Magnetic resonance imaging (MRI) revealed a contrast enhancing pituitary mass. The patient underwent endonasal-transsphenoidal surgery of the pituitary lesion under the diagnosis of a non-secreting pituitary adenoma. Intraoperative histological findings suggested an inflammatory lesion and we performed subtotal resection of the mass. Histopathological examination confirmed the diagnosis of lymphocytic hypophysitis. Postoperatively, she received methylprednisolone pulse therapy and her severe headache resolved. This case report suggests that methylprednisolone pulse therapy may improve the clinical symptoms of lymphocytic hypophysitis.

Prognostic significance of p53 mutation in suboptimally resected advanced ovarian carcinoma treated with the combination chemotherapy of paclitaxel and carboplatin.

The prognostic significance of p53 mutation, microsattelite instability and DNA mismatch protein hMLH1 expression in suboptimally resected advanced ovarian carcinoma treated with the combination chemotherapy of paclitaxel and carboplatin was evaluated. The overall combination chemotherapy response rate and the complete remission rate were significantly higher among patients with mutant p53 tumors than those with wild-type p53 tumors (35/42 (83%) vs. 32/58 (55%); P=0.003 and 18/42 (43%) vs. 16/58 (28%); P=0.03, respectively). This tendency apparently existed in non-serous carcinoma, but not in serous carcinoma. Univariate analysis showed that the risk of death due to disease and risk of progression was significantly lower among patients with p53 mutation (P=0.0357 and 0.0281, respectively). However, the presence of microsattelite instability or loss of hMLH1 expression was not associated with either the clinical response or prognosis. Determining p53 mutational status can be useful in predicting therapeutic response to drugs in ovarian carcinoma, especially in non-serous tumors.

Boron neutron capture therapy for recurrent malignant meningioma. Case report.

Malignant meningioma is a rare brain tumor with a high risk of recurrence. If this tumor recurs after complete resection and adjuvant radiotherapy, there is no optimal treatment to control it. The authors report the first case of recurrent malignant meningioma treated using boron neutron capture therapy (BNCT). This 25-year-old pregnant woman presented with a large frontal tumor. After her baby was born, she underwent gross-total resection of the tumor. A second resection and three Gamma Knife surgeries could not control progression of the enhancing mass; therefore, the authors applied BNCT based on their experience with it in the treatment of malignant gliomas. The minimum tumor dose and maximum brain tissue dose were estimated as 39.7 Gy-Eq and less than 9.0 Gy-Eq, respectively. Before BNCT the patient was mobile by wheelchair only, whereas 1 week after therapy she was able to walk. Twenty-two weeks later she underwent a second BNCT for tumor regrowth on the contralateral side, and the lesion was subsequently reduced. The tumor volume was markedly decreased from 65.6 cm3 at the time of the first BNCT to 31.8 cm3 at 26 weeks thereafter. The treatment of recurrent malignant meningioma is difficult and has been discouraging thus far. Data in the present case indicate that BNCT may be a promising treatment option for this challenging tumor.

[Long-term suppressive effect of falecalcitriol on parathyroid hormone secretion in secondary hyperparathyroidism in hemodialysis patients].

Alfacarcidol and calcitriol are widely used to treat secondary hyperparathyroidism associated with chronic renal failure, but it is often not possible to administer doses high enough to sufficiently inhibit parathyroid hormones because of the risk of hypercalcemia and hyperphosphatemia. We administered falecalcitriol (Hornel) Tablets) to patients with poorly controlled secondary hyperparathyroidism. The usefulness of falecalcitriol was demonstrated by the fact that control of intact-PTH was maintained for up to 24 months without a clear increase in serum Ca x serum inorganic phosphorus (iP), iP, and ALP levels.