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This paper highlights the design of the third eye for the blind personnels. One of the biggest problems that people who are blind face on a daily basis is movement. The loss of their eyesight severely limits their quality of life and activities. In their long-term exploration, they typically use a blind navigation system or their stored recollections. The major goal of the current effort is to provide a strong, dependable, user-friendly, portable, low-power, low-cost solution for efficient navigation. As stated in this study (Smart Glasses for Blind People), the intended audience is those who are visually handicapped. It includes a built-in sensor that emits ultrasonic waves in the direction the user is moving while scanning a maximum of 5–6 metres over a 30 degree angle. The sensor recognises the impediment and transmits a signal to the buzzer, which alerts the user with a beeping sound. The work given here is a mini-project that is taken up as a part of the curriculum completed by electronics and communication engineering students in the second year of the electronics & communication engineering department at Dayananda Sagar College of Engineering in Bangalore.

The work presented in this paper deals with the wireless notice board design using bluetooth technologies. This project deals with an innovative rather an interesting manner of intimating the message to the people using a wireless electronic display board which is synchronized using the Bluetooth technology. This will help us in passing any message almost immediately without any delay just by sending a SMS or voice message which is better and more reliable than the old traditional way of passing the message on notice board. This proposed technology can be used in colleges, many public places, malls or big buildings to enhance the security system and also create awareness of the emergency situations and avoid many dangers. Using Bluetooth module message can be displayed on the LCD display board and using GSM module SMS or voice message can be sent to the Bluetooth module. The Electronic notice board is wireless and needs no wires for displaying the information on the LCD Display. It is very easy to operate and consumes less power. The circuit of the wireless notice board is portable. The work presented here is the mini-project work of the second semester engineering students of electronics & communication engineering department of Dayananda Sagar College of Engg., Bangalore, Karnataka.

GGF2 is a recombinant human neuregulin-1β in development for chronic heart failure. Phase 1 clinical trials of GGF2 were put on hold when transient elevations in serum aminotransferases and total bilirubin were observed in 2 of 43 subjects who received single doses of GGF2 at 1.5 or 0.378 mg/kg. However, aminotransferase elevations were modest and not typical of liver injury sufficient to result in elevated serum bilirubin. Cynomolgus monkeys administered a single 15 mg/kg dose of GGF2 had similar transient elevations in serum aminotransferases and bilirubin as well as transient elevations in serum bile acids. However, no hepatocellular necrosis was observed in liver biopsies obtained during peak elevations. When sandwich-cultured human hepatocytes were treated with GGF2 for up to 72 h at concentrations approximately 0.8-fold average plasma Cmax for the 0.378 mg/kg dose, no cytotoxicity was observed. Gene expression profiling identified approximately 50% reductions in mRNAs coding for bilirubin transporters and bile acid conjugating enzymes, as well as changes in expression of additional genes mimicking the interleukin-6-mediated acute phase response. Similar gene expression changes were observed in GGF2-treated HepG2 cells and primary monkey hepatocytes. Additional studies conducted in sandwich-cultured human hepatocytes revealed a transient and GGF2 concentration-dependent decrease in hepatocyte bile acid content and biliary clearance of taurocholate without affecting biliary taurocholate efflux. Taken together, these data suggest that GGF2 does not cause significant hepatocellular death, but transiently modifies hepatic handling of bilirubin and bile acids, effects that may account for the elevations in serum bilirubin observed in the clinical trial subjects.

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1β isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.

Remyelination promoting human IgMs effectively increase the number of myelinated axons in animal models of multiple sclerosis. Hence, they ultimately stimulate myelin production by oligodendrocytes (OLs); however, their exact mechanism of action remains to be elucidated, and in particular, it remains unclear whether they are directly targeting OLs, or their action is mediated by effects on other cell types. We assessed the effect of remyelination promoting antibody rHIgM22 on the proliferative response and on the ceramide/sphingosine 1-phosphate rheostat in mixed glial cell cultures (MGCs). rHIgM22 treatment caused a time-dependent increase in PDGFαR protein in MGCs. Forty-eight hours of treatment with rHIgM22 induced a dose-dependent proliferative response (evaluated as total cell number and as EdU(+) cell number) in MGCs. When the proliferation response of MGCs to rHIgM22 was analyzed as a function of the cell types, the most significant proliferative response was associated with GLAST(+) cells, i.e., astrocytes. In many cell types, the balance between different sphingolipid mediators (the “sphingolipid rheostat”), in particular ceramide and sphingosine 1-phosphate, is critical in determining the cell fate. rHIgM22 treatment in MGCs induced a moderate but significant inhibition of total acidic sphingomyelinase activity (measured in vitro on cell lysates), the main enzyme responsible for the stimulus-mediated production of ceramide, when treatment was performed in serum containing medium, but no significant differences were observed when antibody treatment was performed in the absence of serum. Moreover, rHIgM22 treatment, either in the presence or in absence of serum, had no effects on ceramide levels. On the other hand, rHIgM22 treatment for 24 h induced increased production and release of sphingosine 1-phosphate in the extracellular milieu of MGC. Release of sphingosine 1-phosphate upon rHIgM22 treatment was strongly reduced by a selective inhibitor of PDGFαR. Increased sphingosine 1-phosphate production does not seem to be mediated by regulation of the biosynthetic enzymes, sphingosine kinase 1 and 2, since protein levels of these enzymes and phosphorylation of sphingosine kinase 1 were unchanged upon rHIgM22 treatment. Instead, we observed a significant reduction in the levels of sphingosine 1-phosphate lyase 1, one of the key catabolic enzymes. Remarkably, rHIgM22 treatment under the same experimental conditions did not induce changes in the production and/or release of sphingosine 1-phosphate in pure astrocyte cultures. Taken together, these data suggest that rHIgM22 indirectly influences the proliferation of astrocytes in MGCs, by affecting the ceramide/sphingosine 1-phosphate balance. The specific cell population directly targeted by rHIgM22 remains to be identified, however our study unveils another aspect of the complexity of rHIgM22-induced remyelinating effect.

Rods and cones are morphologically and developmentally distinct photoreceptor types with different functions in vision. Cones mediate daylight and color vision and in most mammals express M and S opsin photopigments for sensitivity to medium-long and short light wavelengths, respectively. Rods mediate dim light vision and express rhodopsin photopigment. The transcription factor networks that direct differentiation of each photoreceptor type are incompletely defined. Here, we report that Rorb −/− mice lacking retinoid-related orphan nuclear receptor β lose rods but overproduce primitive S cones that lack outer segments. The phenotype reflects pronounced plasticity between rod and cone lineages and resembles that described for Nrl −/− mice lacking neural retina leucine zipper factor. Rorb −/− mice lack Nrl expression and reexpression of Nrl in Rorb −/− mice converts cones to rod-like cells. Thus, Rorb directs rod development and does so at least in part by inducing the Nrl -mediated pathway of rod differentiation.

Thyroid hormone is necessary for cochlear development and auditory function, but the factors that control these processes are poorly understood. Previous evidence indicated that in mice, the serum supply of thyroid hormone is augmented within the cochlea itself by type 2 deiodinase, which amplifies the level of T3, the active form of thyroid hormone, before the onset of hearing. We now report that type 3 deiodinase, a thyroid hormone-inactivating enzyme encoded by Dio3, is expressed in the immature cochlea before type 2 deiodinase. Dio3−/− mice display auditory deficits and accelerated cochlear differentiation, contrasting with the retardation caused by deletion of type 2 deiodinase. The Dio3 mRNA expression pattern in the greater epithelial ridge, stria vascularis, and spiral ganglion partly overlaps with that of thyroid hormone receptor β (TRβ), the T3 receptor that is primarily responsible for auditory development. The proposal that type 3 deiodinase prevents premature stimulation of TRβ was supported by deleting TRβ, which converted the Dio3−/− cochlear phenotype from one of accelerated to one of delayed differentiation. The results indicate a protective role for type 3 deiodinase in hearing. The auditory system illustrates the considerable extent to which tissues can autoregulate their developmental response to thyroid hormone through both type 2 and 3 deiodinases.

Color vision requires the expression of opsin photopigments with different wavelength sensitivities in retinal cone photoreceptors. The basic color visual system of mammals is dichromatic, involving differential expression in the cone population of two opsins with sensitivity to short (S, blue) or medium (M, green) wavelengths. However, little is known of the factors that directly activate these opsin genes and thereby contribute to the S or M opsin identity of the cone. We report that the orphan nuclear receptor RORβ (retinoid-related orphan receptor β) activates the S opsin gene (Opn1sw) through binding sites upstream of the gene. RORβ lacks a known physiological ligand and activates the Opn1sw promoter modestly alone but strongly in synergy with the retinal cone-rod homeobox factor (CRX), suggesting a cooperative means of enhancing RORβ activity. Comparison of wild-type and mutant lacZ reporter transgenes showed that the RORβ-binding sites in Opn1sw are required for expression in mouse retina. RORβ-deficient mice fail to induce S opsin appropriately during postnatal cone development. Photoreceptors in these mice also lack outer segments, indicating additional functions for RORβ in photoreceptor morphological maturation. The results identify Opn1sw as a target gene for RORβ and suggest a key role for RORβ in regulating opsin expression in the color visual system.

Glial growth factor (GGF2) is a Neuregulin-1 (NRG-1), which binds ErbB receptors and activates downstream cell signaling processes. NRG-1 ligands and their receptors are required for cardiac development and adult cardiac function. GGF2 has been shown to improve left ventricular function in several models of heart failure though the mechanisms by which GGF2 is efficacious are poorly understood. GGF2 is currently in clinical trials for treatment of congestive heart failure. Many studies have focused on GGF2 regulation of PI3 kinase (PI3K) as measured by formation of pAKT in vivo and in numerous cell lines, including HL-1 cells, neonatal rat ventricular myocytes (NRVMs) and human iPSC-derived cardiomyocytes. NRG-1s also activate the MAP kinase (MAPK) pathway as measured by pERK1/2 formation. To better understand GGF2 action in the stressed heart, we have developed in vitro systems to study GGF2 protection of cardiomyocytes from doxorubicin induced toxicity. After serum starvation, cells were pre-incubated with GGF2 (0.15 pM to 9.5 nM) for 1 hr followed by exposure to 1 μM doxorubicin for 18 hrs. After doxorubicin treatment MTT labeling index of cultures was used as an endpoint measurement of cell metabolic status. Doxorubicin decreases MTT labeling index by 90% while GGF2 prevented this toxicity by almost 50% compared to untreated cells, with an EC 50 of 83.3±19.4 pM . This effect appears to be dependent upon AKT signaling and not MAPK as assessed using inhibitors of both pathways. Inhibition of MAPK increases pAKT formation without changing extent of GGF2 protection. Blocking ErbB4 receptor, highly expressed in cardiomyocytes, causes a decrease in pAKT formation, suggesting that this receptor is important for mediating GGF2 action in these cells. Our results demonstrate that, in HL-1 cells, GGF2 mediates cytoprotective responses which require PI3K activation. Similar studies are being pursued in doxorubicin-treated NRVMs and human iPS derived cardiomyocytes. Initial results indicate GGF2 also mediates cytoprotective effects in these cell types. Future efforts will be aimed at elucidating potential roles for PI3K-dependent GGF2 regulation of mitochondrial function, Ca 2+ signaling or REDOX regulation in the observed cytoprotective actions.

Neuregulin-1β is essential for fetal cardiac development and adult cardiac function. Previous reports indicate that neuregulins improve left ventricular function in heart failure models, however the duration of the functional improvements with early or late initiation of neuregulin treatment has not been characterized. The present studies examine the effects of early and delayed initiation of intravenous GGF2 treatment on left ventricular (LV) function in rats with myocardial infarction (MI). Rats underwent surgically-induced MI by left anterior coronary artery ligation. Treatment with vehicle or GGF2 (2.6 mg/kg) was initiated at 2 or 16 w post-MI and continued once or twice weekly or once every two weeks for the in-life duration of the study (approximately 40 weeks). LV function was assessed echocardiographically up to once weekly for the duration of the study. Early and delayed initiation of GGF2 treatment caused sustained and significant improvement (p < 0.05) in both ejection fraction (EF) and fractional shortening (FS) in all regimens tested. The greatest improvements were seen with the once weekly dosing paradigm after early initiation (average EF (%) at 40 weeks post initiation of dosing: vehicle = 44.4 ± 6.0, n = 8 rats, vs. GGF2 = 64.7±6.1. n = 9 rats) and twice weekly dosing paradigm after delayed initiation (average EF (%) at 4 weeks post initiation of dosing: vehicle = 34.18±1.6, n = 7 rats, vs. GGF2 = 50.69±4.68, n = 7 rats). In addition, LV function improved when rats were re-challenged with GGF2 following an extended wash out period. This observation indicates potential efficacy for treatment paradigms that utilize intermittent dosing. These findings suggest that GGF2 produces sustained improvement in LV function after early or delayed initiation of treatment following MI in rats.

Neuregulins are a family of growth factors essential for normal cardiac and nervous system development. The EGF-like domain of neuregulins contains the active site which binds and activates signaling cascades through ErbB receptors. A neuregulin-1 gene EGF-like fragment demonstrated neuroprotection in the transient middle cerebral artery occlusion (MCAO) stroke model and drastically reduced infarct volume (Xu et al., 2004). Here we use a permanent MCAO rat model to initially compare two products of the neuregulin-1 gene and also assess levels of recovery with acute versus delayed time to treatment. In the initial study full-length glial growth factor 2 (GGF2) and an EGF-like domain fragment were compared with acute intravenous delivery. In a second study GGF2 only was delivered starting at 24h, 3 days or 7 days after permanent ischemia was induced. In both studies daily intravenous administration continued for 10 days. Recovery of neurological function was assessed using limb placing and body swing tests. GGF2 had similar functional improvements compared to the EGF-like domain fragment at equimolar doses, and a higher dose of GGF2 demonstrated more robust functional improvements compared to a lower dose. GGF2 improved sensorimotor recovery with all treatment paradigms, even enhancing recovery of function with a delay of 7 days to treatment. Histological assessments did not show any associated reduction in infarct volume at either 48 h or 21 days post-ischemic event. Neurorestorative effects of this kind are of great potential clinical importance, given the difficulty of delivering neuroprotective therapies within a short time after an ischemic event in human patients. If confirmed by additional work including additional data on mechanism(s) of improved outcome with verification in other stroke models, one can make a compelling case to bring GGF2 to clinical trials as a neurorestorative approach to improving outcome following stroke injury.

Maturation of the mammalian nervous system requires adequate provision of thyroid hormone and mechanisms that enhance tissue responses to the hormone. Here, we report that the development of cones, the photoreceptors for daylight and color vision, requires protection from thyroid hormone by type 3 deiodinase, a thyroid hormone-inactivating enzyme. Type 3 deiodinase, encoded byDio3, is expressed in the immature mouse retina. InDio3−/−mice, ∼80% of cones are lost through neonatal cell death. Cones that express opsin photopigments for response to both short (S) and medium-long (M) wavelength light are lost. Rod photoreceptors, which mediate dim light vision, remain essentially intact. Excessive thyroid hormone in wild-type pups also eliminates cones. Cone loss is mediated by cone-specific thyroid hormone receptor β2 (TRβ2) as deletion of TRβ2 rescues cones inDio3−/−mice. However, rescued cones respond to short but not longer wavelength light because TRβ2 under moderate hormonal stimulation normally induces M opsin and controls the patterning of M and S opsins over the retina. The results suggest that type 3 deiodinase limits hormonal exposure of the cone to levels that safeguard both cone survival and the patterning of opsins that is required for cone function.

Most mammals have two types of cone photoreceptors, which contain either medium wavelength (M) or short wavelength (5) opsin. The number and spatial organization of cone types varies dramatically among species, presumably to fine-tune the retina for different visual environments. In the mouse, 5- and M-opsin are expressed in an opposing dorsal-ventral gradient. We previously reported that cone opsin patterning requires thyroid hormone β2, a nuclear hormone receptor that regulates transcription in conjunction with its ligand, thyroid hormone (TH). Here we show that exogenous TH inhibits 5-opsin expression, but activates M-opsin expression. Binding of endogenous TH to TRβ2 is required to inhibit 5-opsin and to activate M-opsin. TH is symmetrically distributed in the retina at birth as 5-opsin expression begins, but becomes elevated in the dorsal retina at the time of M-opsin onset (postnatal day 10). Our results show that TH is a critical regulator of both 5-opsin and M-opsin, and suggest that a TH gradient may play a role in establishing the gradient of M-opsin. These results also suggest that the ratio and patterning of cone types may be determined by TH availability during retinal development. © 2006 by The National Academy of Sciences of the USA., This work was supported by National Institutes of Health Grants T32 EY07031 and NS28308 (to M.R.R. and T.A.R.), by the National Institute on Deafness and Other Communication Disorders, a Hirschl award, and the intramural program at National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (to M.S. and D.F.), and by Instituto de Salud Carlos III, Red de Centros de Metabolismo y Nutricion (03 08) and Instituto de Salud Carlos III PI031417 (03 1417) (to G.M.d.E.).

Thyroid hormone profoundly influences the development of the vertebrate nervous system. The thyroid hormone receptor beta gene (Thrb) is a key mediator of many of these actions. The Thrb gene is complex, spanning up to 400 kb in mammals, and differentially expresses distinct receptor subtypes through independent tissue-specific promoters and alternative splicing. These receptors serve a range of functions in the brain as well as particularly sensitive functions in the auditory and visual sensory systems. The Thrb gene illustrates how versatility in neurodevelopmental control can be achieved at the receptor level.

Color vision is facilitated by distinct populations of cone photoreceptors in the retina. In rodents, cones expressing different opsin photopigments are sensitive to middle (M, 'green') and short (S, 'blue') wavelengths, and are differentially distributed across the retina. The mechanisms that control which opsin is expressed in a particular cone are poorly understood, but previous in vitro studies implicated thyroid hormone in cone differentiation. Thyroid hormone receptor beta 2 (TR beta 2) is a ligand-activated transcription factor that is expressed in the outer nuclear layer of the embryonic retina. Here we delete Thrb (encoding Tr beta 2) in mice, causing the selective loss of M-cones and a concomitant increase in S-opsin immunoreactive cones. Moreover, the gradient of cone distribution is disturbed, with S-cones becoming widespread across the retina. The results indicate that cone photoreceptors throughout the retina have the potential to follow a default S-cone pathway and reveal an essential role for Tr beta 2 in the commitment to an M-cone identity. Our findings raise the possibility that Thrb mutations may be associated with human cone disorders.