Terahertz Detection by Asymmetric Dual Grating Gate Bilayer Graphene FETs with Integrated Bowtie Antenna.

An asymmetric dual-grating gate bilayer graphene-based field effect transistor (ADGG-GFET) with an integrated bowtie antenna was fabricated and its response as a Terahertz (THz) detector was experimentally investigated. The device was cooled down to 4.5 K, and excited at different frequencies (0.15, 0.3 and 0.6 THz) using a THz solid-state source. The integration of the bowtie antenna allowed to obtain a substantial increase in the photocurrent response (up to 8 nA) of the device at the three studied frequencies as compared to similar transistors lacking the integrated antenna (1 nA). The photocurrent increase was observed for all the studied values of the bias voltage applied to both the top and back gates. Besides the action of the antenna that helps the coupling of THz radiation to the transistor channel, the observed enhancement by nearly one order of magnitude of the photoresponse is also related to the modulation of the hole and electron concentration profiles inside the transistor channel by the bias voltages imposed to the top and back gates. The creation of local n and p regions leads to the formation of homojuctions (np, pn or pp+) along the channel that strongly affects the overall photoresponse of the detector. Additionally, the bias of both back and top gates could induce an opening of the gap of the bilayer graphene channel that would also contribute to the photocurrent.

Resonant plasmonic detection of terahertz radiation in field-effect transistors with the graphene channel and the black-As[Formula: see text]P[Formula: see text] gate layer.

We propose the terahertz (THz) detectors based on field-effect transistors (FETs) with the graphene channel (GC) and the black-Arsenic (b-As) black-Phosphorus (b-P), or black-Arsenic-Phosphorus (b-As[Formula: see text]P[Formula: see text]) gate barrier layer. The operation of the GC-FET detectors is associated with the carrier heating in the GC by the THz electric field resonantly excited by incoming radiation leading to an increase in the rectified current between the channel and the gate over the b-As[Formula: see text]P[Formula: see text] energy barrier layer (BLs). The specific feature of the GC-FETs under consideration is relatively low energy BLs and the possibility to optimize the device characteristics by choosing the barriers containing a necessary number of the b-As[Formula: see text]P[Formula: see text] atomic layers and a proper gate voltage. The excitation of the plasma oscillations in the GC-FETs leads to the resonant reinforcement of the carrier heating and the enhancement of the detector responsivity. The room temperature responsivity can exceed the values of [Formula: see text] A/W. The speed of the GC-FET detector's response to the modulated THz radiation is determined by the processes of carrier heating. As shown, the modulation frequency can be in the range of several GHz at room temperatures.

Boosting photoconductive large-area THz emitter via optical light confinement behind a highly refractive sapphire-fiber lens.

We report on a sapphire-fiber-based lens that can be used to enhance the emitted THz power of a large-area photoconductive antenna (PCA). Using numerical simulations, we demonstrate that the lens provides a spatial redistribution of the photocarriers density in the PCA's gap. By optimizing the diameter of the sapphire-fiber, one could reach efficient confinement of the photocarriers in the vicinity of the PCA electrodes with a 10-µm gap size for a 220-µm-thick sapphire-fiber. This allows enhancing the coupling of the incident electromagnetic waves at the interface between the sapphire fiber and the semiconductor with the antenna terminals by ∼40 times for a single PCA element, as well as boosting the total efficiency of the large-area PCA-emitter up to ∼7-10 times. To validate our approach, we propose a step-by-step process that can be used for the precise and controllable placement of the sapphire-fiber on the surface of a single PCA.

Manifestation of plasmonic response in the detection of sub-terahertz radiation by graphene-based devices.

We report on the sub-terahertz (THz) (129-450 GHz) photoresponse of devices based on single layer graphene and graphene nanoribbons with asymmetric source and drain (vanadium and gold) contacts. Vanadium forms a barrier at the graphene interface, while gold forms an Ohmic contact. We find that at low temperatures (77 K) the detector responsivity rises with the increasing frequency of the incident sub-THz radiation. We interpret this result as a manifestation of a plasmonic effect in the devices with the relatively long plasmonic wavelengths. Graphene nanoribbon devices display a similar pattern, albeit with a lower responsivity.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Nonresonant detection of terahertz radiation in high-electron-mobility transistor structure using InAIAs/InGaAs/InP material systems at room temperature.

In this paper, we report on nonresonant detection of terahertz radiation using the rectification mechanism of two-dimensional plasmons in high-electron-mobility transistors using InAIAs/InGaAs/InP material systems. The experiments were performed at room temperature using a Gunn diode operating at 0.30 THz as the THz source. The measured response was dependent on the polarization of the incident THz wave; The device exhibited higher response when the electric-field vector of the incident radiation was directed in the source-drain direction. The 2D spatial distribution image of the transistor responsivity extracted from the measured response shows a clear beam focus centered on the transistor position, which ensures the appropriate coupling of the terahertz radiation to the device. The device also demonstrated excellent sensitivity/noise performances of approximately 125 V/W and approximately 10(-11) W/Hz(0.5) under 0.30 THz radiation.

Terahertz surface plasmons in optically pumped graphene structures.

We analyze the surface plasmons (SPs) propagating along optically pumped single-graphene layer (SGL) and multiple-graphene layer (MGL) structures. It is shown that at sufficiently strong optical pumping when the real part of the dynamic conductivity of SGL and MGL structures becomes negative in the terahertz (THz) range of frequencies due to the interband population inversion, the damping of the THz SPs can give way to their amplification. This effect can be used in graphene-based THz lasers and other devices. Due to the relatively small SP group velocity, the absolute value of their absorption coefficient (SP gain) can be large, substantially exceeding that of optically pumped structures with dielectric waveguides. A comparison of SGL and MGL structures shows that to maximize the SP gain the number of graphene layers should be properly chosen.

Room temperature detection of sub-terahertz radiation in double-grating-gate transistors.

Room temperature photovoltaic non-resonant detection by large area double-grating-gate InGaP/InGaAs/GaAs heterostructures was investigated in sub-THz range (0.24 THz). Semi-quantitative estimation of the characteristic detection length combined with self-consistent calculations of the electric fields excited in the structure by incoming terahertz radiation allowed us to interpret quantitatively the results and conclude that this detection takes place mainly in the regions of strong oscillating electric field excited in depleted portions of the channel.

Preliminary ocular histopathological observations on heterozygous NEMO-deficient mice.

The majority of patients with incontinentia pigmenti (IP) have a mutation in the nuclear factor-kappa-beta essential modulator (NEMO) gene, and mice with a targeted deletion of NEMO exhibit skin pathology remarkably similar to the human disease. This study characterizes the retinal vascular abnormalities of NEMO-deficient mice, and compares this phenotype to known features of human IP. Nineteen heterozygous NEMO-deficient female mice, ages ranging from post-natal day 8 (P-8) through 6.5 months of life, were studied. Eyes were sectioned and stained either whole or as retinal flat mounts after incubation for enzyme histochemical demonstration of ADPase, which labels the vasculature. With maturation, retinal arteriolar abnormalities became evident at 3 months of age. Global assessment of the retinal vasculature with ADPase staining showed increased vascular tortuosity. Microscopic examination of sections of ADPase-incubated retinas revealed arteriolar luminal narrowing due to endothelial cell hypertrophy and increased basement membrane deposition. Venous morphology was normal. This study characterized the histological retinal phenotype of heterozygous NEMO-deficient female mice. Most striking were retinal arteriolar abnormalities, including luminal narrowing, endothelial cell hypertrophy, and basement membrane thickening. Retinal flat mounts revealed arteriolar tortuosity without evidence of vaso-occlusion or neo-vascularization.

Emission of terahertz radiation from dual grating gate plasmon-resonant emitters fabricated with InGaP/InGaAs/GaAs material systems.

This paper reviews recent advances in our original 2D-plasmon-resonant terahertz emitters. The structure is based on a high-electron-mobility transistor and featured with doubly interdigitated grating gates. The dual grating gates can alternately modulate the 2D electron densities to periodically distribute the plasmonic cavities along the channel, acting as an antenna. The device can emit broadband terahertz radiation even at room temperature from self-oscillating 2D plasmons under the DC-biased conditions. When the device is subjected to laser illumination, photo-generated carriers stimulate the plasma oscillation, resulting in enhancement of the emission. The first sample was fabricated with standard GaAs-based heterostructure material systems, achieving room temperature terahertz emission. The second sample was fabricated in a double-decked HEMT structure in which the grating gate metal layer was replaced with the semiconducting upper-deck 2D electron layer, resulting in enhancement of emission by one order of magnitude.

Mechanism of self-excitation of terahertz plasma oscillations in periodically double-gated electron channels.

We develop a device model for a heterostructure device with an electron channel and with a periodic system of interdigitated gates. Using this model, we find the conditions of the self-excitation of plasma oscillations in portions of the channel. It is shown that the self-excitation of plasma oscillations in these devices and the terahertz emission observed in the experiments (Otsuji et al 2006 Appl. Phys. Lett. 89 263502; Meziani et al 2007 Appl. Phys. Lett. 90 061105; Otsuji et al 2007 Solid-State Electron. 51 1319) might be attributed to the electron-transit-time effect in the barrier regions.

Ocular structure and function in an aged monkey with spontaneous diabetes mellitus.

Diabetes mellitus develops spontaneously in middle-aged, obese rhesus monkeys, thus making them a good model for examining the effects of co-morbid factors on the development of end-organ damage. Changes in structure and function in the eyes of one monkey who spontaneously developed type 2 diabetes are reported here. This animal had concomitant hypertension, high levels of triglycerides and serum cholesterol, and a low fraction of high-density lipoprotein. The eyes showed intraretinal hemorrhages and large areas of retinal capillary nonperfusion. Indo-cyanin green (ICG) angiography revealed a large area of non- or poorly perfused choriocapillaris in one eye, and immunohistochemistry showed loss of viable choriocapillaries in this region. Both basal laminar deposits and hard drusen were present on areas of Bruch's membrane adjacent to nonviable choriocapillaris. Blood flow via the nasal posterior ciliary arteries to this section of choroid was not detectable by color duplex Doppler ultrasound, indicating contribution of extraocular vascular disease to ischemia in this eye. There was a severe decline in number of photoreceptor inner and outer segments, and corresponding reductions in the multifocal electroretinogram (ERG), in the areas of choriocapillaris loss. The ganzfeld ERG indicated loss in both inner and outer retinal function. Much of the ganglion cell layer was absent throughout the retina, possibly reflecting the effect of diabetes as well as chronic open angle glaucoma; the latter diagnosis supported by elevated intraocular pressures and excavated optic disks. In summary, high resolution, enzyme histochemical and histopathological analyses of a diabetic hypertensive monkey retina and choroid after serial functional in vivo analyses have demonstrated the relationship between vascular dysfunction and visual function loss. Choroidal vascular dysfunction in both large and small vessels was associated with age-related macular degeneration-like changes in Bruch's membrane and photoreceptor degeneration.

Expression of pigment epithelium derived factor and vascular endothelial growth factor in choroidal neovascular membranes and polypoidal choroidal vasculopathy.

AIMS: To determine whether pigment epithelium derived factor (PEDF), a protein that inhibits angiogenesis, is expressed in human choroidal neovascular membranes (CNVMs) and in tissues from an eye with polypoidal choroidal vasculopathy (PCV). In addition, to compare the expression of PEDF with that of vascular endothelial growth factor (VEGF), a known stimulator of angiogenesis, in these tissues. METHODS: CNVMs, associated with age related macular degeneration (AMD), angioid streaks, and PCV, were obtained during surgery. The expression of PEDF and VEGF in the excised subretinal fibrovascular membranes was determined by immunohistochemistry. RESULTS: PEDF and VEGF were strongly expressed in the vascular endothelial cells and retinal pigment epithelial (RPE) cells in the CNVMs where numerous new vessels were prominent (clinically active CNVMs). On the other hand, immunoreactivity for PEDF and VEGF was weak in the new vessels where fibrosis was prominent (clinically quiescent CNVMs). However, the RPE cells were still positive for PEDF and VEGF. The specimens from the eye with PCV also showed strong expression of PEDF and VEGF in the vascular endothelial cells and the RPE cells. CONCLUSION: Because PEDF is an inhibitor of ocular angiogenesis and an inhibitor of ocular cell proliferation, our results suggest that PEDF along with VEGF may modulate the formation of subfoveal fibrovascular membranes.

Epstein-Barr virus involvement is mainly restricted to lymphoepithelial type of gastric carcinoma among various epithelial neoplasms.

To demonstrate the association of Epstein-Barr virus (EBV) with primary epithelial neoplasms in the south part of Kyushu, Japan, 761 carcinomas consisting of 75 lung, 61 breast, 107 esophagus, 102 colon, 58 pancreas, 45 thyroid, and 313 gastric cancers were examined by EBER-1 in situ hybridization. EBER-1 was detected in 23 cases (7.3%) out of 313 gastric carcinomas, while none of the other carcinomas was positive for EBER-1. Twenty-eight (9.4%) out of 313 gastric carcinomas were differentiated poorly to moderately carcinomas with prominent lymphoid cell infiltration, similar to so-called lymphoepithelioma-like carcinoma, and 19 cases (67.9%) were positive for EBER-1. Although two (2.6%) and 11(10.3%) out of 75 lung and 107 esophagus carcinomas were so-called lymphoepithelioma-like carcinomas, respectively, but EBER-1 was not detected in other epithelial neoplasms that originated from the lung, esophagus, breast, colon, pancreas, and thyroid in the south of Kyushu, Japan. As a result, EBV was associated with only some gastric carcinomas but not with other epithelial neoplasms originating from the lung, esophagus, breast, colon, pancreas, and thyroid in southern Japan.

Optical coherence tomographic findings of idiopathic polypoidal choroidal vasculopathy.

BACKGROUND AND OBJECTIVE: To identify the histological level of abnormal vessels associated with idiopathic polypoidal choroidal vasculopathy (IPCV), we examined IPCV with Optical Coherence Tomography (OCT). PATIENTS AND METHODS: Fourteen patients diagnosed with IPCV were examined with Indocyanine green (ICG) angiography and OCT. RESULTS: ICG angiography demonstrated branching vascular networks with polypoidal dilatations at the terminals beneath the retinal pigment epithelium (RPE). OCT showed dome-like elevation of the RPE, and moderate reflex or nodular appearance were seen beneath the RPE. CONCLUSION: The abnormal vessel associated with IPCV is supposed to be choroidal neovascularization with polypoidal dilatations at the terminals between Bruch's membrane and RPE. We consider that this disease is a peculiar form of age-related macular degeneration.

In vivo gene transfer into choroidal neovascularization by the HVJ liposome method.

PURPOSE: To evaluate the efficacy of the HVJ liposome method for gene transfer in rats with experimentally induced choroidal neovascularization. METHODS: Plasmid DNA containing the LacZ reporter gene, or fluorescein isothiocyanate (FITC)-labeled double-stranded phosphorothioate oligodeoxynucleotides (S-ODNs), was encapsulated in liposomes. The liposomes were coated with the envelope of inactivated hemagglutinating virus of Japan (HVJ). Intense laser burns were applied to the posterior pole of the retina of pigmented rats to induce choroidal neovascularization. Following photocoagulation, HVJ liposome suspension was injected into the vitreous. On days 3, 7, 14, and 28 after injection, the eyes were removed and fixed. The eyes injected with LacZ gene were reacted with X-gal, frozen, and cut into thin sections. The sections were examined for the expression of the LacZ gene by light microscopy. The enucleated eyes injected with double-stranded S-ODNs were frozen, cut into thin sections, and examined a confocal scanning laser microscope for FITC labeling. Eyes without injection of HVJ liposomes served as controls. RESULTS: Expression of LacZ genes (beta-galactosidase activity), or localization of FITC labeling, was observed mainly in the laser-induced choroidal neovascular tissue from 3 to 28 days after the intravitreal injection of HVJ liposome. CONCLUSIONS: We conclude that the HVJ liposome method achieved effective gene transfer into choroidal neovascular tissue. Thus, this method can be used as a nonviral gene therapy system for the treatment of choroidal neovascularization in vivo.

Phosphorothioate oligonucleotides induction into experimental choroidal neovascularization by HVJ-liposome system.

PURPOSE: The purpose of this study was to determine whether the inactivated hemagglutinating virus of Japan (HVJ)-liposome method can induce phosphorothioate oligonucleotides effectively into an experimentally-induced choroidal neovascularization of rats. We also examined whether antisense phosphorothioate oligonucleotides against VEGF could be induced into choroidal neovascularization as a therapeutic agent by the HVJ-liposome method. METHODS: The experiments were conducted on a rat model of choroidal neovascularization. FITC-labeled phosphorothioate oligonucleotides were coencapsulated in liposomes. The liposomes were coated with the envelope of inactivated HVJ and injected into the vitreous cavity following photocoagulation of pigmented rat eyes. The eyes were removed following injection, fixed, frozen and cut into thin sections. Induction of oligonucleotides was observed under a laser confocal scanning microscope for fluorescence and the development of choroidal neovascularization was evaluated histopathologically. RESULTS: Phosphorothioate oligonucleotides were effectively induced into ganglion cells and into the cells of the choroidal neovascularization induced by laser photocoagulation. Highly effective induction of oligos was observed 3 to 14 days after intravitreal injection of HVJ-liposomes after which the level decreased. Antisense oligonucleotides against VEGF were induced specifically into cells in the choroidal neovascularization, however neovascularization was still observed. CONCLUSIONS: Phosphorothioate oligonucleotides can be effectively induced into ganglion cells, and specifically into cells in choroidal neovascularization. Although antisense oligonucleotides against VEGF failed to prevent choroidal neovascularization, the HVJ-liposome method provided a highly effective means of inducing antisense oligos for in vivo antisense therapy.

Expression of vascular endothelial growth factor and its receptor (KDR/flk-1) mRNA in experimental choroidal neovascularization.

PURPOSE: Vascular endothelial growth factor (VEGF) is an angiogenic peptide that has been suggested to be important in the pathogenesis of choroidal neovascularization. We investigated the transcription of VEGF and its receptor KDR/flk-1 genes during the development of experimentally induced choroidal neovascularization. METHODS: Rat VEGF or KDR cDNA was inserted in PGEM or pBluescript to prepare antisense or sense riboprobes. Multiple krypton laser burns were applied to the posterior pole of pigmented rat eyes according to a previously described protocol which produces choroidal neovascularization. At intervals of up to 4 weeks after photocoagulation, the eyes were removed and cut into thin sections. The sections were subjected to in situ hybridization with digoxigenin (DIG)-labeled single-strand rat VEGF and KDR cDNA riboprobes. RESULTS: In normal adult rat retinas, VEGF and KDR mRNA expression was mainly observed in the ganglion cell and the inner nuclear layers. During the development of neovascularization, VEGF and KDR mRNAs were detected in retinal pigment epithelial-like cells, fibroblast-like cells and endothelial cells in neovascular lesions. The level of expression was strongest at 1 week after photocoagulation in lasered lesions, and decreased by 4 weeks after photocoagulation. CONCLUSIONS: Our findings demonstrate that expression of VEGF and its receptor KDR may play a role in the formation of experimentally induced choroidal neovascularization. In this study, VEGF and its receptor were co-localized, suggesting that an autocrine and/or paracrine mechanism may be operative.

An experimental model of symptomatic vasospasm induced by oxyhemoglobin in rabbits.

BACKGROUND AND PURPOSE: There are many experimental models for studies of cerebral vasospasm. However, no ideal model has been established thus far to comparatively reproduce the ischemic state of the brain that may occur in patients after subarachnoid hemorrhage. METHODS: In the present study, we attempted to induce severe vasospasm in rabbits by using an oxyhemoglobin-rich blood product prepared from hemolyzed arterial blood and evaluate neurological symptoms, cerebral angiogram, cerebral blood flow, and histology. RESULTS: Clinically significant neurological symptoms were observed in about half of the rabbits. There was no significant correlation between angiographic results of the vasospastic state of the main artery and the severity of neurological symptoms observed. However, the cerebral blood flow was significantly lower than in the control group and significantly correlated with the severity of neurological symptoms. On histological examination, lesions were found in about half of the rabbits. Development of obvious infarction was found more frequently than in other reported models. CONCLUSIONS: These results suggest that this model is appropriate as an experimental model of vasospasm occurring after subarachnoid hemorrhage and is especially useful in that it induces vasospasm intense enough to cause obvious infarction.

Platelet-activating factor and cerebral vasospasm following subarachnoid hemorrhage.

This study examines whether platelet-activating factor (PAF) is involved in the occurrence of vasospasm after subarachnoid hemorrhage (SAH). A vasospasm model was produced in rabbits, with animals in six experimental groups receiving two subarachnoid injections of autologous arterial blood with the addition of one of the following; saline (Control Group 1), 25% dimethyl sulfoxide (Control Group 2), PAF (1, 2.5, 5, or 10 micrograms), CV6209 (10 or 100 micrograms), BN52021 (10 or 100 micrograms), or anti-PAF immunoglobulin G (IgG, 50 or 500 micrograms). No significant differences were detected between Control Groups 1 and 2 with regard to neurological deterioration and basilar artery constriction after SAH was induced. Administration of PAF together with autologous blood aggravated neurological deficits in a dose-dependent manner (r = 0.724, p < 0.001) and produced basilar artery constriction at two doses each of 2.5 micrograms (p < 0.05), 5 micrograms (p < 0.01), and 10 micrograms (p < 0.01). Neurological deterioration was prevented in rabbits receiving an intracisternal administration of either PAF antagonist CV6209 or BN52021 or anti-PAF IgG (p < 0.01 at a total dose of 20 micrograms and p < 0.05 at a total dose of 200 micrograms CV6209, p < 0.01 at total doses of 20 and 200 micrograms BN52021, and p < 0.01 at total doses of 100 and 1000 micrograms anti-PAF IgG). A reduction in basilar artery constriction was achieved by the injection of anti-PAF IgG (p < 0.05 at total doses of 100 and 1000 micrograms). Histological examination at autopsy on Days 14 to 21 showed mainly ischemic changes in the brain, including selective neuronal necrosis and cerebral infarction. The control and PAF groups showed marked ischemic changes. On the other hand, no ischemic changes were noted in the anti-PAF IgG group, and only 9% of animals in the CV6209 group and 25% in the BN52021 group demonstrated selective neuronal necrosis or infarction. This study thus provides evidence to support the role of PAF in the pathogenesis of vasospasm after SAH.