Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice

BAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100β, serum miR370-3p, brain miR370-3p, brain TNF-α, and apoptosis), systemic inflammation (cytokines, cell-free DNA, endotoxemia, and bacteremia), and blood–brain barrier (BBB) damage (Evan’s blue dye and the presence of green fluorescent E. coli in brain after an oral administration). In parallel, brain miR arrays demonstrated miR370-3p at 24 h but not 120 h post-CLP, which was correlated with metabolic pathways. Either lipopolysaccharide (LPS) or TNF-α upregulated miR370-3p in PC12 (neuron cells). An activation by sepsis factors (LPS, TNF-α, or miR370-3p transfection) damaged mitochondria (fluorescent color staining) and reduced cell ATP, possibly through profound mitochondrial activity (extracellular flux analysis) that was attenuated by BAM15. In bone-marrow-derived macrophages, LPS caused mitochondrial injury, decreased cell ATP, enhanced glycolysis activity (extracellular flux analysis), and induced pro-inflammatory macrophages (iNOS and IL-1β) which were neutralized by BAM15. In conclusion, BAM15 attenuated sepsis through decreased mitochondrial damage, reduced neuronal miR370-3p upregulation, and induced anti-inflammatory macrophages. BAM15 is proposed to be used as an adjuvant therapy against sepsis hyperinflammation.     

Quantifying key uncertainties in the costs of nuclear power

In power system portfolio decisions, cost risk (uncertainty over cost) should be an important consideration, in addition to central estimates of cost. This study quantifies the uncertainty in each of the cost components for nuclear power, and combines them using a Monte Carlo analysis, allowing a direct assessment of cost risk for this technology. This can be used as an input to sophisticated portfolio optimisation modelling tools that take cost risk into account. Levelised cost of energy (LCOE) estimates are also provided here to allow an indicative comparison of the scale of cost risk, compared with other technologies. The most important contributors to cost risk for nuclear power generation are identified to be overnight capital cost (OCC) estimates, the degree of cost escalation over the construction and pre‐construction periods and the duration of those periods. In the absence of cost escalation, the mean LCOE of nuclear power is found to be AU$145/MWh in jurisdictions excluding Asia (or AU$130/MWh if Asian plant costs are included in the distributions), with a standard deviation of AU$62/MWh. However, when cost escalation over construction and pre‐construction periods is included at rates observed during nuclear build programs in France and the USA, the mean LCOE increases to AU$515/MWh, with a standard deviation of AU$2646/MWh. These results indicate that nuclear power costs have an 80% probability of exceeding AU$170/MWh, and a 50% probability of exceeding AU$278/MWh, based upon Monte Carlo analysis. This suggests that for OECD jurisdictions without an established nuclear industry (such as Australia), nuclear power may be comparable in cost with ‘dispatchable’, synchronous renewable alternatives such as concentrating solar thermal. Furthermore, the considerable cost risk associated with nuclear power is a significant disadvantage. Copyright © 2016 John Wiley & Sons, Ltd.     

More Prominent Inflammatory Response to Pachyman than to Whole-Glucan Particle and Oat-β-Glucans in Dextran Sulfate-Induced Mucositis Mice and Mouse Injection through Proinflammatory Macrophages

(1→3)-β-D-glucans (BG) (the glucose polymers) are recognized as pathogen motifs, and different forms of BGs are reported to have various effects. Here, different BGs, including Pachyman (BG with very few (1→6)-linkages), whole-glucan particles (BG with many (1→6)-glycosidic bonds), and Oat-BG (BG with (1→4)-linkages), were tested. In comparison with dextran sulfate solution (DSS) alone in mice, DSS with each of these BGs did not alter the weight loss, stool consistency, colon injury (histology and cytokines), endotoxemia, serum BG, and fecal microbiome but Pachyman–DSS-treated mice demonstrated the highest serum cytokine elicitation (TNF-α and IL-6). Likewise, a tail vein injection of Pachyman together with intraperitoneal lipopolysaccharide (LPS) induced the highest levels of these cytokines at 3 h post-injection than LPS alone or LPS with other BGs. With bone marrow-derived macrophages, BG induced only TNF-α (most prominent with Pachyman), while LPS with BG additively increased several cytokines (TNF-α, IL-6, and IL-10); inflammatory genes (iNOS, IL-1β, Syk, and NF-κB); and cell energy alterations (extracellular flux analysis). In conclusion, Pachyman induced the highest LPS proinflammatory synergistic effect on macrophages, followed by WGP, possibly through Syk-associated interactions between the Dectin-1 and TLR-4 signal transduction pathways. Selection of the proper form of BGs for specific clinical conditions might be beneficial.     

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

Although the enhanced responses against serum cell-free DNA (cfDNA) in cases of sepsis—a life-threatening organ dysfunction due to systemic infection—are understood, the influence of the cytosolic DNA receptor cGAS (cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase) on sepsis is still unclear. Here, experiments on cGAS deficient (cGAS^-/-) mice were conducted using cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection sepsis models and macrophages. Severity of CLP in cGAS^-/- mice was less severe than in wildtype (WT) mice, as indicated by mortality, serum LPS, cfDNA, leukopenia, cytokines (TNF-α, IL-6 and IL-10), organ histology (lung, liver and kidney) and spleen apoptosis. With the LPS injection model, serum cytokines in cGAS^-/- mice were lower than in WT mice, despite the similar serum cfDNA level. Likewise, in LPS-activated WT macrophages, the expression of several mitochondria-associated genes (as revealed by RNA sequencing analysis) and a profound reduction in mitochondrial parameters, including maximal respiration (determined by extracellular flux analysis), DNA (mtDNA) and mitochondrial abundance (revealed by fluorescent staining), were demonstrated. These data implied the impact of cfDNA resulting from LPS-induced cell injury. In parallel, an additive effect of bacterial DNA on LPS, seen in comparison with LPS alone, was demonstrated in WT macrophages, but not in cGAS^-/- cells, as indicated by supernatant cytokines (TNF-α and IL-6), M1 proinflammatory polarization (iNOS and IL-1β), cGAS, IFN-γ and supernatant cyclic GMP–AMP (cGAMP). In conclusion, cGAS activation by cfDNA from hosts (especially mtDNA) and bacteria was found to induce an additive proinflammatory effect on LPS-activated macrophages which was perhaps responsible for the more pronounced sepsis hyperinflammation observed in WT mice compared with the cGAS^-/- group.     

Blood Bacteria-Free DNA in Septic Mice Enhances LPS-Induced Inflammation in Mice through Macrophage Response

Although bacteria-free DNA in blood during systemic infection is mainly derived from bacterial death, translocation of the DNA from the gut into the blood circulation (gut translocation) is also possible. Hence, several mouse models with experiments on macrophages were conducted to explore the sources, influences, and impacts of bacteria-free DNA in sepsis. First, bacteria-free DNA and bacteriome in blood were demonstrated in cecal ligation and puncture (CLP) sepsis mice. Second, administration of bacterial lysate (a source of bacterial DNA) in dextran sulfate solution (DSS)-induced mucositis mice elevated blood bacteria-free DNA without bacteremia supported gut translocation of free DNA. The absence of blood bacteria-free DNA in DSS mice without bacterial lysate implies an impact of the abundance of bacterial DNA in intestinal contents on the translocation of free DNA. Third, higher serum cytokines in mice after injection of combined bacterial DNA with lipopolysaccharide (LPS), when compared to LPS injection alone, supported an influence of blood bacteria-free DNA on systemic inflammation. The synergistic effects of free DNA and LPS on macrophage pro-inflammatory responses, as indicated by supernatant cytokines (TNF-α, IL-6, and IL-10), pro-inflammatory genes (NFκB, iNOS, and IL-1β), and profound energy alteration (enhanced glycolysis with reduced mitochondrial functions), which was neutralized by TLR-9 inhibition (chloroquine), were demonstrated. In conclusion, the presence of bacteria-free DNA in sepsis mice is partly due to gut translocation of bacteria-free DNA into the systemic circulation, which would enhance sepsis severity. Inhibition of the responses against bacterial DNA by TLR-9 inhibition could attenuate LPS-DNA synergy in macrophages and might help improve sepsis hyper-inflammation in some situations.     

Assessing the sustainability challenges for electricity industries in ASEAN newly industrialising countries

Rapid social and economic progress in fast developing countries such that among the countries in the Association of Southeast Asian Nations (ASEAN) have driven substantial growth in electricity consumption in this region. Whilst this represents significant societal and economic development, it has potentially growing adverse environmental impacts. This raises a concern on sustainable development in the electricity sector in this region. This study evaluates key sustainability challenges in the electricity industries in the five largest energy consumers in ASEAN: Indonesia, Thailand, Malaysia, the Philippines and Vietnam. The 3A's energy sustainability objectives: Accessibility, Availability and Acceptability are used as the sustainability analytical framework. This study also draws together a set of associated indicators and criteria within the analytical framework to analyse the status of the electricity industries in these countries. The analysis shows that key sustainability challenges in the ASEAN-5 are attributable to satisfying rapid demand growth; enhancing security of electricity supply; and mitigating the increase in CO₂ emissions from electricity generation. Given the promising resource and technical potential in this region, renewable energy emerges as a favourable option to address these challenges; however, increasing the share of renewable energy in electricity generation requires considerable policy support. This study suggests that there is an opportunity for the ASEAN countries to strengthen regional collaborations through experience and resource sharing to enhance sustainability in the electricity industries. This study also highlights some of the key issues facing the electricity industry, and the need for new generation investment decision support tools which can address these issues.     

电力市场环境下购电协议的形成方法

专用购电协议（Special PPA）作为一种具有选择性的支付方式,融合了2种不同的电力市场结构,即基于传统购电协议的垄断市场和基于电力联营体模式的竞争市场．为支付发电公司最初的投资,专用购电协议把电厂容量的一半作为保证量,按容量费用方式支付;对于没有得到保证的部分容量,按照类似电力联营体的方式参与市场竞争．专用购电协议提供了不同的优先调度方式,可以使得更多的发电机组得到利用;同时对发电公司有所倾斜,能够激励和吸引发电投资．