Abstract

Graphical abstract

Keywords

Abbreviations

1. Introduction

2. Materials and methods

3. Results

4. Discussion

5. Conclusions

Author contributions

Declaration of Competing Interest

Acknowledgments

Appendix A. Supplementary data

References

Abstract

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.

1. Introduction

As the third leading cause of cancer-related deaths worldwide (e.g., 881,000 deaths estimated in 2018)1, colorectal cancer (CRC, a cancer of the colon or rectum) is an obvious disease burden requiring effective, safe and widely-applicable treatments. Recent research in cancer immunology has led to the development of different immunotherapeutic strategies2, 3, 4. Among these, strategies that exert the blockade of immune checkpoint pathways [e.g., cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1)] have achieved favorable outcomes in a range of solid tumors5. However, it has been reported that only a minority of patients (up to 15% of the CRC population), who are identified with mismatch repair (MMR)-deficient CRC, respond positively to immune checkpoint blockade therapy6, while the response rate remains low in MMR-proficient CRC patients7. This failure is strongly attributed to the immunosuppressive feature of the tumor microenvironment (TME)8. Therefore, approaches designed to reprogram the TME may improve the therapeutic efficacy of immune checkpoint inhibitors9, potentially providing therapeutic benefit for the wide spectrum of CRC patients.

Immunogenic cell death (ICD) is characterized as immunogenic apoptosis that activates damage-associated molecular patterns (DAMPs) in dying or dead tumor cells in response to certain stimuli10. DAMPs as danger signals activate dendritic cells (DCs) for the presentation of tumor-associated antigens (TAAs), which subsequently induce T cell-mediated immunological responses against living tumor cells of the same kind10. The concept of ICD has revolutionized the traditional view of chemotherapeutic agents that are considered cytotoxic and poorly immunogenic. For example, chemotherapeutic drugs such as anthracyclines11, oxaliplatin12, bortezomib13 and cardiac glycosides14 have been identified as the putative ICD inducers. Recently, evaluation of chemotherapeutics as potential ICD inducers has gained increasing attention. In addition, ICD is often concomitant with the production of reactive oxygen species (ROS)10, and the efficacy of ICD may be enhanced by ROS-inducing strategies15, 16, 17. Therefore, it is hypothesized that a combination of ICD- and ROS-inducing strategies will mediate the remodeling of immunosuppressive TME and achieve synergistic immunotherapeutic efficacy with immune checkpoint blockade.

A healthy symbiotic relationship between corals and S ymbiodiniaceae relies on suitable temperature and adequate nutrients including trace metals. Besides global warming, trace metal deficiency has been shown to cause coral bleaching, a phenomenon responsible for extensive coral reef degradation around the world. How trace metal deficiency impacts Symbiodiniaceae and coral symbiosis is poorly understood, however . In this study, we applied RNA -seq to investigate how Fugacium kawagutii responds to the deficiency of five trace metal s (Fe2+, Zn2+, Cu2+ , Mn2+, Ni2+). We identified 685 to 2805 differentially expressed genes (DEGs) from these trace metal deficiency conditions, among which 372 were commonly regulated by all the five trace metal s and were significantly enriched in energy metabolism (e.g. fatty acid synthesis) . Furthermore, genes associated with extracellular matrix (ECM), cell surface structure and cell adhesion were impacted, suggesting that the ability of recognition and adhesion of F. kawagutii may be altered by trace metal deficiencies. In addition, among the five metals, Fe2+ deficiency exhibited the strongest influence, with F e -rich redox elements and many antioxidant synthesis genes being markedly down -regulated, indicative of adaptive reduction of Fe demand but a compromised ability to combat oxidative stress . Overall , deficiency of trace metal s (especially Fe) seems to repress growth and ability of ROS scavenging , elevat e energy metabolism and innate immunity, and alter cell adhesion capability, with implications in symbiosis disruption and coral bleaching.

Introduction

Mutualistic nutritional symbioses between coral animals and photosynthetic dinoflagellates of Symbiodiniaceae are the foundation of the highly biodiverse and productive coral reef ecosystem ( Peixoto et al., 2017). A symbiotic Symbiodiniaceae provide s its coral host with vital photosynthesis product s that can meet up to 95% of the coral ’s energy requirements; in exchange, the coral host provide s inorganic nutrients and serve s as shelter (Muscatine and Porter, 1997) for the symbiont . This mutualistic relationship, however, is delicate and susceptible to the environment factors including thermal stress, high light and extreme salinity (Davy et al., 2012; Kuanui et al., 2015; Nielsen et al., 2018; Skirving et al., 2019). These stress condition s often lead to the expulsion , death, or pigment loss of the Symbiodiniaceae from the host, known as coral bleaching. Global warming and anthropogenic activities have been responsible for massive bleaching and coral degradation , and posed major threats to the precious coral reef ecosystem around the world (Hughes et al ., 2017). Reef coral s liv e in tropical nutrient -poor waters , and they can experience limitation of nutrients, including trace metals ( Measures and Vink 2000; Obata et al ., 2008 ). It has been shown that trace metal deficiency can also induce coral bleaching (Ferrier -Pages et al ., 2018). Trace metal s are essential components of electron transport chains or important cofactors for enzymes involved in various biological processes, such as chlorophyll synthesis, nitrate reduction, and photoprotection or photorepair (Twining and Baines, 2013; Andresen, et al., 2018) .

Removal of oxygen atoms from triglycerides is the most important step in their conversion into hydrocarbons. Basic catalysts have proven to be highly efficient in deoxygenation, whereby the oxygen atoms are removed in the form of CO and CO2, yielding pyrolytic oil with acid number below 10 mg KOH,g
1 . We have now investigated the deoxygenation abilities of composite basic catalysts during the thermochemical conversion process. The dynamics of the catalytic cracking reaction using metal oxides, such as calcium oxide, in the presence of sodium carbonate, has been tested. According to thermogravimetric analysis (TGA) data, the activation energy for catalytic cracking was influenced by cations. By using calcium oxide as a catalyst, the activation energy was reduced from 260 kJ/mol to 185 kJ/mol, leading to a reduction in the reaction temperature of approximately 20e40 C. The yield of the cracked liquid fraction was of the order of 66e70%, more than 90% of which could be recovered as liquid hydrocarbons. The results presented herein indicate an alternative reaction pathway, allowing thermochemical conversion to be conducted at a lower operational temperature, which would be beneficial for industrial production with lower energy consumption.

Introduction

Biomass is a renewable resource that can be transformed into a variety of chemicals (Dodds and Gross, 2007), biofuels (Dupont et al., 2009a,b), and solid carbon (Simona et al., 2016) through physical and chemical techniques (Liu et al., 2017). The global biomass potential amount is about 200 EJ (up to 600 EJ), accounting for about one-third of the world’s total energy consumption (Rong and Tao, 2016). Making full use of this resource is attractive for addressing resource shortages (Zhang et al., 2018) and environmental pollution problems (Taromi and Kaliaguine, 2018). However, there are economic obstacles to making full use of biomass energy; to obtain the full environmental benefit, green production routes need to be ensured by considering technical conditions, which means green supply chain management (Oliveira. and Rebula, 2018
). Compared with other research, many cases of biomass production are significantly favorable from an environmental point of view, but government subsidies are needed to fully realize the economic benefits (Haskov
a. et al., 2016). So, it is important for economic and environmental friendly production when utilization the biomass energy. Triglycerides are important biomass materials, occurring widely in plant oils and animal fats, and have been used as biofuels for transportation in place of petroleum-based fuels (Lin et al., 2018). Many such oils are used as edible oils in China. As such, considering the economic benefit and resource efficiency, they are not suitable raw materials for hydrocarbon fuels. Nevertheless, abundant waste oil is produced in the refining and consumption of edible oils (Xu et al., 2016). Therefore, non-edible (Marousek et al., 2013) and waste cooking oils (Di_zge N et al., 2009) are primarily used as raw materials.

In-situ gasification chemical looping combustion (iG-CLC), which has been tested on pilot plant level, is regarded as an advanced carbon capture and storage (CCS) technology for reducing CO2 emissions. A life cycle global warming impact (GWI) analysis is performed to consider the lifetime emissions of the lowcarbon iG-CLC technology. Herein, the capacity is considered to be 610 MWe using natural ilmenite as oxygen carrier and steam as gasification agent. At the condition of operational pressure of 15 atm and air reactor temperature of 1050
C, the net power efficiency of 37.7% for achieving 93.5% inherent CO2 capture is obtained in simulations with thermodynamically optimum condition. The life cycle GWI is calculated equal to be 160.3 kg CO2-equivalent/MW h. The effects of several essential parameters, including steam to carbon ratio (S/C), oxygen carrier to fuel ratio (ф), different oxygen carriers and lifetime of oxygen carriers, on the lifecycle GWI have been analyzed and discussed to meet the potential possibility for further reducing greenhouse gas (GHG) emissions. To obtain sufficient carbon capture efficiency, the S/C ratio and ф are suggested to be 1.3 and 1.2 in this study, respectively. The life cycle GWI is heavily dependent on lifetime of ferrum (Fe) when it is less than 2000 h, beyond that range, the GWI is decreasing, but very slowly.

Introduction

Increasing concerns associated with irreversible climate change have led policy-makers to design climate policies to reduce the anthropogenic Greenhouse gas (GHG) emissions. For example, the Chinese government committed to reduce its CO2 emissions per unit of GDP by 40%e45% of 2005 levels by 2020 (Yi et al., 2011). Significant R&D efforts are underway worldwide to mitigate GHG emissions, including (1) switching to low-carbon fossil fuels, such as biofuels, natural gas or hydrogen; (2) decarbonisation of fuel or flue gas and then carbon sequestration, i.e. carbon capture and storage (CCS); (3) accelerating the use of renewable energy (such as bioenergy, direct solar and wind energy). The share of low-carbon electricity supply (including renewable energy, nuclear and CCS) is expected to be increased from currently 30% (2014) to more than 80% by 2050 (IPCC, 2014). Yet still in a very early stage of technical demonstration, the cost of renewable energy is not currently competitive; the current CCS technology incorporating into a power plant has also not reached large-scale commercial maturity owing to the efficiency losses (e.g. CO2 capture by amine scrubbing reduces the power output by 20e30% for a typical coal-fired power plant) as well as cost enhancement on CCS. Though numerous power plants can be incorporated with CCS activity, very limited demonstration plants have gained any measure of acceptance from an industrial viewpoint as more than 20 large-scale CCS projects have been cancelled in 2010e2016 owing to the sharply fluctuated policy and financial support (IEA, 2016). Up-to-date information related to CCS can be found elsewhere (Boot-Handford et al., 2014; Macdowell et al., 2010).

Introduction

In 2016, the national total output of aquatic products in China was 69 Mt, of which 32 Mt (46%) were freshwater aquatic products. The freshwater aquaculture area was 6.18
105 ha, of which 2.76
105 ha (44.71%) were freshwater fishponds. There is a huge increase in demand for freshwater aquatic products in China. However, the total aquaculture area is rapidly diminishing because of industry’s need for land. For example, the annual national decrease in total aquaculture area was 0.9% in 2015 and 1.4% in 2016 (Wang et al., 2017). To alleviate the situation, some intelligent systems which can contribute to increased production and reduced costs are being applied in freshwater aquaculture to monitor important water environmental variables in real time, such as dissolved oxygen (DO) concentration in water, water temperature, pH etc. (Simbeye & Yang, 2014; Simbeye, Zhao, & Yang, 2014). Siemens Corporation developed a system for monitoring 5 to 12 online water parameters in 2011 (Jawad, Nordin, Gharghan, Jawad, & Ismail, 2017). The American YSI Corporation also developed the YSI5200 aquaculture monitoring system for monitoring six kinds of water quality parameters in 2008. Researchers from the Chinese Academy of Fishery Sciences developed a multi-point online water quality testing system which can simultaneously monitor six water parameters in 2010. Scientists from Jiangsu University in China, developed a distribution monitoring system to determine a variety of key water parameters in real time, and the system had capacity for wireless data transmission in 2011 (Huan, Liu, & Chong, 2014; Huang et al., 2013). However, most of these existing monitoring systems, utilised in freshwater fishpond aquaculture, exchange information between the remote intelligent unit and monitoring computer through cable transmission. Cable communication systems carry many wires which results in a complex system and complications of data measurements and transmission. Moreover, such systems, once deployed, are inconvenient to expand to cover more targets. Further development of the freshwater fishpond aquaculture industry based on a cable communication system is limited, as cable communication systems are more suitable for a simple and small-scale scenario.

SUMMARY

Purpose: In simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), increased neuronal activity from epileptiform spikes commonly elicits positive blood oxygenation level–dependent (BOLD) responses. Negative responses are also occasionally seen and have not been explained. Recent studies describe BOLD signal changes before focal EEG spikes. We aimed to systematically study if the undershoot of a preceding positive response might explain the negative BOLD seen in the focus.

Methods: Eighty-two patients with focal epilepsy who underwent EEG-fMRI at 3T were retrospectively studied. Studies with a focal negative BOLD response in the region of the spike field were reanalyzed using models with hemodynamic response functions (HRFs) peaking from )9 to +9 s around the spike.

Results: Eight patients met the inclusion criteria, showing negative BOLD responses in the spike field on standard analysis. None had positive BOLD responses immediately adjacent to the areas of deactivation. Regions of deactivation were found to have congruent preceding positive responses in two cases. These early activations were seen at the combined maps of )5 to )9 s.

Discussion: This study indicates that in a small proportion of patients with focal epilepsy in whom the standard analysis reveals focal negative responses, an earlier positive BOLD response is probably the cause. The origin of negative BOLD signal changes in the focus as a result of an epileptic event remains, however, unexplained in most of the patients in whom it occurs. KEY WORDS: fMRI, Focal epilepsy, Spike, Deactivation.

1. Introduction

The past three decades have seen major advances in our understanding of mass extinctions, and yet consensus has not been reached on the causes of each of Earth’s greatest biotic catastrophes, and much less so its numerous lesser calamities. The past decade in particular has seen research efforts directed toward understanding the context and nature of environmental changes associated with extinction events. This has resulted in significant new data and observations from the fields of geochronology, geochemistry, mineralogy, palaeontology, sedimentology, stratigraphy, palaeomagnetism, volcanology and geophysics, several of which are the focus case studies in this Special Issue. Mass extinction theories have developed from the simple death-bysea-level-change hypothesis first proposed almost fifty years ago (Newell, 1967) into ever more complex, multicausal scenarios. The body of evidence associated with mass extinctions lends much support to proximal kill mechanisms that include anoxia (e.g. House, 1985; Buggisch, 1991; Wignall and Hallam, 1992; Brenchley et al., 1994, 2001; Isozaki, 1994, 1997; Wignall and Twitchett, 1996; Bond et al., 2004; Grice et al., 2005; Bond and Wignall, 2010; Shen et al., 2016; Wang et al., 2016), global warming (e.g. McElwain et al., 1999, 2005; Beerling and Berner, 2002; Wilf et al., 2003; Joachimski et al., 2009, 2012; Gómez and Goy, 2011; Sun et al., 2012, 2015; Punekar et al., 2014; Petersen et al., 2016), and ocean acidification (e.g. Hautmann, 2004; Payne et al., 2007; Hautmann et al., 2008a, 2008b; Clapham and Payne, 2011; Montenegro et al., 2011; Beauchamp and Grasby, 2012; Greene et al., 2012; Hinojosa et al., 2012; Martindale et al., 2012; Heydari et al., 2013; Clarkson et al., 2015) coupled with changes in atmospheric greenhouse gases, notably CO2, to name just a few. Advances in analytical capabilities have led to the identification of new kill mechanisms, such as toxic metal poisoning (e.g. Sanei et al., 2012; Sial et al., 2013, 2014; Grasby et al., 2015, 2016; Percival et al., 2015; Font et al., 2016; Thibodeau et al., 2016). It is increasingly widely thought that large igneous province (LIP) eruptions might be the driver of many of the purported proximal kill mechanisms, and the temporal link between volcanism and extinction is now well-established (Courtillot, 1999; Wignall, 2001; Courtillot and Renne, 2003; Bond and Wignall, 2014). However, the link between the two phenomena is still not fully understood. Whilst the deleterious effects of LIP volcanism are implicated in many extinction scenarios, a role for extra-terrestrial drivers should not be ignored. Bolide impact is of course famously implicated in the end-Cretaceous crisis (Alvarez et al., 1980; Hildebrand et al., 1991), and a role for deadly bursts of cosmic gamma rays also has advocates (Piran and Jimenez, 2014), notably for the Late Ordovician extinction (Melott et al., 2004).

Oral cancer is one of the most common malignancies worldwide [1]. Oral squamous cell carcinoma is the most prevalent type and accounts for 90% of oral cancers [2]. Despite great advances in surgical treatment, radiotherapy, and chemotherapy, the high reoccurrence and poor prognosis of oral cancer appear frequently owing to the rapid growth, local invasiveness, and distant metastasis [3–5]. Thus, exploring the underlying mechanisms of oral cancer growth and metastasis and identifying a potential therapeutic agent for oral cancer are imperative. Reactive oxygen species (ROS) are highly associated with several pathological conditions, including cancers [6]. It is established that cancer cells usually generate a large amount of ROS [7]. ROS can activate Akt signaling responsible for the proliferation and apoptosis evasion in several cancers, including oral cancer [8, 9]. ROS are highly involved in cancer metastasis, which are proposed to be putative mediators or modulators of epithelial-mesenchymal transition (EMT) [10–12]. EMT plays important roles in cancer metastasis and mainly endows cancer cells with invasive phenotypes [13]. During EMT, epithelial cells lose their epithelial markers, such as E-cadherin, and gain the mesenchymal markers, including Vimentin and Snail [14]. Reportedly, Snail is a transcriptional repressor of E-cadherin in tumor cells [15]. Mechanistically, the activation of phosphatidylinositide 3- kinases (PI3K)/Akt pathway is essential for ROS-driven EMT in colon cancer cells; in detail, ROS-dependent Akt activation enhances the expression of Snail and Vimentin and simultaneously reduces E-cadherin expression [16]. ROS is also a critical regulator of angiogenesis that is essential for cancer metastasis [17, 18]. ROS induces the expression of hypoxia-inducible factor 1α (HIF-1α) and increases its stabilization, thereby leading to the upregulation of vascular endothelial growth factor (VEGF) and subsequent angiogenesis [19, 20]. Both extracellular-regulated protein kinases (ERK) and PI3K/Akt pathways greatly contribute to the ROS-enhanced HIF-1α and VEGF during the malignant transformation of human bronchial epithelial cells [21]. Thus, targeting ROS is a potential therapeutic strategy to reduce the malignant phenotypes of oral cancer. Melatonin (N-acetyl-5-methoxytryptamine), which is mainly produced and secreted by the pineal gland, was initially found to be involved in the regulation of chronobiological rhythm [22]. Recently, as a potent antioxidant, melatonin scavenges a variety of free radicals directly and stimulates the activities of antioxidative enzymes indirectly [23, 24]. Melatonin exerts suppressive effects on multiple types of tumors partly depending on free radical scavenging and antioxidative activities [25–27]. Previously, melatonin was utilized as a preventive and curative agent for oral cancers by abolishing oxidative stress [28, 29]. Nevertheless, whether melatonin hampers oral cancer by reducing ROS-increased proliferation, EMT, and angiogenesis remains unknown.

Simultaneous measurement of multiple hemodynamic parameters is of high importance for the understanding of tissue function and disease progression. Hemodynamic responses are normally produced in response to physical or organ activity, environmental changes as well as neural activity to guarantee proper oxygen delivery to tissues [1,2]. Majority of cardiac and vascular disorders are similarly related to systemic hemodynamic dysfunction, so that hemodynamic measurements are essential in their timely diagnosis and treatment monitoring [3]. Color Doppler ultrasound (US) has arguably become the gold standard for mapping the distribution of blood flow. Handheld US scanners are extensively employed in the clinics for diagnosing blood clots, defects in heart valves, blockage in arteries and numerous other conditions [4]. Owing to its unique capability for non-invasive label-free mapping of the distribution of oxy- and deoxyhemoglobin deep in living tissues, multi-spectral optoacoustic tomography (MSOT) has recently found widespread use in preclinical imaging applications [5,6] and is undergoing rapid clinical translation in various point-of-care diagnostic applications, such as melanomas [7,8], inflammatory bowel (Crohn’s) disease [9], breast abnormalities [10], thyroid cancer [11,12] or peripheral vascular diseases [13]. Efficient integration between MSOT and US in a hybrid handheld scanner is expected to further accelerate clinical translation of MSOT and significantly enhance imaging performance of the stand-alone systems by simultaneously delivering their highly complementary contrasts. While a number of possible hybridization approaches have been previously suggested [14–18], such an efficient combination is inherently challenged by the fundamentally different excitation and image formation strategies behind the two modalities. Recently, a hand-held probe based on a multi-segment detector array combining linear and concave segments with different inter-element pitch has been reported [19,20]. The different parts of the array provide optimized performance for each modality, hence enabling accurate multi-modal optoacoustic and pulse-echo US imaging. The linear segment may additionally be exploited for other US modes, such as Doppler US. Here we adopted the multi-segment array approach in order to achieve multi-modal MSOT, pulse-echo US and color Doppler imaging in a hand-held mode. The experimental performance of the multi-modal approach is further showcased by imaging the carotid artery region of a healthy volunteer, where Doppler US is commonly used for the detection of vascular abnormalities, such as stenosis or intraluminal turbulence [21].

Climate change is a global problem that requires a co-ordinated, ambitious and large scale research program to halt or, indeed, to reverse it. The evidence, accumulated over the past few years, is now overwhelming and clearly shows that this problem has been caused by mankind’s unrestrained consumption of fossil fuels. The realisation of this central point is the reason so many countries came together last year (2016) in Paris, under the auspices of the United Nations, to develop an ambitious plan to combat climate change. It is, however, often difficult to persuade countries that they should allow their own research funding to be spent on transnational research projects where they would also be paying for research carried out by foreign scientists working outside the funding country’s borders. This requires the funding countries to put aside narrow self-interest and to have the confidence that these funded projects are the optimal ones to solve the problem, in this case to mitigate climate change. To overcome the very practical issues involved, a ‘Grand Challenge’ approach has been proposed in an open letter that was published in Nature [1]. This type of approach has been previously used to great effect in tackling major health related diseases (http://www.grandchallenges.org/). In this approach, a panel of the world’s best experts come together to establish a road map that sets out research steps needed to overcome the problem, with the best international teams then assembled to carry out the required science. This process allows both governments and philanthropic funders to be fully assured that their money is being appropriately spent. More recently in Marrakesh a group of twenty-three countries and the EU agreed to establish Mission Innovation. The aim of this forum is to coordinate increased funding to tackle both climate change and the problems it is causing. Table 1 details the seven major areas that were identified where this effort should be focused. In the context of this paper it is Challenge No. 5, ‘Converting Sunlight Innovation Challenge – to discover affordable ways to convert sunlight into storable solar fuels,’ that is relevant here. Research into artificial photosynthesis, the subject of our recent conference, is designed exactly to do this. Currently electricity can be efficiently produced from clean renewable sources of energy using solar panels, wind turbines, etc. [2, 3, 4]. However, we do not yet have sufficiently ‘smart’ grids to properly cope with the complicated problems associated with mid- to long-term electricity generation, such as; the transition from fossil fuels to renewables, the intermittency of renewable sources of energy and the difficulty in storing large amounts of electricity for long periods of time [5]. It is apparent ways of storing electricity in chemical bonds are urgently needed, i.e., as a fuel, and artificial photosynthesis aims to do exactly this.

In short-duration endurance events, such as middledistance running and sprint cross-country skiing, performance is not only related to the rate of aerobic energy supply but also to anaerobic energy provision (Duffield et al., 2005; Losnegard et al., 2012). This is also the case, at least to some extent, during longer-duration endurance events performed over undulating terrains and at fluctuating intensities, since the oxygen uptake (VO˙ 2) demand will at times exceed the maximal oxygen uptake (VO˙ 2max) (Norman et al., 1989; Skiba et al., 2012). In comparison to aerobic energy supply, anaerobic energy supply has a far more limited capacity (i.e., limited amount of energy that can be produced anaerobically) but can provide adenosine triphosphate at a much faster rate than the oxidative pathway. Therefore, the relative contribution of anaerobic energy production decreases with exercise duration (Gastin, 2001). In highly-trained runners, for example, anaerobic metabolism has been shown to account for ∼34 and ∼16% of the total energy turnover during 800-m and 1500-m events (lasting ∼1:53 and ∼3:55 min), respectively (Spencer and Gastin, 2001). In addition to energy supply, the efficacy of converting metabolic energy to external work (i.e., gross efficiency, GE) is an important component of endurance performance (Joyner and Coyle, 2008). Energetic contributions from aerobic pathways during wholebody exercise can easily be quantified using measurements of VO˙ 2, while a direct quantification of the anaerobic energy yield is more complicated and only possible via sophisticated, invasive and expensive technologies (Bangsbo et al., 1990). Therefore, a common approach during whole-body exercise is to indirectly estimate anaerobic energy production using the maximal accumulated oxygen (O2) deficit (MAOD) method (Medbø et al., 1988), which is based on calculating a linear relationship between submaximal VO˙ 2 and speed (or power output) and estimating VO˙ 2 demand at supramaximal speeds by extrapolation.

The main function of mitochondria is the production of ATP in the process of oxidative phosphorylation. The main byproduct that is formed in the course of electron transport in the respiratory chain is superoxide anion radical. Superoxide emerges as a result of one-electron reduction of molecular oxygen in various parts of the respiratory chain, including Complex I (NADH: ubiquinone oxidoreductase), Complex II (succinate dehydrogenase), Complex III (ubiquinol: cytochrome oxidoreductase), and mitochondrial matrix dehydrogenases [Grivennikova and Vinogradov, 2013]. Subsequently, the superoxide gives rise to various reactive oxygen species (ROS). Normally, only 1-2% of the oxygen consumed by the cells are used for ROS formation in mitochondria (mtROS) [Turrens, 2003, Inoue et al., 2003]. Until recently, it was believed that mtROS predominantly play a destructive role causing cell damage and accelerating aging [Harman, 2003]. These views are exemplified by the ideas that are expressed in the work of Huang and co-workers [1997]. It was established that mice with a knockout of cytosolic CuZn-dependent superoxide dismutase gene are viable, while mice with a nonfunctional mitochondrial Mn-dependent superoxide dismutase gene do not survive. Recently, it has been established that mtROS formation is mandatory for the functioning of virtually all organs and tissues, being involved in numerous metabolic pathways and in the regulation of signaling processes [Dan Dunn et al., 2015]. Importantly, mtROS are essential for the functioning of the immune system. However, their influence may be either positive or negative, depending on the quantity of the mtROS involved. From the immunological viewpoint, the positive effects of mtROS are primarily based on their activating influence on antimicrobial immunity, while their negative effects, caused by their excessive production, result in the induction of autoinflammatory [van der Burgh and Boes, 2015] and autoimmune processes [Lee et al., 2016; Lood et al., 2016]. The formation of mtROS plays an important role in the development of the antiviral immunity including the production of proinflammatory cytokines by immune system cells [Kim et al., 2015]. This review is concerned with the analysis of the mtROS role in terms of antibacterial innate immunity.

مقاله سال 2016

مقدمه
اگرچه گیاهان اکسیژن را از طریق فتوسنتز تولید می کنند ، اما کمبود یک سیستم کارآمد برای انتقال اکسیژن به ارگان های غیر فتوسنتزی نشان می دهد که این ارگان ها ممکن است در صورت محدود شدن اکسیژن از خارج ، از اکسیژن محدود شوند. علاوه بر این ، غوطه ور شدن کامل گیاه به واسطه ی سیل ممکن است منجر به دسترسی پایین به اکسیژن در اندام های بالاتر از زمین شود ، به خصوص زمانی که آلودگی آب فتوسنتز را محدود می کند. زمانی که اکسیژن برای تنفس محدود شود ، گیاهان هیپوکسی را تجربه می کنند ، در حالی که فقدان کامل اکسیژن (آنوکسی) برای بقای گیاه بیش تر مضر است. هم هیپوکسی و هم آنوکسی (کمبود اکسیژن) موجب برنامه نویسی مجدد ساختار ژن با القای متابولیسم خمیری می شوند و گیاه را قادر به استفاده از گلیکولیز برای تولید ATP می سازند. تغییرات آب و هوا باعث دسترسی بیش از اندازه به آب می شوند و در برخی نواحی منجر به خشکسالی می شوند ، در حالی که جاری شدن سیل به علت بارندگی شدید سایر مناطق جغرافیایی را تحت تاثیر قرار می دهد. به غیر از این در برخی از موارد انواع جدید محصولات قادر به مقاومت در برابر تنش های غیر زنده می باشند ، و حاصلخیزی به شدت تحت تاثیر قرار خواهد گرفت. تا یک دهه پیش اطلاعات کمی در رابطه با ژن هایی که تحمل در برابر غوطه ور شدن را افزایش می دادند وجود داشت ، و در طول سال های اخیر مکانیسم های ملکولی مربوط به سنجش اکسیژن و سیگنال دهی در گیاهان توسعه یافتند. در این بررسی ، یافته های اخیر در زمینه ی گیاهان غیرهوازی از اکوفیزیولوژی گیاهان که در تالاب ها رشد می کنند ، مورد توجه قرار دارند.