TNF-α blockade is ineffective in animal models of established polycystic kidney disease

BACKGROUND: Given the large medical burden of polycystic kidney disease (PKD) and recent clinical trial failures, there is a need for novel, safe and effective treatments for the disorder. METHODS: In PCK rat and PKD2((ws25/w183)) mouse models, entanercept was administered once every three days at 5 or 10 mg/kg, once daily. Mozavaptan was administered as a pilot control, provided continuously via milled chow at 0.1%. Animals were assessed for measures of pharmacodynamic response, and improvements in measures of polycystic kidney disease. RESULTS: Entanercept treatment modulated inflammatory markers, but provided limited therapeutic benefit in multiple animal models of established polycystic kidney disease. Kidney weight, cyst burden and renal function markers remained unchanged following administration of etanercept at various dose levels and multiple treatment durations. CONCLUSIONS: While it remains possible that TNF-α inhibition may be effective in truly preventative settings, our observations suggest this pathway is less likely to exhibit therapeutic or disease-modifying efficacy following the standard clinical diagnosis of disease

Differential Effects of Cyclosporin and Etanercept Treatment on Various Pathologic Parameters in a Murine Model of Irradiation-Induced Mucositis

AbstractBackgroundRadiation therapy is the most prescribed treatment for many oncologic indications. One of its common side effects is mucositis with hallmark apoptosis in the intestinal crypt and diarrhea.ObjectiveWe investigated the potential beneficial effects of etanercept and cyclosporin treatment during radiation exposure. The effects of these drugs on intestinal apoptosis, long-term weight loss, diarrhea severity, and survival were examined.MethodsFor acute observation studies, animals pretreated with phosphate buffer saline (PBS) vehicle, either etanercept, or cyclosporin were challenged with either 1 Gy or 13 Gy irradiation and sacrificed 6 hours later. The animals' small intestines were then harvested for histologic analysis. For chronic survival studies, 14.5 Gy irradiation was applied. Etanercept or cyclosporin treatments were given 15 minutes before the irradiation, followed by daily administration.ResultsAt 6 hours postirradiation the maximum apoptotic index observed in the small intestine was ∼25% for both 1 Gy and 13 Gy irradiation. Etanercept and cyclosporin pretreatment had no effect on the irradiation-induced apoptosis. During chronic observation, the rate of weight loss was similar in all test groups. At 7 days postirradiation, the weight loss in phosphate buffered saline-treated control, etanercept, and cyclosporin groups reached a maximum at 19%, 24%, and 31.8%, respectively. The weight lost in the cyclosporin group was significantly higher than in the control group. Neither treatment reduced the severity of diarrhea, but cyclosporin increased the survival rate. Sixty percent of cyclosporin-treated animals survived compared with 27% in the PBS-treated control group and 47% in the etanercept-treated group. Serum tumor necrosis factor-α levels, a biomarker for both etanercept's mechanism of action and treatment efficacy, was inhibited by etanercept throughout the study, but cyclosporin only showed an inhibitory effect at 48 hours postirradiation.ConclusionsOur study demonstrates that cyclosporin increases the survival rate of irradiated animals without affecting parameters such as intestinal histology, weight loss, and diarrhea severity

Pulmonary Function Tests In Young Healthy Subjects Of North India

Study Objectives : The diagnosis of disease done by skiagram can be substantiated by pulmonary function tests. Substantial data of Indians on PFTs is not available. The present study therefore has been planned on young healthy north Indians. Setting : 119 males and 49 female medical students of North India. Measurements : PFT's, T.V. FEV1, FVC, FER and PEFR were measured. P<0.05 was considered as significant. Results : In North Indian males, mean T. V was 437.56 ± 65.83 ml, FEV1 3.26 ±041 L, FVC 3.82 ± 0.48 L, FER 85.09 ± 2.42% and PEFR was 495.42 ± 101.82 L / min. In North Indian females, average T. V was 386.12 ± 37.90 ml, FEV1 2.39 ± 0.38 L, FVC 2.79 ± 0.43 L, FER 85.38 ± 257% and PEFR was 307.12 ± 75.74 L / min. Conclusions: Males in comparison to females had more value of PFTs. All the PFTs showed positive correlation with Height, Weight and Surface area except Tidal Volume and FER

Topological Superconductivity by Engineering Noncollinear Magnetism in Magnet/ Superconductor Heterostructures: A Realistic Prescription for 2D Kitaev Model

We report on a realistic and rather general scheme where noncollinear magnetic textures proximitized with the most common $s$-wave superconductor can appear as the alternative to $p$-wave superconductor{--}the prime proposal to realize two-dimensional (2D) Kitaev model for topological superconductors (TSCs) hosting Majorana flat edge mode (MFEM). A general minimal Hamiltonian suitable for magnet/superconductor heterostructures reveals robust MFEM within the gap of Shiba bands due to the emergence of an effective ``$p_x+p_y$"-type $p$-wave pairing, spatially localized at the edges of a 2D magnetic domain of spin-spiral. We finally verify this concept by considering Mn (Cr) monolayer grown on a $s$-wave superconducting substrate, Nb(110) under strain (Nb(001)). In both 2D cases, the antiferromagnetic spin-spiral solutions exhibit robust MFEM at certain domain edges that is beyond the scope of the trivial extension of 1D spin-chain model in 2D. This approach, particularly when the MFEM appears in the TSC phase for such heterostructure materials, offers a perspective to extend the realm of the TSC in 2D.Comment: This is the published versio

Near-direct bandgap WSe2WSe_2/ReS2ReS_2 type-II pn heterojunction for enhanced ultrafast photodetection and high-performance photovoltaics

PN heterojunctions comprising layered van der Waals (vdW) semiconductors have been used to demonstrate current rectifiers, photodetectors, and photovoltaic devices. However, a direct or near-direct bandgap at the heterointerface that can significantly enhance optical generation, for high light absorbing few/multi-layer vdW materials, has not yet been shown. In this work, for the first time, few-layer group-6 transition metal dichalcogenide (TMD) $WSe_2$ is shown to form a sizeable (0.7 eV) near-direct bandgap with type-II band alignment at its interface with the group-7 TMD $ReS_2$ through density functional theory calculations. Further, the type-II alignment and photogeneration across the interlayer bandgap have been experimentally confirmed through micro-photoluminescence and IR photodetection measurements, respectively. High optical absorption in few-layer flakes, large conduction and valence band offsets for efficient electron-hole separation and stacking of light facing, direct bandgap $ReS_2$ on top of gate tunable $WSe_2$ are shown to result in excellent and tunable photodetection as well as photovoltaic performance through flake thickness dependent optoelectronic measurements. Few-layer flakes demonstrate ultrafast response time (5 $\mu$s) at high responsivity (3 A/W) and large photocurrent generation and responsivity enhancement at the heterostructure overlap region (10-100X) for 532 nm laser illumination. Large open-circuit voltage of 0.64 V and short-circuit current of 2.6 $\mu$A enables high output electrical power. Finally, long term air-stability and a facile single contact metal fabrication process makes the multi-functional few-layer $WSe_2$/$ReS_2$ heterostructure diode technologically promising for next-generation optoelectronic applications.Comment: Manuscript- 27 pages, 8 figures. Supporting Information- 17 pages, 17 figure

Study on Hydrographical Characteristics near the Luzon Strait

本论文基于Argo剖面资料、融合的卫星高度计资料、现场水文资料和数值模式OFES(由YukioMasumoto教授提供)的输出结果，分析吕宋海峡附近的水文特征。本论文的特色在于，我们揭示2008年秋季南海东北部一个反气旋涡的来源并展示其西传特征，以及探讨黑潮弯曲南部的气旋涡对黑潮南海分支和黑潮主轴的影响。 Argo剖面资料得到的2008年秋季20.5°N断面的温度、盐度分布态势与气候态秋季的分布基本一致。动力计算表明：Argo浮标剖面资料(选取1200m为速度零面)与融合的卫星高度计产品得到的20.5°N、117.5°～124.5°E断面的表层地转流北分量的分布比较吻合；吕宋海峡中部的黑潮主...The hydrographical characteristics near the Luzon Strait were analyzed by using Argo profiling floats dataset, merged altimeter data, in situ hydrographic data and OFES (ocean general circulation model for the Earth Simulation) outputs provided by Dr. Yukio Masumoto. We indicated that an anticyclonic eddy was generated in the interior SCS (South China Sea), and demonstrated that the anticyclonic e...学位：理学硕士院系专业：海洋与环境学院海洋学系_物理海洋学学号：2242007115082

In Vivo Effects of Immunomodulators in a Murine Model of Fluorouracil-Induced Mucositis

AbstractBackgroundFluorouracil (5-FU) is a pyrimidine analogue used as a cancer treatment. Its toxic side effects, including mucositis, are reported to occur in 40% of the treated patients. Because of the inflammatory component of mucositis, we explored the possibility of modulating this condition with an immunomodulatory agent and a tumor necrosis factor-α inhibitor.ObjectiveThe aim of this study was to evaluate the effect of 2 immunosuppressive agents, etanercept and cyclosporine, in a murine model of 5-FU–induced mucositis.MethodsTo study the short-term effects of 5-FU on mucositis, cyclosporine and etanercept were administered to mice after an injection of 5-FU. The animals (n = 8) were euthanized at 6 hours post-challenge. Hematoxylin and eosin–stained histologic sections of the small intestine were examined for signs of apoptosis. To further examine the potential of cyclosporine in the treatment of 5-FU–induced mucositis in a longer duration, the animals (N = 15) were given 2 challenges of 5-FU within 6 hours. All mice were dosed daily until day 9 with either cyclosporine (100 mg/kg) or phosphate-buffered saline (PBS).ResultsSix hours after 5-FU challenge, 25 mg/kg etanercept and 50 mg/kg cyclosporine had no effect on 5-FU–induced apoptosis (P > 0.05). However, 100 mg/kg cyclosporine significantly reduced the cumulative level of apoptosis >41.6% of the intestinal crypt surface (P < 0.05). During long-term observation, all mice began to lose weight at a rate of approximately 0.8 g/day after 5-FU exposure. The rates of weight loss and survival were not affected by cyclosporine treatment. The diarrhea onset began on day 4 with 46.7% of the PBS-treated mice showing signs of diarrhea compared with 53.3% in the cyclosporine group. The diarrhea score for both groups plateaued on day 7, with a cumulative score of 41 for the PBS group and 50 for the cyclosporine group. Cyclosporine treatment did not affect the diarrhea onset day or severity compared with the PBS-treated group (P > 0.05).ConclusionsOur data indicated that etanercept is not a suitable treatment for 5-FU–induced mucositis. Despite decreased apoptosis in the gut, cyclosporine did not affect the severity of the diarrhea or survival. Therefore, we concluded that cyclosporine treatment was only effective in mediating the short-term apoptotic events in the intestines but has no long-term effect on the animals' survival and diarrhea

A Redetermination of the Hubble Constant with the Hubble Space Telescope from a Differential Distance Ladder

We report observations of 240 Cepheid variables obtained with the Near Infrared Camera (NICMOS) through the F160W filter on the Hubble Space Telescope (HST). The Cepheids are distributed across six recent hosts of Type Ia supernovae (SNe Ia) and the "maser galaxy" NGC 4258, allowing us to directly calibrate the peak luminosities of the SNe Ia from the precise, geometric distance measurements provided by the masers. New features of our measurement include the use of the same instrument for all Cepheid measurements across the distance ladder and homogeneity of the Cepheid periods and metallicities thus necessitating only a differential measurement of Cepheid fluxes and reducing the largest systematic uncertainties in the determination of the fiducial SN Ia luminosity. The NICMOS measurements reduce differential extinction in the host galaxies by a factor of 5 over past optical data. Combined with an expanded of 240 SNe Ia at z<0.1 which define their magnitude-redshift relation, we find H_0=74.2 +/-3.6, a 4.8% uncertainty including both statistical and systematic errors. We show that the factor of 2.2 improvement in the precision of H_0 is a significant aid to the determination of the equation-of-state of dark energy, w = P/(rho c^2). Combined with the WMAP 5-year measurement of Omega_M h^2, we find w= -1.12 +/- 0.12 independent of high-redshift SNe Ia or baryon acoustic oscillations (BAO). This result is also consistent with analyses based on the combination of high-z SNe Ia and BAO. The constraints on w(z) now with high-z SNe Ia and BAO are consistent with a cosmological constant and improved by a factor of 3 from the refinement in H_0 alone. We show future improvements in H_0 are likely and will further contribute to multi-technique studies of dark energy.Comment: 60 pages, 15 figures Accepted for Publication, ApJ. This is the second of two papers reporting results from a program to determine the Hubble constant to 5% precision from a refurbished distance ladder based on extensive use of differential measurement