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71.
72.
The discovery of melanopsin-dependent inner retinal photoreceptors in mammals has precipitated a fundamental reassessment of such non-image forming (NIF) light responses as circadian photoentrainment and the pupil light reflex. By contrast, it remains unclear whether these new photoreceptors also play a role in classical image-forming vision. The retinal ganglion cells that subserve inner retinal photoreception (ipRGCs) project overwhelmingly to brain areas involved in NIF responses, indicating that, in terms of central signaling, their predominant function is non-image forming. However, ipRGCs also exhibit intraretinal communication via gap junction coupling, which could allow them to modulate classical visual pathways within this tissue. Here, we explore this second possibility by using melanopsin knockout (Opn4-/-) mice to examine the role of inner retinal photoreceptors in diurnal regulation of retinal function. By using electroretinography in wild-type mice, we describe diurnal rhythms in both the amplitude and speed of the retinal cone pathway that are a function of both prior light exposure and circadian phase. Unexpectedly, loss of the melanopsin gene abolishes circadian control of these parameters, causing significant attenuation of the diurnal variation in cone vision. Our results demonstrate for the first time a melanopsin-dependent regulation of visual processing within the retina, revealing an important function for inner retinal photoreceptors in optimizing classical visual pathways according to time of day. 相似文献
73.
Peter Charbel Issa Samantha R. De Silva Daniel M. Lipinski Mandeep S. Singh Alexandre Mouravlev Qisheng You Alun R. Barnard Mark W. Hankins Matthew J. During Robert E. MacLaren 《PloS one》2013,8(4)
Adeno-associated viral vectors (AAV) have been shown to be safe in the treatment of retinal degenerations in clinical trials. Thus, improving the efficiency of viral gene delivery has become increasingly important to increase the success of clinical trials. In this study, structural domains of different rAAV serotypes isolated from primate brain were combined to create novel hybrid recombinant AAV serotypes, rAAV2/rec2 and rAAV2/rec3. The efficacy of these novel serotypes were assessed in wild type mice and in two models of retinal degeneration (the Abca4−/− mouse which is a model for Stargardt disease and in the Pde6brd1/rd1 mouse) in vivo, in primate tissue ex-vivo, and in the human-derived SH-SY5Y cell line, using an identical AAV2 expression cassette. We show that these novel hybrid serotypes can transduce retinal tissue in mice and primates efficiently, although no more than AAV2/2 and rAAV2/5 serotypes. Transduction efficiency appeared lower in the Abca4−/− mouse compared to wild type with all vectors tested, suggesting an effect of specific retinal diseases on the efficiency of gene delivery. Shuffling of AAV capsid domains may have clinical applications for patients who develop T-cell immune responses following AAV gene therapy, as specific peptide antigen sequences could be substituted using this technique prior to vector re-treatments. 相似文献
74.
Njeuhmeli E Forsythe S Reed J Opuni M Bollinger L Heard N Castor D Stover J Farley T Menon V Hankins C 《PLoS medicine》2011,8(11):e1001132
Background
There is strong evidence showing that voluntary medical male circumcision (VMMC) reduces HIV incidence in men. To inform the VMMC policies and goals of 13 priority countries in eastern and southern Africa, we estimate the impact and cost of scaling up adult VMMC using updated, country-specific data.Methods and Findings
We use the Decision Makers'' Program Planning Tool (DMPPT) to model the impact and cost of scaling up adult VMMC in Botswana, Lesotho, Malawi, Mozambique, Namibia, Rwanda, South Africa, Swaziland, Tanzania, Uganda, Zambia, Zimbabwe, and Nyanza Province in Kenya. We use epidemiologic and demographic data from recent household surveys for each country. The cost of VMMC ranges from US$65.85 to US$95.15 per VMMC performed, based on a cost assessment of VMMC services aligned with the World Health Organization''s considerations of models for optimizing volume and efficiencies. Results from the DMPPT models suggest that scaling up adult VMMC to reach 80% coverage in the 13 countries by 2015 would entail performing 20.34 million circumcisions between 2011 and 2015 and an additional 8.42 million between 2016 and 2025 (to maintain the 80% coverage). Such a scale-up would result in averting 3.36 million new HIV infections through 2025. In addition, while the model shows that this scale-up would cost a total of US$2 billion between 2011 and 2025, it would result in net savings (due to averted treatment and care costs) amounting to US$16.51 billion.Conclusions
This study suggests that rapid scale-up of VMMC in eastern and southern Africa is warranted based on the likely impact on the region''s HIV epidemics and net savings. Scaling up of safe VMMC in eastern and southern Africa will lead to a substantial reduction in HIV infections in the countries and lower health system costs through averted HIV care costs. Please see later in the article for the Editors'' Summary. 相似文献75.
Background
This paper proposes an approach to estimating the costs of demand creation for voluntary medical male circumcision (VMMC) scale-up in 13 countries of eastern and southern Africa. It addresses two key questions: (1) what are the elements of a standardized package for demand creation? And (2) what challenges exist and must be taken into account in estimating the costs of demand creation?Methods and Findings
We conducted a key informant study on VMMC demand creation using purposive sampling to recruit seven people who provide technical assistance to government programs and manage budgets for VMMC demand creation. Key informants provided their views on the important elements of VMMC demand creation and the most effective funding allocations across different types of communication approaches (e.g., mass media, small media, outreach/mobilization). The key finding was the wide range of views, suggesting that a standard package of core demand creation elements would not be universally applicable. This underscored the importance of tailoring demand creation strategies and estimates to specific country contexts before estimating costs. The key informant interviews, supplemented by the researchers'' field experience, identified these issues to be addressed in future costing exercises: variations in the cost of VMMC demand creation activities by country and program, decisions about the quality and comprehensiveness of programming, and lack of data on critical elements needed to “trigger the decision” among eligible men.Conclusions
Based on this study''s findings, we propose a seven-step methodological approach to estimate the cost of VMMC scale-up in a priority country, based on our key assumptions. However, further work is needed to better understand core components of a demand creation package and how to cost them. Notwithstanding the methodological challenges, estimating the cost of demand creation remains an essential element in deriving estimates of the total costs for VMMC scale-up in eastern and southern Africa. 相似文献76.
Fisher SP Godinho SI Pothecary CA Hankins MW Foster RG Peirson SN 《Journal of biological rhythms》2012,27(1):48-58
Sleep is a fundamental biological rhythm involving the interaction of numerous brain structures and diverse neurotransmitter systems. The primary measures used to define sleep are the electroencephalogram (EEG) and electromyogram (EMG). However, EEG-based methods are often unsuitable for use in high-throughput screens as they are time-intensive and involve invasive surgery. As such, the dissection of sleep mechanisms and the discovery of novel drugs that modulate sleep would benefit greatly from further development of rapid behavioral assays to assess sleep in animal models. Here is described an automated noninvasive approach to evaluate sleep duration, latency, and fragmentation using video tracking of mice in their home cage. This approach provides a high correlation with EEG/EMG measures under both baseline conditions and following administration of pharmacological agents. Moreover, the dose-dependent effects of sedatives, stimulants, and light can be readily detected. This approach is robust yet relatively inexpensive to implement and can be easily incorporated into ongoing screening programs to provide a powerful first-pass screen for assessing sleep and allied behaviors. 相似文献
77.
Barth BM Gustafson SJ Hankins JL Kaiser JM Haakenson JK Kester M Kuhn TB 《Cellular signalling》2012,24(6):1126-1133
A persistent inflammatory reaction is a hallmark of chronic and acute pathologies in the central nervous system (CNS) and greatly exacerbates neuronal degeneration. The proinflammatory cytokine tumor necrosis factor alpha (TNFα) plays a pivotal role in the initiation and progression of inflammatory processes provoking oxidative stress, eicosanoid biosynthesis, and the production of bioactive lipids. We established in neuronal cells that TNFα exposure dramatically increased Mg(2+)-dependent neutral sphingomyelinase (nSMase) activity thus generating the bioactive lipid mediator ceramide essential for subsequent NADPH oxidase (NOX) activation and oxidative stress. Since many of the pleiotropic effects of ceramide are attributable to its metabolites, we examined whether ceramide kinase (CerK), converting ceramide to ceramide-1-phosphate, is implicated both in NOX activation and enhanced eicosanoid production in neuronal cells. In the present study, we demonstrated that TNFα exposure of human SH-SY5Y neuroblastoma caused a profound increase in CerK activity. Depleting CerK activity using either siRNA or pharmacology completely negated NOX activation and eicosanoid biosynthesis yet, more importantly, rescued neuronal viability in the presence of TNFα. These findings provided evidence for a critical function of ceramide-1-phospate and thus CerK activity in directly linking sphingolipid metabolism to oxidative stress. This vital role of CerK in CNS inflammation could provide a novel therapeutic approach to intervene with the adverse consequences of a progressive CNS inflammation. 相似文献
78.
Aarti Jagannath Rachel Butler Sofia I.H. Godinho Yvonne Couch Laurence A. Brown Sridhar R. Vasudevan Kevin C. Flanagan Daniel Anthony Grant C. Churchill Matthew J.A. Wood Guido Steiner Martin Ebeling Markus Hossbach Joseph G. Wettstein Giles E. Duffield Silvia Gatti Mark W. Hankins Russell G. Foster Stuart N. Peirson 《Cell》2013
79.
Yi Sui Hai-Lu Zhao Heung Man Lee Jing Guan Lan He Fernand MM Lai Peter CY Tong Juliana CN Chan 《Translational oncology》2009,2(4):258-263
Nephrectomized rats have widely been used to study chronic renal failure. Interestingly, renal cell carcinoma occurred in the remnant kidney after uninephrectomy (UNX). In this study, we probed insulin-like growth factor (IGF)-1 signaling pathway in UNX-induced renal cancer. Adult male Sprague-Dawley rats were randomized into two groups: UNX rats (n = 22) and sham-operated rats (n = 12). Rats were killed at 3, 7, and 10 months. After 7 months after nephrectomy, the UNX rats developed renal cell carcinoma with increased expression of proliferating cell nuclear antigen, and 68.2% (15/22) of the animals exhibited invasive carcinoma. Western blot demonstrated significant down-regulation of IGF binding protein 3 contrasting with the up-regulation of protein kinase Cζ and Akt/protein kinase B in the renal cancer tissues. These findings indicate a unique rat model of UNX-induced renal cancer associated with enhanced IGF-1 signaling pathway. 相似文献
80.
Prasanth Rayorath Wajahatullah Khan Ravishankar Palanisamy Shawna L. MacKinnon Roumiana Stefanova Simon D. Hankins Alan T. Critchley Balakrishan Prithiviraj 《Journal of Plant Growth Regulation》2008,27(4):370-379
Extracts of the brown seaweed Ascophyllum nodosum have been used as a biostimulant to promote growth and productivity in a number of agricultural production systems. Although
the extracts have been shown to improve seedling emergence and vigor in a variety of plants, including barley, the mechanism(s)
of this growth-promoting effect is(are) largely unknown. In our study, A. nodosum extract induced amylase activity in barley seed-halves; a significant difference in amylase activity was observed in seeds
without an embryo. The addition of activated charcoal to the treatment media negated the bioactivity of the extracts suggesting
the organic nature of bioactive compounds in A. nodosum extracts. The extracts induced amylase activity in a gibberellic acid (GA)-deficient barley mutant (grd2). LC-MS-MS analysis failed to detect the presence of GA3 in the extracts. ABA supplementation of the medium caused a significant reduction of amylase activity in GA-treated seeds
compared with those treated with the A. nodosum extract. Taken together, our results suggest that the organic components of A. nodosum extract induce amylase activity independent of GA3 and might act in concert with GA-dependent amylase production leading to enhanced germination and seedling vigor in barley.
Being derived from a renewable resource, the bioactive compounds from A. nodosum could be used to improve crop productivity in sustainable agricultural systems. 相似文献