Effect of knocking down the insulin receptor on mouse rod responses.

Previous experiments have shown that the insulin receptor (IR) is expressed in mammalian rods and contributes to the protection of photoreceptors during bright-light exposure. The role of the insulin receptor in the production of the light response is however unknown. We have used suction-electrode recording to examine the responses of rods after conditionally knocking down the insulin receptor. Our results show that these IR knock-down rods have an accelerated decay of the light response and a small decrease in sensitivity by comparison to littermate WT rods. Our results indicate that the insulin receptor may have some role in controlling the rate of rod response decay, but they exclude a major role of the insulin receptor pathway in phototransduction

Protein tyrosine phosphatase-1B regulates the tyrosine phosphorylation of the adapter Grb2-associated binder 1 (Gab1) in the retina

Abstract Background Gab1 (Grb2-associated binder 1) is a key coordinator that belongs to the insulin receptor substrate-1 like family of adaptor molecules and is tyrosine phosphorylated in response to various growth factors, cytokines, and numerous other molecules. Tyrosine phosphorylated Gab1 is able to recruit a number of signaling effectors including PI3K, SHP2 and PLC-γ. In this study, we characterized the localization and regulation of tyrosine phosphorylation of Gab1 in the retina. Results Our immuno localization studies suggest that Gab1 is expressed in rod photoreceptor inner segments. We found that hydrogen peroxide activates the tyrosine phosphorylation of Gab1 ex vivo and hydrogen peroxide has been shown to inhibit the protein tyrosine phosphatase PTP1B activity. We found a stable association between the D181A substrate trap mutant of PTP1B and Gab1. Our studies suggest that PTP1B interacts with Gab1 through Tyrosine 83 and this residue may be the major PTP1B target residue on Gab1. We also found that Gab1 undergoes a light-dependent tyrosine phosphorylation and PTP1B regulates the phosphorylation state of Gab1. Consistent with these observations, we found an enhanced Gab1 tyrosine phosphorylation in PTP1B deficient mice and also in retinas treated ex vivo with a PTP1B specific allosteric inhibitor. Conclusions Our laboratory has previously reported that retinas deficient of PTP1B are resistant to light damage compared to wild type mice. Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well. In summary, our data suggest that PTP1B regulates the phosphorylation state of retinal Gab1 in vivo

Human adenovirus type 19 infection of corneal cells induces p38 MAPK-dependent interleukin-8 expression

<p>Abstract</p> <p>Background</p> <p>Human adenovirus type 19 (HAdV-19) is a major cause of epidemic keratoconjunctivitis, the only ocular adenoviral infection associated with prolonged corneal inflammation. In this study, we investigated the role of p38 mitogen-activated protein kinase (MAPK) in HAdV-19 infection, with particular attention to the role of p38 MAPK in the transcriptional control of interleukin-8 (IL-8), a chemokine previously shown to be central to the initiation of adenovirus keratitis.</p> <p>Results</p> <p>We found that infection of corneal cells with HAdV-19 led to activation of p38 MAPK and its downstream targets, HSP-27 and ATF-2, within 15 to 30 minutes post-infection. Infection also induced phosphorylation of IκB and NFκB in a p38 MAPK-dependent fashion. Furthermore, HAdV-19 induced an interaction between p38 MAPK and NFκB-p65, followed by nuclear translocation of activated NFκB-p65 and its binding to the IL-8 promoter. The interaction between p38 MAPK and NFκB-p65 was inhibited in concentration-dependent fashion by SB203580, a chemical inhibitor of p38 MAPK, but not by SP600125, an inhibitor of JNK – another MAPK implicated in chemokine expression by HAdV-19 infected cells. IL-8 gene expression in HAdV-19 infection was significantly reduced in the presence of sequence-specific p38 MAPK siRNA but not control siRNA.</p> <p>Conclusion</p> <p>These results provide the first direct evidence for transcriptional regulation of IL-8 in HAdV-19 infected cells through the activation of the p38 MAPK signaling pathway. The p38 MAPK pathway may play a biologically important role in regulation of IL-8 gene expression in the adenovirus-infected cornea.</p

Discovering Closely Related Peers of a Person in Social Networks

In social networks, finding a group of similar people of a specified person is meaningful task in many areas like substitution/alternate recommendation system. For a given person, considering hobbies, interests etc., as base forming a group of peers from social networks. Here we propose mutual unique identification group(MUID) algorithm for identifying closely related peers

Antibacterial studies and phytochemical constituents of South Indian Phyllanthus species

Antibacterial activity and phytochemical tests of the methanol extracts of six Phyllanthus species were evaluated. In agar well diffusion assay the diameter of inhibition zones ranged from 3 - 22 mm. Phyllanthus amarus showed maximum activity of 22 mm. The minimum inhibition concentration (MIC)and minimum bactericidal concentration (MBC) observed for Bacillus stearothermophilus, Staphylococcus aureus, Bacillus subtilis, Micrococcus leuteus, Salmonella typhi, Enterobacter aerogens, Proteus mirabilis, and Proteus vulgaris were 30 - 205 ìg/ml and 40 - 230 ìg/ml, respectively.P. amarus, P. hookeri and P. maderaspatensis showed the lowest MIC (30 ìg/ml) as well as MBC (40 ìg/ml) and thus an effective inhibitor of the tested bacteria. Lignans, triterpenoids and phenols were detected in all the 6 tested plants

Spinning Conformal Correlators

We develop the embedding formalism for conformal field theories, aimed at doing computations with symmetric traceless operators of arbitrary spin. We use an index-free notation where tensors are encoded by polynomials in auxiliary polarization vectors. The efficiency of the formalism is demonstrated by computing the tensor structures allowed in n-point conformal correlation functions of tensors operators. Constraints due to tensor conservation also take a simple form in this formalism. Finally, we obtain a perfect match between the number of independent tensor structures of conformal correlators in d dimensions and the number of independent structures in scattering amplitudes of spinning particles in (d+1)-dimensional Minkowski space.Comment: 46 pages, 3 figures; V2: references added; V3: tiny misprint corrected in (A.9

Spinning Conformal Blocks

For conformal field theories in arbitrary dimensions, we introduce a method to derive the conformal blocks corresponding to the exchange of a traceless symmetric tensor appearing in four point functions of operators with spin. Using the embedding space formalism, we show that one can express all such conformal blocks in terms of simple differential operators acting on the basic scalar conformal blocks. This method gives all conformal blocks for conformal field theories in three dimensions. We demonstrate how this formalism can be applied in a few simple examples.Comment: 29 page

Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32

Hearing loss is often caused by death of the mechanosensory hair cells of the inner ear. Hair cells are susceptible to death caused by aging, noise trauma, and ototoxic drugs, including the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Ototoxic drugs result in permanent hearing loss for over 500 000 Americans annually. We showed previously that induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. In order to begin to translate these findings into a clinical therapy aimed at inhibiting ototoxic drug-induced hearing loss, we have now examined a pharmacological HSP inducer, celastrol. Celastrol induced upregulation of HSPs in utricles, and it provided significant protection against aminoglycoside-induced hair cell death in vitro and in vivo. Moreover, celastrol inhibited hearing loss in mice receiving systemic aminoglycoside treatment. Our data indicate that the major heat shock transcription factor HSF-1 is not required for celastrol-mediated protection. HSP32 (also called heme oxygenase-1, HO-1) is the primary mediator of the protective effect of celastrol. HSP32/HO-1 inhibits pro-apoptotic c-Jun N-terminal kinase (JNK) activation and hair cell death. Taken together, our data indicate that celastrol inhibits aminoglycoside ototoxicity via HSP32/HO-1 induction

Indian summer monsoon onset forecast skill in the UK Met Office initialized coupled seasonal forecasting system (GloSea5-GC2)

Accurate and precise forecasting of the Indian monsoon is important for the socio-economic security of India, with improvements in agriculture and associated sectors from prediction of the monsoon onset. In this study we establish the skill of the UK Met Office coupled initialized global seasonal forecasting system, GloSea5-GC2, in forecasting Indian monsoon onset. We build on previous work that has demonstrated the good skill of GloSea5 at forecasting interannual variations of the seasonal mean Indian monsoon using measures of large-scale circulation and local precipitation. We analyze the summer hindcasts from a set of three springtime start-dates in late April/early May for the 20-year hindcast period (1992-2011). The hindcast set features at least fifteen ensemble members for each year and is analyzed using five different objective monsoon indices. These indices are designed to examine large and local-scale measures of the monsoon circulation, hydrological changes, tropospheric temperature gradient, or rainfall for single value (area-averaged) or grid-point measures of the Indian monsoon onset. There is significant correlation between onset dates in the model and those found in reanalysis. Indices based on large-scale dynamic and thermodynamic indices are better at estimating monsoon onset in the model rather than local-scale dynamical and hydrological indices. This can be attributed to the model's better representation of large-scale dynamics compared to local-scale features. GloSea5 may not be able to predict the exact date of monsoon onset over India, but this study shows that the model has a good ability at predicting category-wise monsoon onset, using early, normal or late tercile categories. Using a grid-point local rainfall onset index, we note that the forecast skill is highest over parts of central India, the Gangetic plains, and parts of coastal India - all zones of extensive agriculture in India. El Niño Southern Oscillation (ENSO) forcing in the model improves the forecast skill of monsoon onset when using a large-scale circulation index, with late monsoon onset coinciding with El Niño conditions and early monsoon onset more common in La Niña years. The results of this study suggest that GloSea5's ensemble-mean forecast may be used for reliable Indian monsoon onset prediction a month in advance despite systematic model errors