Activation of COX-2/PGE2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production.

Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E2 (PGE2), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE2 pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE2 production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE2 pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. IMPORTANCE: Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E2 (PGE2) pathway. Targeting of COX-1/2 using nonsteroidal anti-inflammatory drugs (NSAIDs) such as the COX-1/2 inhibitor indomethacin and the COX-2-specific inhibitors NS-398 and celecoxib or siRNAs targeting COXs, inhibited PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We further demonstrate that the production of PGE2 provides a protective effect against the antiviral effector mechanism of nitric oxide. Our findings uncover a new mechanism by which PSaV manipulates the host cell to provide an environment suitable for efficient viral growth, which in turn can be a new target for treatment of sapovirus infection.Wellcome Trust (097997/Z/11/Z); Grant (2014R1A2A2A01004292) of Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning, the Korea Basic Science Institute grant (C33730), and Bio-industry Technology Development Program (315021-04) funded by the Ministry of Agriculture, Food and Rural Affairs, Republic of Korea

Al-enabled, implantable, multichannel wireless telemetry for photodynamic therapy

Photodynamic therapy (PDT) offers several advantages for treating cancers, but its efficacy is highly dependent on light delivery to activate a photosensitizer. Advances in wireless technologies enable remote delivery of light to tumors, but suffer from key limitations, including low levels of tissue penetration and photosensitizer activation. Here, we introduce DeepLabCut (DLC)-informed low-power wireless telemetry with an integrated thermal/light simulation platform that overcomes the above constraints. The simulator produces an optimized combination of wavelengths and light sources, and DLC-assisted wireless telemetry uses the parameters from the simulator to enable adequate illumination of tumors through high-throughput (<20 mice) and multi-wavelength operation. Together, they establish a range of guidelines for effective PDT regimen design. In vivo Hypericin and Foscan mediated PDT, using cancer xenograft models, demonstrates substantial suppression of tumor growth, warranting further investigation in research and/or clinical settings

AI-enabled, implantable, multichannel wireless telemetry for photodynamic therapy

Photodynamic therapy (PDT) offers several advantages for treating cancers, but its efficacy is highly dependent on light delivery to activate a photosensitizer. Advances in wireless technologies enable remote delivery of light to tumors, but suffer from key limitations, including low levels of tissue penetration and photosensitizer activation. Here, we introduce DeepLabCut (DLC)-informed low-power wireless telemetry with an integrated thermal/light simulation platform that overcomes the above constraints. The simulator produces an optimized combination of wavelengths and light sources, and DLC-assisted wireless telemetry uses the parameters from the simulator to enable adequate illumination of tumors through high-throughput (<20 mice) and multi-wavelength operation. Together, they establish a range of guidelines for effective PDT regimen design. In vivo Hypericin and Foscan mediated PDT, using cancer xenograft models, demonstrates substantial suppression of tumor growth, warranting further investigation in research and/or clinical settings

Concepts, protocol, variations and current trends in surgery first orthognathic approach: A literature review

In the current era of expedited orthodontics, among many clinicians, tertiary care hospitals and patients, surgery first orthognathic approach (SFOA) has gained popularity. The advantages of SFOA (face first approach) are the reduced overall treatment duration and the early improvement in facial esthetics. In SFOA, the absence of a presurgical phase allows surgery to be performed first, followed by comprehensive orthodontic treatment to achieve the desired occlusion. The basic concepts of surgery early, surgery last, SFOA and Sendai SFOA technique along with its variations are reviewed in the present article. The recent advancement in SFOA in the context of preoperative preparation, surgical procedures and post-surgical orthodontics with pertinent literature survey are also discussed

Soil pH effects on the interactions between dissolved zinc, non-nano- and nano-ZnO with soil bacterial communities

Zinc oxide nanoparticles (ZnO NPs) are used in an array of products and processes, ranging from personal care products to antifouling paints, textiles, food additives, antibacterial agents and environmental remediation processes. Soils are an environment likely to be exposed to manmade nanoparticles due to the practice of applying sewage sludge as a fertiliser or as an organic soil improver. However, understanding on the interactions between soil properties, nanoparticles and the organisms that live within soil is lacking, especially with regards to soil bacterial communities. We studied the effects of nanoparticulate, non-nanoparticulate and ionic zinc (in the form of zinc chloride) on the composition of bacterial communities in soil with a modified pH range (from pH 4.5 to pH 7.2). We observed strong pH dependent effects on the interaction between bacterial communities and all forms of zinc, with the largest changes in bacterial community composition occurring in soils with low and medium pH levels (pH 4.8 and 5.9). The high pH soil (pH 7.2) was less susceptible to the effects of zinc exposure. At the highest doses of zinc (2500 mg/kg dw soil) both nano and non-nano particulate zinc applications elicited a similar response in the soil bacterial community, and this differed significantly to the ionic zinc salt treatment. The results highlight the importance of considering soil pH in nanotoxicology studies, although further work is needed to determine the exact mechanisms controlling the toxicity and fate and interactions of nanoparticles with soil microbial communities