Inspired by natural photonic structures , researchers have demonstrated varying artificial color display devices using different designs. Photonic-crystal/plasmonic color filters have drawn increasing attention most recently. In this review article, we show the developing trend of artificial structural color pixels from photonic crystals to plasmonic nanostructures. Such devices normally utilize the distinctive optical features of photonic/plasmon resonance, resulting in high compatibility with current display and imaging technologies. Moreover, dynamical color filtering devices are highly desirable because tunable optical components are critical for developing new optical platforms which can be integrated or combined with other existing imaging and display techniques. Thus, extensive promising potential applications have been triggered and enabled including more abundant functionalities in integrated optics and nanophotonics. Rather than using colorant-based pigmentation, structural color filtering devices ,5,6,7,8 Furthermore, investigations on magnetophotonic composites and relevant devices ,71,72,73In general, the working principle of dyes or pigments is based on light-matter interaction which in fact is that they can absorb light of only certain wavelengths and reflect the remaining frequency bands of the spectrum, leading to resonance peaks in either transmission or reflection. People have long benefited from nature’s capability of creating coloration. The famous Morpho butterfly wings  were onepn) on top of a glass substrate (refractive index = sn), which can function as a planar waveguide. Periodicity, width, and height are labeled as L, d and h, respectively. Generally speaking, these 2D nanogratings can work as filters under phase-matching conditions. Diffracted waves can be generated and the reflected energy can be dramatically strengthened within certain frequency ranges. These 2D color filters exhibit unique optical properties compared with 1D nanogratings which have strong angle dependency on incident light. Theoretically, one can avoid relying on grating coupling for resonance mode excitation to minimize angle sensitivity. Different from grating coupling, plasmon-assisted resonators and nano-antennae normally need a large density for effectively scattering light to either viewers’ eyes or photodetectors in the visible range. The angle dependence for plasmonic crystals is directly related to the surface plasmon polariton excitation via grating coupling which limits the practical applications due to relatively low coupling efficiencies since it is inherently angle-dependent because of momentum matching conditions. Overcoming this angle-dependent spectrum response will allow these structural filters to be integrated into practical applications such as high resolution visual displays, miniature hyperspectral imaging, and high sensitivity sensing devices.Inspired by distinctive Morpho butterfly wings, reflective photonic crystal color filters consisting of nanogratings were proposed and experimentally fabricated . As showNote that these 2D photonic crystal filters utilized the coupling between the incident light and the resonant modes (guided-mode resonance) to generate individual colors. Such filters show high reflectance (>70%) and angular tolerance and they can suppress the incident-angle dependency and enhance the chromatic properties  compared with traditional 1D color filters, leading to useful applications for display techniques. The geometry can also be further optimized to make the optical effect close to being independent of the tilt angle and therefore enable wide use in ambient light conditions, paving the way to more practical applications in displays. The pioneering experiments on angle robust optical devices were performed by Wu and coworkers  who utilFurthermore, the reflectivity for s- and p-polarization is different. For s-polarization, it does not change greatly in the Brillouin zone, while for p-polarization it lessens through the range. Thanks to the fast development of nanotechnology, color filters can be fabricated by using electron-beam lithography (EBL) and nanoimprint lithography (NIL) followed by inductively coupled plasma reactive ion etching (ICP-RIE) to transfer patterns from resists to silicon substrates. However, one should note that the crystallinity of the fabricated silicon color filters may affect the device performance significantly. For instance, the maximum reflectance is reduced tremendously for amorphous silicon due to large internal absorption. Therefore, the reflectance spectrum may vary due to different silicon crystallinity properties and various refractive indices. Using NIL and multi-scan excimer laser annealing, 2D photonic crystal color filters were experimentally demonstrated by Cho and coworkers . This coPlasmon-assisted nanophotonic devices have drawn particular attention in recent years because of their tremendous latent capacity for new imaging and display technologies ,87,88 siUsing simple nanostructures, various color filters have been demonstrated, including nanoslit antennae , ultrathAs shown in The development of plasmon related/enhanced reflective filtering devices is mainly limited by efficiency since metals have significant absorption at visible frequencies. To receive acceptable reflected energy, normally, high aspect ratio structures  are needed, resulting in challenging fabrication processes. Normal lift-off processes are only effective for thin devices because resists can be hardly removed if they are covered by thick metal films. One feasible solution to overcome the difficulties mentioned above is to use a dry etching method to transfer patterns (top-down fabrication process). By using argon ion milling, large aspect ratio silver nanorods were fabricated  and reflTo experimentally demonstrate the reflection-mode color filtering devices, high aspect ratio nanorod arrays were fabricated in silver films by using EBL followed by argon ion milling. Inter-rod spacing of 20 nm smallest was achieved to reveal blue color as shown in Structural color pixels can outperform their chemical counterparts since they can bear long-time constant illumination with stronger light intensities. In addition, they can achieve high compactness and resolution beyond the diffraction limit with wide tunability and highly stable device performance. Moreover, structure color filtering devices can enable high efficiency and low power consumption with dramatically slimmed dimensions and enhanced resolution. However, the incident angle tolerance limits the practical applications of such optical components. To achieve more promising applications, thinner spectral response is desired for vivid colors with high angle tolerance. Researchers have made every effort to realize angle robust optical filters with narrow broad spectral response and high optical performance to yield a superior color contrast. To obtain angle-insensitivity, one has to avoid relying on grating coupling for plasmonic mode excitation. In contrast to grating coupling, plasmon assisted resonators and antennae have been experimentally demonstrated as candidates for structure colors which have advantageous features such as brilliancy and color vividness. Gratings in metal surfaces without involving diffraction effects can be used to control the light polarization so that it is possible to use an analyzing polarizer to manipulate the transmitted colors, which are largely independent of the angle of incidence. Significant work remains to develop a reflective display that can provide a bright and full-color image comparable to printed media with low power consumption as a new class of display element, which allows the full-color emission from a single pixel under a broad range of ambient lighting conditions. However, one can still obtain individual colors based on tuning the incident angle of white light illuminated onto nanostructures. Instead of adjusting geometry parameters, different color outputs can be achieved via incidence scanning with a fixed design. Using a single plasmonic chip, photon-plasmon coupling interactions can be triggered and further engineered to reach continuous color tuning effects across the whole visible range .2) can be realized by using interference lithography to define patterns and ion milling to transfer patterns. As demonstrated in A large functional area  devices are enabled which may pave the way for next generation display productions. However, researchers still need to further improve the optical performance of color filtering devices for more practical applications. Filters with both high transmission intensity and narrow passing band are critical to produce high throughput and low-cost optical components for new optical devices. Additionally, high speed actively tunable devices are extremely important for future development of multiple-functional assemblies. In practice, low-cost and high-throughput approaches are desired because they are more suitable for industrial applications.


Since the seminal finding almost 50 years ago that exercise training increases mitochondrial content in skeletal muscle, a considerable amount of research has been dedicated to elucidate the mechanisms inducing mitochondrial biogenesis. The discovery of peroxisome proliferator-activated receptor γ co-activator 1α as a major regulator of exercise-induced gene transcription was instrumental in beginning to understand the signals regulating this process. However, almost two decades after its discovery, our understanding of the signals inducing mitochondrial biogenesis remain poorly defined, limiting our insights into possible novel training modalities in elite athletes that can increase the oxidative potential of muscle. In particular, the role of mitochondrial reactive oxygen species has received very little attention; however, several lifestyle interventions associated with an increase in mitochondrial reactive oxygen species coincide with the induction of mitochondrial biogenesis. Furthermore, the diminishing returns of exercise training are associated with reductions in exercise-induced, mitochondrial-derived reactive oxygen species. Therefore, research focused on altering redox signaling in elite athletes may prove to be effective at inducing mitochondrial biogenesis and augmenting training regimes. In the context of exercise performance, the biological effect of increasing mitochondrial content is an attenuated rise in free cytosolic adenosine diphosphate (ADP), and subsequently decreased carbohydrate flux at a given power output. Recent evidence has shown that mitochondrial ADP sensitivity is a regulated process influenced by nutritional interventions, acute exercise, and exercise training. This knowledge raises the potential to improve mitochondrial bioenergetics in the absence of changes in mitochondrial content. Elucidating the mechanisms influencing the acute regulation of mitochondrial ADP sensitivity could have performance benefits in athletes, especially as these individuals display high levels of mitochondria, and therefore are subjects in whom it is notoriously difficult to further induce mitochondrial adaptations. In addition to changes in ADP sensitivity, an increase in mitochondrial coupling would have a similar bioenergetic response, namely a reduction in free cytosolic ADP. While classically the stoichiometry of the electron transport chain has been considered rigid, recent evidence suggests that sodium nitrate can improve the efficiency of this process, creating the potential for dietary sources of nitrate  to display similar improvements in exercise performance. The current review focuses on these processes, while also discussing the biological relevance in the context of exercise performance. Strenuous exercise can increase the energetic demands of skeletal muscle by 100-fold over resting requirements, placing an enormous challenge on bioenergetic pathways to maintain concentrations of adenosine triphosphate (ATP), the basic unit of energy within muscle. Skeletal muscle is equipped with an intricate series of enzymatic reactions that resynthesize ATP to ensure cellular survival during these conditions. The diverse reactions buffering ATP fluctuations within muscle display a continuum of speed  relative to the capacity for ATP production. For instance, the breakdown of phosphocreatine (PCr) can produce ATP extremely rapidly for a relatively short period of time, while in contrast, aerobic metabolism within mitochondria produces ATP at a lower maximal rate, but essentially has a limitless capacity. As a result, aerobic metabolism dominates ATP production during most continuous exercise situations, highlighting the importance of mitochondria to overall metabolic homeostasis. This simplistic view of metabolism is efficient for teaching purposes as it enables ‘compartmentalization’ of each system; however, in reality, there is considerable integration between each bioenergetic process. Historically, an increase in mitochondrial content represents a fundamental exercise training response , contribIt has been known for almost a century that elite athletes have a higher maximal rate of oxygen consumption, higher maximal mitochondrial enzymatic activities, and ultimately improved performance. While originally attributed to genetics, Holloszy’s landmark research in 1967 demonstrated the remarkable plasticity of skeletal muscle to increase mitochondrial content and improve exercise capacity . This seIn 1984, Holloszy postulated that an increase in mitochondrial content would alter the sensitivity of oxidative metabolism to ADP , and, inSpecifically, ADP activates glycogen phosphorylase kinase to covalently modify phosphorylase, while AMP allosterically regulates phosphorylase by increasing the sensitivity of the enzyme to glycogen, promoting glycogen breakdown. In the context of phosphofructokinase, ADP and AMP decrease the sensitivity of the allosteric inhibitory binding site for ATP, essentially removing an inhibitor for enzymatic flux, while ADP also inhibits PDH kinase activity, maintaining PDH in an active state and promoting pyruvate flux towards aerobic respiration. As a result, a reduction in cytosolic ADP levels, and the subsequent production of AMP, as occurs following training , provideGiven that increasing mitochondrial content represents a key mechanism for the improvement in exercise performance following training, it is understandable that research has focused on elucidating the molecular events responsible for the initiation of mitochondrial biogenesis. The induction of mitochondrial biogenesis requires the transcription of proteins contained within both the nuclear and the mitochondrial DNA genomes. The mitochondrial proteome consists of ~1600 proteins, the vast majority of which are encoded within the nucleus, as the mitochondrial DNA only encodes for 13 subunits of the electron transport chain and proteins required for messenger RNA translation within this organelle . The inA large body of literature has been devoted to studying the role of energy turnover and activation of AMP activated protein kinase (AMPK) as a key signal to induce mitochondrial biogenesis. However, high-intensity interval training and ‘classical’ endurance training result in similar accumulations of mitochondrial proteins, suggesting this process is not directly influenced by the rate of ATP hydrolysis . In addi2+/calmodulin-dependent protein kinase (CaMKII)] and reactive oxygen species (ROS)-mediated processes. Activation of CaMKII has been shown to induce the nuclear translocation of PGC-1α and the expression of mitochondrial genes [The other ‘signals’ implicated in the regulation of mitochondrial content include calcium [specifically Caal genes , while pal genes . While Ral genes . Howeveral genes , 25, a ral genes . Moreoveal genes . These dal genes  reportedal genes , potentiThe notion that mitochondrial ROS contributes to exercise-induced mitochondrial biogenesis may help explain the lack of mitochondrial biogenesis observed in humans consuming antioxidants while exercise training . In thisThe induction of mitochondrial biogenesis, and the subsequent improvement in mitochondrial ADP sensitivity, has become synonymous with exercise training adaptations. This classical working model is premised on the belief that mitochondrial ‘function’ remains unaltered following a chronic training intervention. However, evidence is starting to accumulate to suggest that mitochondrial ADP transport is a regulated process, raising the possibility that lifestyle interventions can influence mitochondrial ADP sensitivity in the absence of the induction in mitochondrial biogenesis.The phosphate shuttling mechanism for energy transfer between matrix and cytosolic compartments includes three major protein complexes see Fig. : voltageTraditional dogma stipulates that mitochondrial function is not externally regulated beyond the provision of substrates required for oxidative phosphorylation. This belief extends from Holloszy’s original observation that in vitro assessments of mitochondrial stoichiometry (P/O ratios: ADP consumed per oxygen atom) remain constant following chronic training . HoweverGiven the relative novelty of identifying mitochondrial ADP transport as a regulated process, very little evidence has been generated with respect to nutritional approaches to augment this process. However, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation has been shown to alter the lipid composition of mitochondrial membranes in association with an increase in mitochondrial ADP sensitivity . IntriguOne of the most characterized responses to exercise training is an improvement in ADP sensitivity, sparing muscle glycogen and improving exercise capacity. Historically, these responses were exclusively attributed to an increase in mitochondrial content. However, recent evidence has accumulated to show that mitochondrial ADP transport is a highly regulated process. A better understanding of the molecular signals influencing the proteins directly controlling mitochondrial ADP transport, namely miCK and ANT, is required, as this knowledge could result in novel training programs aimed at optimizing muscle performance. While beetroot juice appears to influence excitation–contraction coupling, as opposed to mitochondrial bioenergetics, a key event in the observed improvement in exercise capacity may involve the increase in mitochondrial ROS. In addition, given the link between mitochondrial ROS and mitochondrial biogenesis, consumption of beetroot juice while training may induce mitochondrial biogenesis and indirectly improve ADP sensitivity. EPA/DHA supplementation similarly increases mitochondrial ROS emission rates, and because PUFAs are potent ligand activators of PPARs, incorporating PUFAs into a training program may augment chronic adaptations. This is particularly interesting, as EPA/DHA supplementation directly improves mitochondrial ADP sensitivity. Clearly, compelling evidence for a nutritional intervention that improves mitochondrial bioenergetics beyond the typical exercise-mediated responses does not exist. The recent advancement in our understanding of the regulation of mitochondrial ADP transport has elucidated gaps in our working models that need to be addressed. However, the awareness of these knowledge gaps creates the possibility for unique experimental approaches to be designed with the aim to improve exercise performance in the future.


Prominent etiological conceptions of psychosis implicate abnormal cortico-striatal circuits. Dysfunction in these critical systems, responsible for filtering information and modulating higher-order function, may account for heterogeneous presentations of symptoms and characteristics of psychosis. Collectively, a body of work from our group and from other teams indicates that evaluating select motor behaviors and abnormalities, which directly reflect function of these circuits, may be a useful method for understanding and predicting the neural underpinnings of psychosis. In the context of the psychosis risk period, partitioning clinical high-risk (CHR) youth based on objective behavior may help guide early detection and intervention efforts, and provide a novel perspective on different etiological pathways or patient subtypes.Using an unsupervised machine learning approach, 69 CHR young adults were included in a K-means cluster analysis based on their performance on instrumental measures of psychomotor slowing, dyskinesia, and neurological soft signs (NSS)—distinct motor domains affected across the psychosis spectrum. We also recruited a group of 70 matched healthy controls (HC) for comparison. All participants were also assessed with a resting-state functional connectivity analysis (rcfMRI). The resulting CHR group clusters and HCs were then compared on positive and negative symptoms, multiple cognitive domains, and cortical-striatal seed based resting state analysis.Results of a 3-cluster solution suggest that there are subtypes of CHR individuals who show psychomotor slowing, average motor performance, and impairment on measures of dyskinesia as well as NSS domains for motor coordination, sequencing and sensory integration. The cluster of individuals showing dyskinesia and abnormal NSS also have more severe negative symptoms and impairment on a number of cognitive domains. Furthermore, the clusters of CHR individuals who show psychomotor slowing and the cluster showing dyskinesia and abnormal NSS have different cortical-striatal connectivity compared to UHR who show average motor behavior and healthy controls.These results provide evidence for etiological theories highlighting altered cortico-striatal networks and the importance of examining motor behavior prior to the onset of psychosis. Taken together, this approach may reflect a novel strategy for promoting tailored risk assessment as well as future research developing individualized medicine.


There are great concerns about the impacts of soil biodiversity loss on ecosystem functions and services such as nutrient cycling, food production, and carbon storage. A diverse community of soil organisms that together comprise a complex food web mediates such ecosystem functions and services. Recent advances have shed light on the key drivers of soil food web structure, but a conceptual integration is lacking. Here, we explore how human-induced changes in plant community composition influence soil food webs. We present a framework describing the mechanistic underpinnings of how shifts in plant litter and root traits and microclimatic variables impact on the diversity, structure, and function of the soil food web. We then illustrate our framework by discussing how shifts in plant communities resulting from land-use change, climatic change, and species invasions affect soil food web structure and functioning. We argue that unravelling the mechanistic links between plant community trait composition and soil food webs is essential to understanding the cascading effects of anthropogenic shifts in plant communities on ecosystem functions and services. As increasingly evidenced by empirical studies, soil food webs play a key role in the functioning of terrestrial ecosystems7. Soil food webs affect carbon (C) cycling (with consequences for C storage and hence mitigation of elevated atmospheric carbon dioxide concentrations) and nutrient cycling. On the one hand, soil food webs play an important role in controlling the supply of nitrogen (N) to plants by mineralizing organic N. However, N mineralized through the soil food web does not necessarily result in nutrients freely available for plants8. Soil food webs can promote retention of N in the soil system either directly through sequestration in their living or dead biomass or indirectly through changes to soil chemistry or structure, thereby preventing it from getting lost through leaching and denitrification. It has been shown how shifts in the composition, network structure, and connectivity of soil food webs can alter the rates of these important ecosystem processes10. The soil food web further plays an important role in disease suppression and plant protection against root pathogens12. Finally, the soil food web is critical to ecosystem resistance and resilience against environmental disturbances and climate change. For example, studies have shown that fungal-based soil food webs associated with extensively managed grasslands  were more resistant to experimental drought than bacterial-based food webs associated with intensively managed crop production13. Collectively, these recent advances indicate that changes in soil food web composition and connectivity have important consequences for ecosystem functioning14.The soil food web consists of a large diversity of organisms differing in size and function. This includes root-associated biota such as pathogens or mutualists, saprotrophs involved in breaking down dead organic matter, and a variety of invertebrate consumers and predators at higher trophic levels15, soil food webs are often simplistically described in terms of distinct trophic levels. Trophic levels are composed of organisms that occupy the same level in a food chain. In the soil food web, this would be primary consumers , secondary consumers , and higher-level consumers or predators  . These inputs form the basal resource pool for the soil food web18  . Each of web18 . Althoug24. This implies that anthropogenic shifts in plant community composition could have major impacts on soil web structure, as has been shown for urban green spaces, for example25. Here, we follow a simple framework describing three mechanistic pathways of how shifts in plant community composition drive soil food webs , and bacteria are more specialized to break down simple, labile organic compounds 33. However, this traditional view has recently been challenged, and evidence has emerged that fungi may use organic compounds that are more labile than previously expected34. Second, there has been increasing interest in exploring how live plant roots affect soil food webs 42. Although each of these three pathways has been studied for individual plant species, these plant-mediated mechanisms are less well understood for plant communities44. We argue that together these three pathways largely explain the responses of soil food web structure and functioning to changes in plant community productivity, diversity, and composition. Finally, we propose that using a trait-based approach to help understand the mechanisms behind these drivers could provide further guidance.In recent years, it has been shown that individual plant species differ in their effects on the soil communities they supportod webs . First, od webs . The cheod webs . Root ch46 provides new avenues for understanding how shifts in plant communities can influence soil food webs. In plant community ecology, aboveground plant functional traits such as specific leaf area, leaf nutrient content, and leaf dry matter content have been widely used in place of taxonomic diversity measures to explain ecosystem processes and function50. Recently, recognition of the importance of root traits has gained increasing attention53, and greater focus has been put on linking root traits such as root dry matter content, nutrient content, and root architecture to soil processes. For example, changes to root traits associated with exudation could shift C allocation in the rhizosphere and have implications for the soil organisms involved in decomposition and C cycling54. Furthermore, biotic root traits that aid in nutrient acquisition, such as arbuscular versus ectomycorrhizal colonization, impact on the nutritional quality and total quantity of shoot and root litter that enters the soil food web55. To further elucidate the functional linkages between plant communities and the soil food web, recent work has developed and applied a trait-based approach to soil microbes57 and soil fauna60. It has been proposed that investigating the relationship between ‘effect traits’  and ‘response traits’  across plant and soil communities could enable better predictions of ecosystem function61.The increased use of functional trait-based approaches in plant community ecology62. However, in affecting soil food web complexity and diversity, trait variability  is probably at least as important as community-weighted mean trait values. Therefore, to better understand how plant community trait composition affects the soil food web, we use the concept of trait packing and diversity. High trait packing in a plant community means a high diversity or variation in litter and root traits, leading to more complex, diverse, and stable soil food web structure and function  strongly control litter decomposition rates, which are determined in part by the substrate quality  available to the microbes63. Therefore, inputs of chemically and structurally highly diverse litter, due to high trait packing within the plant community, could foster the development of a trait-packed microbial community and a more diverse soil food web that could help maintain the delivery of multiple ecosystem functions related to nutrient and C cycling and plant productivity. Furthermore, changes to plant community trait composition that affect indirect interactions initiated by belowground predators  could change the productivity and defense strategy traits of soil organisms on lower trophic levels in ways that affect soil food web connectivity64, which is important because more tightly connected soil food webs are known to promote nutrient retention9.In trait-based ecology, there is often a strong focus on community-weighted mean traits unction . If a stBelow, we explore this framework of trait packing and diversity and, more generally, shifts in litter and root trait values. We focus on areas of research that illustrate how anthropogenic disturbances can affect plant community trait values, leading to shifts in soil food webs. Specifically, we focus on (1) land-use change and secondary succession, (2) climate change and species loss, and (3) plant invasions and range shifts because they are all topical areas of research that are heavily driven by anthropogenic disturbance. We show that under these different scenarios, changes to plant community traits can generate major shifts in the soil food web, leading to positive or negative effects on how soil ecosystems function.67. For example, root exudate chemical traits have been shown to slow down soil microbial processes, and cereal crops cause slower phosphorus mineralization compared with legumes and this is potentially because of differences in exudate chemical composition68. Crop species and varieties may also strongly vary in root nutrient acquisition strategy, root chemical composition, and root architectural traits 69. Although studies so far have focused mostly on coarse traits, such as C:N ratio and specific root length, such trait differences can impact upon microbial communities68 and higher trophic levels of the soil food web70. Crop species also vary in their attractiveness to soil pests and pathogens, such as host-specific nematodes, because of their distinct root chemistry traits71. Given these inter-specific differences in crop traits, moving from monoculture cropping to mixed cropping would add traits to the system, thereby increasing trait packing and leading to positive effects on soil food web diversity and functioning  increased fungi and bacteria and those nematode groups that fed upon them. Interestingly, these two litters were also most effective in suppression of plant-parasitic nematodes. Taken together, agricultural practices that promote plant trait packing and diversity will likely generate higher connectivity in the soil food web, which will lead to increased resistance and resilience to anthropogenic disturbances in cropping systems80.Plant trait shifts associated with agricultural practices strongly drive soil ecosystem functions. Crop residues  and crops with contrasting root traits can have major impacts on soil food web functioningtioning . Mixed cructure , Leslie81. Depending on the management and grazing intensity after abandonment, plant communities typically develop toward species-rich grassland or forest83. Successional changes in plant community composition result in important shifts in litter and root traits, and increases in plant diversity result in more trait packing 9. Furthermore, increased dominance of slow-growing, later-successional plant species, which more strongly depend on associations with mycorrhizal fungi than early species, could shift the fungal community from fast-growing and pathogenic species to slower-growing, beneficial species87. This could affect the rate of C flow through the soil food web8.A relatively large body of research has focused on how shifts in plant community composition after conversion of agricultural land to (semi)natural systems affect soil food webs and their functioningpacking . For exa89 and how climate-induced changes in plant community composition can cause major shifts in root and litter trait spectra 92. Warming affects plant physiology and phenology and ultimately can result in altered plant dominance and shifts in range distributions of plant species (see ‘Plant invasions and range shifts’ section below). However, changes in precipitation regime, such as longer and more intense droughts, could be expected to most dramatically affect plant community trait spectra, at least in short to moderate timescales93. For example, along an aridity gradient, root tissue density and specific root length may shift to more conservative values with increasing aridity, and the diversity of acquisition trait values may increase, facilitating a wider array of resource acquisition strategies under conditions of water stress94. In old-field communities, experimental drought shifted plant cover dominance from a woody, N-fixing sub-shrub to a C3 bunchgrass and had far-reaching consequences for soil food web structure. Moreover, microbial enzyme activities and nematode feeding group composition indicated higher soil food web complexity but slower rates of nutrient cycling in soils beneath the sub-shrub compared with the grass, most likely because of high concentrations of polyphenolics and lignin in organic residues from the sub-shrub43. In general, drought- and other climate-induced changes in plant trait spectra could greatly modify or counteract direct climate impacts on the soil food web96.Climatic changes driven in part by anthropogenic activities can strongly influence plant community composition. An increasing number of studies have shown how plant traits are related to climatic adaptation98. In turn, loss of species from the plant community will lower litter and root trait diversity and packing  litter inputs caused by deciduous shrub removal may have detrimentally impacted on the microbial and nematode communities because these two groups are highly dependent on such inputs as both direct and indirect food sources101. For randomly assembled plant communities, the effects of lower plant species and functional group richness on soil biota are mostly negative but weaker for soil biota occupying higher levels in the soil food web102. For nematodes, these effects of plant species and functional group diversity have been linked to changes in litter quality 103, but potential effects mediated through shifts in root nutrient acquisition, architectural, and chemical traits remain to be tested.Climate change not only may alter plant species composition but also can result in species losspacking . Althoug104, and debate concerning the consequences of plant invasions for ecosystem functioning continues105. Invasive plants generally have higher values for traits associated with growth rate, tissue nutrient content, and competitive ability  compared with natives107. Therefore, invasive plants can introduce novel traits into the existent plant community that could affect the soil food web. For example, allelopathic chemicals produced by the invasive treeAilanthus altissima can hinder soil microbial activity and thereby nutrient mineralization, while high litter production can increase earthworm abundance, potentially offsetting this negative effect108. Furthermore, invasion by the forbSolidago gigantea increased fungal biomass and had disproportionate cascade effects on certain fungal-feeding nematode taxa that were probably due to disparate feeding abilities among the nematodes109. In contrast, invasion by a grass resulted in less allocation of C to higher trophic levels of soil nematodes compared with a native grass species110. Taken collectively, traits associated with contrasting functional groups of invasive plants  could lead to reduced trait packing  but that native congeners tended to use top-down control through changes to the microbial community. This finding corroborates the novel weapons hypothesis113 and showcases the role that range-expanding plant traits can play in changing the soil food web. Range-expanding plants might also escape their enemies in the soil food web 114, and this, combined with favorable climatic conditions, could lead to successful establishment115. Furthermore, range-expanding plants might fail to find suitable decomposer organisms for their litter 116 because of mismatches in litter chemistry traits and soil organisms specialized in breaking down this litter. Finally, range-expanding plants may not establish mycorrhizal associations  has the potential to introduce new species with new traits into the community and have repercussions for the soil food web. The widening of niche envelopes  that leads to range expansionood web .95, which link more strongly to ecosystem processes and function. (5) Soil food webs often respond slowly and show remarkable resistance to environmental changes. Hence, the effects of shifts in plant community composition may become apparent only at larger timescales. This requires long-term studies and awareness of long-lasting soil legacies. (6) Many studies exploring the relationships between plant communities and soil food webs use observational approaches122. Although observations allow coverage of large spatial and temporal scales , these studies do not disentangle the mechanisms. We advocate for additional empirical studies explicitly manipulating litter and root trait spectra and diversity. Only through continued research will we be able to better understand how anthropogenically driven shifts in plant community composition will affect complex soil food web interactions and the ecosystem services that they provide.Anthropogenic shifts in plant community composition and diversity are likely to have major implications for the composition and function of soil food webs as well as the services they provide. Much recent progress has been made, and our trait-based conceptual model provides guidance for future studies to elucidate the underlying mechanisms of how shifts in plant community traits could lead to cascade effects belowground. The following areas in particular warrant future attention: (1) We know relatively well how functional differences among individual plant species affect soil food webs, but much less is known about the effects of complex plant communities where multiple species coexist and interact. Here, it would be of interest to separate the effects of community-weighted mean values from the diversity of traits represented in the community. (2) The majority of studies inferring changes in soil food web functioning focus exclusively on microbes or use soil nematode communities as indicators of soil food web structure. These approaches have yielded important insights, but to fully understand the role of soil food webs in how shifts in plant community composition affect soil ecosystem functioning, we need to look at whole soil food webs, including organisms at higher trophic levels. (3) Knowledge about the quality and quantity of substrate required by soil microbes and fauna is increasing, and ideas about interactions between different trophic levels are being revised. However, further studies are needed to understand the complex transferring of energy between the different organisms in the soil food web. Therefore, it is integral to investigate how energy transfer within the soil food web is driving key ecosystem processes and to focus particularly on the traits involved. (4) Plant trait-based research has seen a steep increase in activity in recent years, including new research explicitly focusing on root traits. However, the traits most commonly used in these studies are not always the most meaningful in terms of their importance for the functioning of soil communities. Instead of focusing on coarse traits, such as C:N ratios of shoots and roots, it would be more ecologically informative to look at the molecular construction of plant-derived C and N compounds, such as phenolics and their derivatives, which are known drivers of soil microbial activity and resource use efficiency


Heavy metals are naturally occurring in the earth‘s crust but anthropogenic and industrial activities have led to drastic environmental pollutions in distinct areas. Plants are able to colonize such sites due to several mechanisms of heavy metal tolerance. Understanding of these pathways enables different fruitful approaches like phytoremediation and biofortification.Therefore, this review addresses mechanisms of heavy metal tolerance and toxicity in plants possessing a sophisticated network for maintenance of metal homeostasis. Key elements of this are chelation and sequestration which result either in removal of toxic metal from sensitive sites or conduct essential metal to their specific cellular destination. This implies shared pathways which can result in toxic symptoms especially in an excess of metal. These overlaps go on with signal transduction pathways induced by heavy metals which include common elements of other signal cascades. Nevertheless, there are specific reactions some of them will be discussed with special focus on the cellular level.The online version of this article (doi:10.1186/1999-3110-55-35) contains supplementary material, which is available to authorized users. Basal heavy metal tolerance is presumably found in all plant species. Thereby, they run a complex system consisting of uptake/efflux, transport/sequestration and chelation Figure . These kThis review will provide an overview about these tolerance mechanisms with focussing on the cellular level and signalling pathways induced by metals. The discussion of some examples will underline the multitude and complexity of signals and responses. It will trigger further work on responses towards heavy metals in plants especially in the way of low, environmentally relevant metal concentrations.The majority of plants can be classified as non-accumulator plants. Nevertheless, all have to cope with heavy metals for nutrition purposes and growing in metalliferous soils, respectively. Hence, they have to possess finely tuned mechanisms for living with even toxic heavy metals Hall 2006. Thea and b  transporter family  across biological membranes. Thereby, HMA2 and HMA4 drive metal efflux out of the cell in A. thaliana  protein family) is highly overexpressed in the aforementioned hyperaccumulating plants compared to their closed related non-accumulators  and organic acids like citrate  which will be discussed in the next chapter. Functionalities of GSH (thiol and carboxylic groups) make it suitable for complex formation with heavy metals  are sulfur containing proteins inherently being highly flexible in their structure. This flexibility allows different coordination geometries for binding of different metals. Nevertheless, each MT exhibits preferences for a special metal ion due to coordination residues other than cysteine and differences in folding and stability in dependence on the bound metal ,Redox-active metals can directly generate ROS via Fenton like reactions and the Haber-Weiss cycle , there was no significant change of GSH whereas the amount of GSSG increased upon exposure of moderate uranium concentrations (≤ 10 μM) in cell suspensions of canola (Brassica napus)  is impaired by heavy metal accumulation. This can be one reason for conflicting results regarding the GSH content upon metal exposure. Furthermore, the different points of sampling time should be attended. Copper or cadmium amendment in This reductive activity eliminates ROS generated either directly or indirectly by metals. The detoxification of ROS is GSH dependent. Such GSH consuming processes and an excess of ROS induce GSH synthesis   exhibited decreased levels of SOD, GR and CAT towards cadmium contact whereas Avena strigosa (Cd tolerant accumulator) showed increased activities towards the same Cd concentrations , Nramps , the cation diffusion facilitator (CDF) family, the ZIP  family, ABC transporters (ATP-binding cassette), cation antiporters and other putative transition metal transporters. A more detailed overview is provided by reviews written by Guerinot , Hall anAs it was mentioned before, metal sequestration in distinct cellular compartments plays a pivotal role in metal tolerance and supplement with essential metals. For this purpose cells provide a coordinated set of transport systems in each cellular membrane. An important metal sink in metal tolerant plants is the vacuole. A prominent example is the transport of metal-phytochelatin complexes into the vacuole by an unknown ABC transporter or by cation/proton exchanger (CAX) . Proton fluxes can establish so-called “pH-signatures” in the cytoplasm . FER encodes bHLH which controls the expression of genes with key functions in iron acquisition such as the iron-regulated transporter (IRT) and the ferric oxidase reductase (FRO) orthologs in tomato  during iron starvation in plants. A detailed review concerning this was published recently  gene expression was detected As it was discussed in a previous chapter heavy metal exposure can cause imbalances in the cellular redox homeostasis either by being itself redox-active or by replacing other metal ions (sometimes even redox-active ions) in biomolecules. A recently discussed issue in animal cells is the zinc coordination with sulphur donors of cysteine resulting in a redox switch with reversible oxidoreduction of the sulfur donor linked to zinc association and dissociation Maret . This phArabidopsis. These cascades end up by phosphorylation of transcription factors  interacting with gene promoters and thus inducing gene expressions. It should be noted that there are differences between metal-sensitive and metal-tolerant plants: ROS-MAPK signals cause several cellular damages like interruption of hormonal signalling, programmed cell death in metal-sensitive plants. In contrast, metal-tolerant plants are able to accumulate repair proteins such as chitinases and heat shock proteins (HSP). A more detailed overview provides a recently published review by Lin and Aarts  which can activate mitogen-activated protein kinase (MAPK) cascades in a plant species and metal dependent manner (Gupta and Luan nd Aarts . HoweverOther important elements are the soluble redox couples like glutathione or NAD(H), NADP(H) which provide a buffering system in the cytoplasm Noctor . Local p2005aAlmost all plants exhibit a basal metal tolerance when facing heavy metals. Some species are even capable of hyperaccumulation running different tolerance reactions compared with nonaccumulating plants. However, general tolerance mechanisms are based on exclusion, chelation and sequestration processes Figure .Attention should be paid on signal transduction pathways induced by metals because they use common signal elements which can be also elicited by other environmental stresses. The critical evaluation of triggered signals and their responses is mandatory for understanding metal homeostasis. The challenge in the future will be the investigation of multiple stress factors as it occurs under real environmental conditions.Predictions about health risk which is caused by metal accumulation in crop plants failing visible symptoms of phytotoxicity.Generation of genetically engineered plants having an enhanced accumulation of metals valuable for nutritional purposes (biofortification).Clean up of metal contaminated soils (phytoremediation) and mining of rare metals which are accumulated in plant tissues (phytomining).Special focus should put on low, environmentally relevant heavy metal concentrations. Therefore, the further development of sensitive detection methods and the combination of different approaches are necessary. These tools enable for instance new insights in the metalloproteome and its interactions . Further knowledge about metal tolerance in plants is mandatory for several purposes:


The varicella zoster virus affects the central or peripheral nervous systems upon reactivation, especially when cell-mediated immunity is impaired. Among varicella zoster virus-related neurological syndromes, meningoradiculitis is an ill-defined condition for which clear management guidelines are still lacking. Zoster paresis is usually considered to be a varicella zoster virus-peripheral nervous system complication and treated with oral antiviral therapy. Yet in the literature, the few reported cases of herpes zoster with mild cerebral spinal fluid inflammation were all considered meningoradiculitis and treated using intravenous antiviral drugs, despite absence of systemic signs of meningitis. Nevertheless, these two clinical pictures are very similar.We report the case of an alcohol-dependent elderly Caucasian man presenting with left lower limb zoster paresis and mild cerebral spinal fluid inflammation, with favorable outcome upon IV antiviral treatment. We discuss interpretation of liquor inflammation in the absence of clinical meningitis and implications for the antiviral treatment route.From this case report we suggest that varicella zoster virus-associated meningoradiculitis should necessarily include meningitis symptoms with the peripheral neurological deficits and cerebral spinal fluid inflammation, requiring intravenous antiviral treatment. In the absence of (cell-mediated) immunosuppression, isolated zoster paresis does not necessitate spinal tap or intravenous antiviral therapy. Varicella zoster virus (VZV) is an exclusively human virus primarily causing chickenpox . After aHere we report the case of an alcohol-dependent older man with zoster paresis in the context of a VZV-associated meningoradiculitis. This clinical entity is not precisely defined in the literature and clear management guidelines about oral versus IV antiviral therapy are scant . ClearlyA 74-year-old Caucasian man was admitted to the Emergency Room, addressed by his general practitioner for a 3-day history of progressive lower left limb weakness. He complained of a non-traumatic lumbar pain since 10 days. Shortly after, a skin rash appeared on his lower back and extended to the left lower limb. He did not have fever or other new neurological complaints (in particular there was no urine or bowel retention or incontinence). His medical history showed arterial hypertension ; alcohol dependence (with macrocytosis and lower limb polyneuropathy) and benign prostate hypertrophy managed using tamsulosin. Otherwise, he took Aspirin Cardio® and tramadol.In addition to lower limb peripheral length-dependent abnormalities , the initial neurological assessment revealed significant weakness in hip flexion (M3) and foot dorsiflexion (M2), absence of the left patellar reflex and disturbed position sense on the lower left limb. The Leri sign was positive on the left side. On general examination, clusters of small erythematous vesicular lesions were present on the anterior and internal sides of his left thigh and upper leg. A few similar lesions were also seen on the left part of the lower back. In summary, the clinical picture of the patient showed left L3–L4 sensory-motor deficit associated with radicular zoster. A lumbar computerized tomography (CT)-scan excluded local compression (there was only degenerative lumbar discopathy) and the skin smear was positive for VZV DNA but negative for Herpes simplex virus 1 and 2. The lumbar puncture  and showed mainly motor improvement . A few days after admission he developed postherpetic neuralgia that improved with pregabaline and subsequent amitriptyline and a fentanyl patch. Unfortunately analgesic overtreatment led to acute encephalopathy  that was reversed with dose adjustment. The patient was then transferred to a stationary neurorehabilitation center before returning home.The patient described here had zoster paresis associated with mild inflammation and VZV activity in the CSF; leading to treatment mainly by IV acyclovir. The very few reported cases of VZV meningoradiculitis in the literature can be divided into two groups. The first corresponds to radiculitis without meningitis symptoms  –16. The peripheral nervous system complication [If meningoradiculitis comprises clinical meningitis with peripheral nerve root involvement, then it should be treated, as with any other VZV-CNS complication, using IV antiviral drugs after spinal tap and other necessary investigations , 6, 12. lication . Such palication . The VZVlication , 15 to tlication , 16? Morlication . Along tNone of the frequently reported immunosuppressive states  triggering VZV reactivation  were fouIn conclusion, the patient had VZV cutaneous infection with radiculitis coincident with mild CSF inflammation. Reactivation of VZV was most probably precipitated by age- and alcohol-induced cell-mediated immunosuppression. He was diagnosed with meningoradiculitis and treated with IV acyclovir, despite the absence of clinical meningitis. In available published cases, we did not find a consensual definition or management scheme for meningoradiculitis. The presence of CNS symptoms or abnormal CSF findings did not allow discrimination of severe from benign cases and these patients were generally IV treated. However, well-designed clinical trials are needed to review severity criteria for patients with VZV-associated (meningo)-radiculitis, to study the efficiency of oral versus IV antiviral treatment and establish clear guidelines for management. Mild elevation of inflammatory markers in the CSF is not specific or sensitive enough to establish a diagnosis of meningitis without evocative clinical symptoms. Therefore we suggest that until otherwise demonstrated, the term “meningoradiculitis” should be used for and IV antiviral drugs prescribed to patients with clinical meningitis associated with neurological peripheral deficit in the context of VZV infection. Patients with isolated VZV radiculitis should be exempt from CSF investigations and be given oral antiviral treatment, unless they are subject to any condition or pathology decreasing immunity, in particular CMI, in which case CSF workup and IV antiviral therapy may be necessary.


Immune therapy has shifted the paradigm of modern cancer treatment: Instead of targeting the tumor itself, it focuses on enhancing tumor recognition and destruction. Harnessing the immune system by using monoclonal antibodies, adoptive T cell transfer or checkpoint inhibitor (CPI) therapy increased progression free survival with less side effects compared to conventional therapy . CheckpoThree of the major questions that arise for caregivers and scientists are: 1) Should pre-therapeutic screening be implemented to assess risk for fatal cardiovascular events and adjust mono- vs. combination CPI therapy? Certain features of the immune system may predispose to immune related adverse events, such as specific HLA phenotypes or composition of their T cell subtypes. 2) Should patients undergoing CPI therapy receive regular surveillance tests for early signs of cardiovascular adverse events? Which non-invasive technologies should be used? 3) Would local therapy be beneficial if cardiotoxicity develops? During CPI therapy, troponin elevation, changes in ECG, arrhythmias, and inflammation or ischemia on cardiac MRI have been observed -clinical signs that will likely guide therapy in the future. In some reported cases that tested for the most common viruses known to cause myocarditis , viral serologies from peripheral blood were negative in all patients . For genIn the event of increasing troponin levels, Wang and colleagues recommend to hold immunotherapy until troponin levels and ECG abnormalities normalize Figure  6]. In . In 6]. While these conclusions and recommendations reflect our interpretation of findings from case reports and case series, no guidelines for the treatment of immune related myocarditis have been published as of today due to limited availability of clinical data.Assuming an immune antigen reaction similar to an allograft rejection or a rheumatic disease, similar pathomechanisms have to be explored to widen treatment options for this rare but often fatal complication. In one reported case of CPI related and steroid resistant myocarditis, treatment with equine anti-thymocyte globulin (ATGAM) led to regression of the disease . Similar


Streptococcus pyogenes infection at 5, 12, and 18 hours post infection and correlated this to parameters of infection. The platelet population in ex-vivo blood samples showed no increased integrin activation or surface presentation of CD62P, however platelet-neutrophil complex formation and plasma levels of CD62P were increased during bacterial dissemination and the progression of sepsis, indicating that platelet activation had occurred in vivo. Platelet-neutrophil complex formation was the most discriminatory marker of platelet activation. Platelet-neutrophil complexes were increased above baseline levels during early sepsis but decreased to significantly lower levels than baseline during late sepsis. The removal of these complexes from the circulation coincided with a significant increase in organ damage and the accumulation of platelets in the liver sinusoids, suggesting that platelet activation in the circulation precedes accumulation of platelets in damaged organs. The results demonstrate that monitoring platelet activation using complementary methods may provide prognostic information during the pathogenesis of invasive S. pyogenes infection.Platelets contribute to inflammation however, the role of platelet activation during the pathophysiological response to invasive bacterial infection and sepsis is not clear. Herein, we have investigated platelet activation in a mouse model of invasive  W. Win vitobserved . The aimS. pyogenes AP1 infection , . PN. PN25]. Among the few studies of PNC formation in sepsis patients, PNC formation has been detected although other parameters of platelet activation were not increased . PNC levIntravital microscopy of liver sinusoids directly treated with LPS has demonstrated platelet dependent stimulation of neutrophil extracellular trap formation  and locaS1 Fig(PDF)Click here for additional data file.


Stem cells are undifferentiated and pluripotent cells that can differentiate into specialized cells with a more specific function. Stem cell therapies become preferred methods for the treatment of multiple diseases. Oral and maxillofacial defect is one kind of the diseases that could be most possibly cured by stem cell therapies. Here we discussed oral diseases, oral adult stem cells, iPS cells, and the progresses/challenges/perspectives of application of stem cells for oral disease treatment. Stem cells are undifferentiated and pluripotent cells that can produce more new stem cells  and differentiate into specialized cells with a more specific function such as skin cells, bone cells, and blood cells , PDLSCs (N = 4), OESCs (N = 12), DPSCs (N = 5), adipose derived stem cells , SHED (N = 1), nasal stem cells (N = 1), and HSCs (N = 1). As outlined in Table N = 3, with autologous SHED or DPSCs), dental diseases correlated with tooth extraction , graft vs. host diseases with oral complications , facial diseases , and Xerostomia/Sjögren's Syndrome . Among them, three trials have reported results. The clinical trials with reported results will be discussed below.Stem cell therapy has become a promising alternative in dentistry and maxillofacial rehabilitation since it could provide better physiological structure and functions . Bio-Oss scaffolds were transplanted together with PDLS cell sheets for the chronic periodontitis therapy in a completed clinical trial (NCT01082822). Commercially available collagen scaffolds (collagen fleece) are used to hold autologous BM-MSCs enriched with autologous fibrin glue in clean room facilities for regeneration of periodontal tissues in periodontal infrabony defects in an ongoing clinical trial (NCT02449005). For adult periodontitis patients, the surgical implantation of autologous MSCs with a 3D woven-fabric composite scaffold and platelet-rich plasma showed no clinical safety problems but decreasing trend of mobility and significantly improved changes in clinical attachment level, pocket depth, and linear bone growth  uses a bioengineered product composed of mesenchymal stem cells and a patented cross-linked matrix of autologous plasma for bone maxillary cysts refilling. Platelet rich fibrin (PRF) and bone allograft  are used to load the buccal fat pad derived stem cells for the treatment of alveolar bone loss in maxillary sinus augmentation (NCT02745379) and in posterior mandible augmentation (NCT02745366). Tissue engineered construction based on a synthetic tricalcium phosphate and autologous MSCs obtained from oral mucosa is used for maxilla alveolar process reconstruction in patients with verified diagnosis partially edentulous maxilla and alveolar bone atrophy (NCT02209311). Similarly, MSCs obtained from bone marrow are mixed with bicalcium phosphate to augment the alveolar ridge (NCT02751125).Stem cells are applied without scaffolds in most clinical trials . Intravenously infused allogeneic MSCs suppressed autoimmunity by directing T cells toward Treg and Th2, while suppressing Th17 and Tfh responses, and restored salivary gland secretory function in both mouse models and Sjögren's Syndrome patients who have been resistant to multiple standard treatments (NCT00953485). The study suggests that allogeneic MSC treatment may provide an effective therapy for Sjögren's Syndrome patients . Allogeneic human DPSCs are injected in local infected periodontal tissue for the treatment of chronic periodontal disease (NCT02523651) and a clinical trial UMIN000002050 aims to establish human dental pulp stem cell bank for dental diseases that extraction of tooth is necessary for treatment. A clinical trial is ongoing to clarify the efficiency of autologous SHED to regenerate pulp and periodontal tissue in the patients with immature permanent teeth and pulp necrosis (NCT01814436).Human PDLSCs, as well as DPSCs, SHEDs, and bone marrow stem cells have been studied to regenerate periodontal tissues  were related to the aspect ratio-dependent cellular internalization, suggesting the promising use of CeNMs to protect stem cells from the ROS-insult environments and ultimately improve the stem cell potential for tissue engineering and regenerative medicine  into a confined space, where biological function and viability of biomaterials are preserved within the printed construct (Murphy and Atala, in vitro without stemness loss or function change; try to speed up self-renewal of the in situ stem cells and precisely control their differentiation. For allogeneic stem cells, the in vitro expand technology is also very important and the technology to lower down the immune rejection is urgently needed. Besides the immune suppression drugs, regulatory immune cells such as Treg and Breg (Sun et al., In summary, there are endogenous/autologous and exogenous/allogeneic adult stem cells and iPS cells for oral disease treatment. As compared in Table BY, YQ, and NZ summarized the literature, wrote the manuscript, and prepared figures. BC, HO, and JD provided critical comments and wrote part of the manuscript. JS supervised all the works and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer VD, VT and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Melatonin administration to high cholesterol-treated and high fat-treated rats has been shown to suppress body weight and visceral adiposity. In addition, in various animal models related to obesity, metabolic syndrome, and diabetes, melatonin has beneficial efficacy in ameliorating various metabolic symptoms, including attenuating weight gain, lowering blood pressure (BP), and improving insulin resistance. This systematic review aims to investigate whether melatonin or melatonin agonists significantly attenuate metabolic side effects among psychiatric populations treated with atypical antipsychotics.Four randomized controlled trials were identified through a comprehensive literature search using MEDLINE, EMBASE, and the Cochrane Library on 22 October 2015. These four trials (including three melatonin studies and one ramelteon study) included 138 patients, of whom 71 were treated with melatonin or ramelteon and 67 were treated with a placebo. Because of high heterogeneity, we did not carry out a meta analysis.Melatonin was beneficial in lowering blood pressure among bipolar disorder patients; this blood pressure-lowering effect was not prominent among schizophrenic patients. Melatonin appeared to improve lipid profiles and body composition and attenuated weight gain among both schizophrenic and bipolar disorder patients. Ramelteon showed a significant efficacy in lowering total cholesterol level.Despite the few studies included, this systematic review provided promising evidence of the potential benefits of melatonin and its agonists in attenuating one or more components of metabolic syndrome among psychiatric patients using atypical antipsychotics.


Sarcopenia, or loss of skeletal muscle mass and quality, has been studied as part of aging and adverse health outcomes in elderly patients but has only recently been evaluated as a separate condition in cancer patients and important indicator of adverse outcomes. Currently, its definition and method of assessment are still being debated. Sarcopenia within an increasingly obese population has led to a subgroup with sarcopenic obesity, at even higher risk of adverse outcomes. Yet, sarcopenia often goes undiagnosed in these patients, hidden beneath higher body mass index. Identifying sarcopenic and sarcopenic obese subpopulations would allow for more effective treatment plans and potential avoidance of suboptimal outcomes, as well as the chance to intervene and combat these modifiable risk factors. This review will examine available literature on the definition and methods of evaluating sarcopenia and sarcopenic obesity, summarize the effectiveness of sarcopenia and sarcopenic obesity as predictors of outcomes after gastrointestinal cancer surgery, including colorectal cancer resection, liver resection, and pancreatic resection, and outline strategies to minimize the impact of sarcopenia. It is clear that untreated sarcopenia and sarcopenic obesity can be associated with suboptimal post-operative outcomes, especially infections and disease-free or overall survival. Sarcopenia, the loss of skeletal muscle mass and quality that occurs as part of natural aging, can be exacerbated by systemic illnesses. Within the last 10 years, this geriatric syndrome has received increasing attention as a possible predictor of adverse outcomes after surgery ) are at higher risk of adverse outcomes, including disability  oncologic surgery outcomes, including colorectal cancer resection, liver resection, and pancreatic resection, and promising methods by which these risk factors can be modified.Early definitions of sarcopenia rely upon measures of muscle mass and neglect a functional specification. Evidence suggests the relationship between low muscle mass and adverse outcomes is not linear or direct; rather, they are linked when low muscle mass is associated with muscle weakness  or time required to complete five chair stands were also useful standards. Muscle strength was assessed through unadjusted grip strength and muscle mass via body mass-adjusted appendicular lean mass  that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment,” which encompasses varying levels of body fat and muscle loss , computerized tomography (CT)-derived total body fat (TBF), or dual x-ray energy absorptiometry (DXA)/bioelectric impedance analysis (BIA)-derived body fat  is an overlooked contributor  index (the sum of lean soft-tissue masses for the arms and legs adjusted by height)  Fig.  (Baumgarht) Fig.  and thosht) Fig. , total pht) Fig. , and psoht) Fig. .Fig. 1CoMuscle mass has traditionally been measured using BIA or DXA  disability than lean sarcopenic, non-sarcopenic obese, or patients with normal body composition  and impaired short-term outcomes after surgery  noted that there is currently no objective, accessible, accurate measure of a patient’s condition before undergoing hepatectomy -sarcopenia and short-term outcomes than with TPA-sarcopenia , a measure of psoas muscle density and fatty infiltration, along with TPA  (Joglekar et al. While sarcopenia assessment can help identify cancer surgery patients at risk of worse outcomes, it is important to note that sarcopenia and SO themselves are modifiable. The most effective interventions to date are physical exercise and adequate nutritional protein intake (Deutz et al. The impact of sarcopenia on post-operative oncologic outcomes and its usefulness as a predictor is still unclear and often conflicting, particularly in the case of hepatectomy for colorectal liver metastases and hepatectomy for hepatocellular carcinoma. However, sarcopenia is promising as a predictor of short-term outcomes following colorectal cancer surgery and long-term outcomes following hepatectomy for hepatocellular carcinoma. SO is promising as a predictor of long-term outcomes following hepatectomy for hepatocellular carcinoma and short-term outcomes following pancreatic resection. The other associations need additional clarification, as studies provided inconsistent results.There remains considerable variation in definition, cutoffs, and assessment methods for sarcopenia and SO, which makes translation to clinical practice complicated. Recent criteria incorporating both grip strength and appendicular skeletal muscle allow more clinically meaningful associations with long-term outcomes and are preferred to definitions excluding a functional component (Studenski et al. Sarcopenia and SO may predict short- and long-term outcomes, and effective identification of patients at risk of poorer outcomes from cancer surgery allows for tailored interventions. As clinicians become increasingly aware of this subtle form of malnutrition, addressing sarcopenia preoperatively can optimize outcomes for at-risk patients.Further research is needed to reach consensus regarding the ideal manner of assessing sarcopenia in order to predict outcomes after various cancer surgeries and across cancers in a broad clinical sense. The prevalence and impact of SO in various cancer surgeries requires further examination. Risk of mortality associated with SO for all types of patients should be further evaluated (Prado et al.


The conventional view that neuroinflammatory lesions contain strictly pro- and anti-inflammatory cytokines is being challenged. Some proinflammatory products e.g. TNF-α are crucial intermediates in axon regeneration, oligodendroglial renewal and remyelination. A more functional system of nomenclature classifies cytokines by their neuro ‘protective’ or ‘suppressive’ properties. Beyond the balance of these ‘environmental’ or ‘extrinsic’ signals, specific ‘intrinsic’ determinants of cytokine signalling appear to influence the outcome of axoglial regeneration. In this commentary, we examine the potential importance of cytokine-induced histone modification on oligodendrocyte differentiation. Neuroinflammation mediates the release of astrocytic leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which potentiates oligodendrocyte differentiation and myelin production. Meanwhile, histone deacetylation strongly suppresses important inhibitors of oligodendrocyte differentiation. Given that LIF and EPO induce histone deacetylases in other systems, future studies should examine whether this mechanism significantly influences the outcome of cytokine-induced remyelination, and whether epigenetic drug targets could potentiate the effects of exogenous cytokine therapy. Amongst an array of important extracellular signals, astrocytes release leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which are neuroprotective cytokines that promote the differentiation of OLs and preserve the integrity of the myelin sheath , or more directly, the DNA itself (DNA methylation). Previous studies have shown that the process of (re)myelination is dependent on a variety of epigenetic remodelling mechanisms including histone modification, DNA methylation and miRNAs  pathway. McCool et al. showed that withdrawal of LIF leads to a global increase in histone acetylation that mimicked the effect of trichostatin A, a histone deacetylase inhibitor myelination. Histone deacetylation is associated with the repression of important inhibitors of oligodendrocyte differentiation and neurotrophic cytokines such as LIF and EPO have demonstrated a potential to induce these HDACs in other systems. Future research should specifically examine the epigenetic processes that occur downstream of LIF and EPO in oligodendrocytes. This could lead to a novel therapeutic approach to demyelinating disease that incorporates epigenetic drug targets e.g. HDACs to bolster the efficacy of exogenous cytokine therapy.


Climate change is driving the thinning and retreat of many glaciers globally. Reductions of ice-melt inputs to mountain rivers are changing their physicochemical characteristics and, in turn, aquatic communities. Glacier-fed rivers can serve as model systems for investigations of climate-change effects on ecosystems because of their strong atmospheric–cryospheric links, high biodiversity of multiple taxonomic groups, and significant conservation interest concerning endemic species. From a synthesis of existing knowledge, we develop a new conceptual understanding of how reducing glacier cover affects organisms spanning multiple trophic groups. Although the response of macroinvertebrates to glacier retreat has been well described, we show that there remains a relative paucity of information for biofilm, microinvertebrate, and vertebrate taxa. Enhanced understanding of whole river food webs will improve the prediction of river-ecosystem responses to deglaciation while offering the potential to identify and protect a wider range of sensitive and threatened species. The sustained dependency of human society on hydrocarbons is predicted to increase global near-surface temperatures, particularly across the second half of the twenty-first century  respond to glacier retreat, predominantly with a Northern Hemisphere focus because this is where most of the relevant research has been undertaken. This knowledge is then integrated within a new conceptual framework that considers simultaneous responses of biota to shrinking glaciers as part of multitrophic river ecosystems. This new multitaxonomic response framework is used subsequently to explore the consequences for how whole-river food webs can be expected to respond to ongoing glacier retreat. Such an approach is required to inform alpine conservation strategies by providing a holistic food-web context for the multiple cold-environment endemic species that are found in glacier-fed rivers around the world  dominating biofilm formation  remains limited in comparison with that of macroinvertebrates  shelter within the riparian vegetation and rocky banks of glacier-fed rivers, across the Pyrenean Region  and the absence of predators, including American mink  mirrors the dependency of the Iberian desman for cold running waters, hunting insects, crustaceans, frogs, and fish below 2500 meters’ altitude  inhabits slow-flowing rivers and lakes of forested alpine floodplains , which is more heavily dependent on diminishing ice-melt reaches  and Soricinae (water shrew) are found in localized populations figure . The IbeSalamandra salamandra) and alpine newt  favor zones of reduced glacier influence, including alpine woodland rivers below 2500 meters  requires fast-flowing, highly oxygenated, cobbled river reaches for larval development (figure Rana temporaria) persists within mountain woodlands and meadows below 2300 meters, using rivers and lakes for larval development and overwintering in open water to avoid freezing conditions  have also colonized low-velocity proximal glacial streams in Arctic Canada and Norway, particularly where they are warmed by upstream glacial lakes  and the Pyrenean brook newt (C. asper) preferentially occupy high-velocity mountain rivers in the Pyrénées, increasing their density and in turn biomass with reducing glacier influence  and meiofauna (rotifers and nematodes), the relationship between taxonomic richness and reducing glacier influence appears to be linear, resulting in increases in biomass with glacier retreat figure . HoweverBaetis alpinus, Lednia tumana, and Rhyacophila angelieri) but can be found at multiple trophic levels within diatoms , algae , and vertebrates  and both epilithic diatoms and detritus  released from the glacier was probably consumed by microbes and then assimilated by macroinvertebrates.In a detailed mountain-river food-web study, Clitherow and colleagues  used gutSalvelinus malma) and America dipper (Cinclus mexicanus), absent from the Austrian glacial food webs. In addition, Khamis and colleagues (Perla grandis) in spring-fed, in situ experimental mesocosm channels. Their results suggested that the future range expansion of this species  will increase trophic height (and therefore food-chain length) and body-size spectrums through invasion, intraguild predation, and interference competition  and that other taxonomic groups can serve as differential indicators of climate change in mountain-river systems. It also holds value beyond alpine rivers because the reorganization of communities within glaciated headwaters will intrinsically influence the species pools available to colonize downstream reaches, potentially reshaping their assembly processes (Brown and Milner


The patient had been taking appetite suppressant  for the last 7 days.Electrocardiography showed no abnormalities although both serum creatinine kinase-MB (3.59ng/mL) and troponin I  were elevated. Coronary angiography revealed extensive and abrupt lumen narrowing in the obtuse marginal with a subtle intraluminal defect within the distal part of the vessel . Optical The etiology and pathogenesis of spontaneous coronary artery dissection are not completely understood, but primary disruption with bleeding of vasa vasorum and intramedial hemorrhage have been proposed as the underlying mechanisms. Alternatively, an intimal tear may result in separation of coronary wall layers with the creation of a false lumen. Pressure-driven expansion of this lumen induces axial propagation of the dissection and true lumen compression, causing myocardial ischemia. Eventually, as occurred in the current case, angiography shows a long eccentric narrowing without the presence of a visible intimal flap.Spontaneous coronary artery dissection is an unusual, underdiagnosed disease, and its clinical presentation ranges from unstable angina to sudden cardiac death. This condition predominantly affects young women without classical cardiovascular risk factors, and it is increasingly diagnosed in those who are not in the peripartum period. specially in doubtful cases by angiography. Optimal treatment is still controversial and includes medical management for asymptomatic patients with normal coronary flow. Percutaneous coronary intervention with stenting or coronary artery bypass graft operation should be considered for patients with ongoing ischemia, clinically unstable or spontaneous coronary artery dissection involving the left main or multiple proximal coronary dissections. Favorable prognosis has been reported in patients managed conservatively since resolution and healing can occur over time. The present case is the first documenting spontaneous coronary artery dissection and healing by high resolution imaging OCT.Thus, an invasive imaging modality, such as OCT or intravascular ultrasound, should be the gold standard to diagnose spontaneous coronary artery dissection,


Cognitive decline is a frequent but undervalued aspect of multiple sclerosis (MS). Currently, it remains unclear what the strongest determinants of cognitive dysfunction are, with grey matter damage most directly related to cognitive impairment. Multi-parametric studies seem to indicate that individual factors of MS-pathology are highly interdependent causes of grey matter atrophy and permanent brain damage. They are associated with intermediate functional effects  representing a balance between disconnection and  adaptive connectivity changes. Therefore, a more comprehensive MRI approach is warranted, aiming to link structural changes with functional brain organization. To better understand the disconnection syndromes and cognitive decline in MS, this paper reviews the associations between MRI metrics and cognitive performance, by discussing the interactions between multiple facets of MS pathology as determinants of brain damage and how they affect network efficiency. Although about 40 to 70% of MS patients develop significant cognitive decline,-,in vivo characterization of GM pathology remains challenging. Detection of focal GM lesions, especially in the cortical GM, requires advanced magnetic resonance imaging (MRI) techniques, such as high-resolution 3D-T1 and 3D-FLAIR,,Although MS has been traditionally classified as a white matter (WM) disease, involvement of grey matter (GM) by demyelination and neurodegeneration has become evident in all stages of the disease.-,,It has been suggested that WM lesions and inflammatory processes have stronger influence as determinants of GM damage in early stages of MS,,,,,,,,,-,-,,,,,,MRI is the main modality used to assess pathological changes in MS and it has been used to quantify WM lesions,,,,-,,,The neurodegenerative process in MS is likely to precipitate changes in brain function. Conventional MRI data  has been compared to neuropsychological tests scores to relate MS pathology to cognitive performance.This paper reviews the associations between MRI metrics and cognitive performance in MS, by discussing the interactions between multiple facets of MS pathology as determinants of brain damage. We also present an overview of new imaging analysis techniques studying structural and functional brain networks towards accessing the interplay between structural damage, functional changes and cognitive outcome. ,Cognitive dysfunction in MS is heterogeneous and usually affects multiple cognitive domains. The more frequently affected domains are memory, attention, information processing speed and executive functions.,Risk factors of cognitive symptoms in MS are not completely understood, but studies have suggested that sex, age and genetic predisposition may play a role. For instance, several studies reported that cognitive symptoms are more severe and occur more often in male patients than in female patients.Neuropsychiatric factors are an important aspect to consider when assessing cognitive performance in patients with MS: studies have shown that cognitive fatigue might be partially responsible for decreases in performance of tasks that require sustained mental effort.,Not surprisingly, progressive MS phenotypes present worse cognitive performance than early relapsing remitting MS (RRMS) or CIS patients.,Although cognitive deficits can be found in early stages of the disease, they are usually a feature of advanced disease. Natural history studies suggest that the cognitive decline tends to progress with increased disease duration and, once it appears in MS patients, it is unlikely to remit.White matter (WM) lesions. Depicting WM lesions disseminated in the CNS is indispensible for the diagnosis and early clinical management of MS.,,,,,,,,,,,,,,,It has been suggested that lesion location might be a stronger determinant of neurological dysfunction in MS,,,Most studies evaluating associations between lesion load and cognition were performed in patients with relative short disease duration. Baseline T2-hyperintense and T1-hypointense lesion loads are significant short-term predictors of disability and cognitive decline in patients with clinical isolated syndromes (CIS)Gray matter (GM) lesions. Renewed interest in MS GM pathology has revealed that the prevalence of GM lesions is high,,,,Double inversion-recovery (DIR) is a relatively new MRI sequence that selectively nulls the signals from WM and cerebrospinal fluid (CSF), leaving only GM and lesions visiblein vivo visualization of the most prevalent subtype - subpial lesions.Although DIR has considerably improved GM lesion detection, a post-mortem evaluation uncovered that about 80% of cortical lesions remain undetected at 1.5T.Despite the fact that multiple studies have shown the clinical relevance of cortical lesions, there are still several limitations to the assessment of cortical lesions in routine clinical practice. First, specific MRI sequences to detect cortical lesions, such as DIR and PSIR, are not available on most clinical scanners. The availability of ultra-high field scanners for clinical practice is even more limited. Second, DIR imaging is prone to artifactsDiffuse MS pathology. Quantitative MRI techniques, such as magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI), enable quantification of the extent and severity of structural changes occurring in NABT outside focal lesions.,,,,,,,,Several studies have shown that correlations between cognitive deterioration in MS and markers of diffuse MS pathology are stronger than correlations observed between cognitive decline and WM lesion load.,,Evidence suggests that MTR and DTI can be used to probe neurodegeneration  and might have prognostic value. First, MTRHowever, most of the MRI parameters used to investigate NAWM and NAGM abnormalities  are pathologically unspecific, and might correspond to (combinations of) demyelination, inflammatory processes or neurodegeneration.Brain atrophy. Brain atrophy is considered to be an end-stage phenomenon, strongly correlated to permanent brain damage / neurodegeneration. Patterns of GM atrophy are being identified from early stages of MS onward,,,,,,Global cortical thinning is mild in early stages of MS such as CIS and increases with disease severity,,Despite these efforts, it is still not well understood which pathological factors determine GM atrophy in MS. Previous studies showed associations between GM atrophy with WM,,,,-Traditional models of brain function employ modular paradigms, in which brain areas are postulated to act as independent processors for specific neural functions.,,,Most DTI studies show signs of microscopic damage/disconnection in several WM pathways involved in cognition. The fiber bundles more frequently associated with neuropsychological performance are the cingulum,,,,,,,Some of the disrupted WM connections are anatomically related to the default mode network (DMN).These results are difficult to interpret. Increased connectivity in cognitively preserved patients could be a sign of beneficial functional reorganization or compensatory mechanisms to sustain normal function, delaying the cognitive decline. Alternatively, it could be a maladaptive response secondary to the disruption of inhibitory WM connections. In this context, one would expect positive correlations between signs of WM disconnection and increased functional connectivity. Louapre et al.,,Different studies found similar results in structuralCognitive decline is an important source of disability in MS patients and an undervalued aspect of disease progression. Even though cognitive impairment is partly related to macroscopic lesion load, focal damage might play an indirect role as a cause of further tissue damage. Reflective of permanent damage and tissue loss, atrophy markers show stronger correlations with cognitive tests, but regional damage in target structures provides limited information about their specific relevance for a given cognitive domain and the integration between brain areas and systems. A more holistic investigation of brain networks seems to better capture the mechanisms of brain damage and adaptation encountered in cognitive dysfunction. However, multimodal imaging techniques and network analyses are still in their infancy and, although it is possible to visualize the associative areas more frequently affected in cognitive impaired MS subjects, we still lack a more specific comprehension of the interplay between function and structure to better understand initial adaptation and subsequent collapse of brain networks.


Oscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia. Here, we focus on the dual role of fast-spiking, parvalbumin (PV+) networks in the generation of gamma oscillations and critical periods of brain plasticity.We generated a mouse model of reduced recurrent inhibition only within local PV+ cell networks by selective removal of GABAA receptor alpha1 subunits (PV-α1 KO mice). Electroencephalography (EEG), PV+ immunohistochemistry, perineuronal net (PNN) labeling and redox balance were compared to cortical measures of brain plasticity  that are typically limited to a critical period early in life.PV-α1 KO mice exhibit chronically enhanced gamma-oscillations and extended juvenile forms of cortical plasticity into adulthood. Acute pharmacological suppression of excitatory input restored E-I balance onto these disinhibited PV+ cells and returned baseline EEG power to normal levels, preventing the extended plasticity. Enhanced gamma oscillations were further found to compromise the integrity of perineuronal nets (PNNs) surrounding PV+ cells, elevating oxidative stress and the turnover of metallopeptidases and structural components of the PNN. All of these aspects were also reversed by pharmacological dampening of excitation onto PV+ cells.Cortical gamma oscillations are associated with plasticity and cognition. Our results provide a cellular explanation of how elevated gamma oscillations may promote ectopic brain plasticity by regulating the extracellular matrix which normally stabilizes cortical circuitry. These results carry broad implications for subjects at-risk for schizophrenia who exhibit heightened gamma oscillations prior to psychosis onset .


Delphinapterus leucas) populations occur between July-November. Our goal was to develop population-specific beluga habitat selection models that quantify relative use of sea ice and bathymetric features related to oceanographic processes, which can provide context to the importance of changing sea ice conditions. We established habitat selection models that incorporated daily sea ice measures  and bathymetric features  to establish quantitative estimates of habitat use for the Eastern Chukchi Sea (‘Chukchi’) and Eastern Beaufort Sea (‘Beaufort’) populations. We applied ‘used v. available’ resource selection functions to locations of 65 whales tagged from 1993–2012, revealing large variations in seasonal habitat selection that were distinct between sex and population groups. Chukchi whales of both sexes were predicted to use areas in close proximity to Barrow Canyon  as well as the continental slope in summer, although deeper water and denser ice were stronger predictors for males than females. Habitat selection differed more between sexes for Beaufort belugas. Beaufort males selected higher ice concentrations (≥40%) than females (0–40%) in July-August. Proximity to shore (<200 km) strongly predicted summer habitat of Beaufort females, while distance to the ice edge was important for male habitat selection, especially during westward migration in September. Overall, our results indicate that sea ice variables were rarely the primary drivers of beluga summer-fall habitat selection. While diminished sea ice may indirectly affect belugas through changes in the ecosystem, associations with bathymetric features that affect prey availability seemed key to habitat selection during summer and fall. These results provide a benchmark by which to assess future changes in beluga habitat use of the Pacific Arctic.There has been extensive sea ice loss in the Chukchi and Beaufort seas where two beluga whale ( Ursus maritimus) and ice-associated pinnipeds such as seals and walruses use sea ice as a platform for foraging, reproduction, and resting . Seas. SeasUrsng  are ice-associated cetaceans that utilize a broad range of habitats from open water, loose annual pack ice, sea ice edge, and multi-year pack ice )Males likely segregate from females as they mature to exploit alternative prey resources and reduce competition with females and calves, as do other socially-structured cetaceans (e.g. ). We fouDue to reductions in sea ice over recent decades as well as projections for continued loss ,81, therAlthough mitigation of sea ice loss primarily requires global reduction of greenhouse gas emissions, habitat models can help inform management of anthropogenic activities and conservation planning efforts that will increasingly need to identify seasonally important areas for this critical species. Our results suggest that belugas select habitat based on a number of factors. Sea ice variables were rarely the most significant factors affecting beluga summer-fall habitat selection compared with bathymetric features. This suggests perhaps sea ice loss may not impact beluga habitat use. However there are other ways changing sea ice cover could affect belugas, and a recent study showed Chukchi belugas shifted fall migration timing as sea ice freeze-up occurred later in the 2000s . Other e


The understanding of mitochondria and their quality control in cancer genesis and progression is increasing exponentially. While the Warburg hypothesis depicts mitochondria as silent within a glycolytic tumorigenic environment, it is now known that in malignant cells mitochondria are constitutively active, priming malignant reprogramming and promoting survival. Thus, in cancer cells mitochondria supply energy, provide building blocks for new cells, control redox homeostasis and define oncogenic signals commanding programmed cell death . Two othm) which provides a putative target for anti-cancer therapy. Mitochondrial redox molecules conjugated to triphenylphosphonium (TPP) exploit such differences and accumulate within the mitochondria as a selective therapeutic approach.Intrinsic aspects of mitochondrial function in cancer cells allow for the selective targeting of tumorigenic cells, including differences in mitochondrial membrane potential (ΔψBiel and Rao, describe how these TPP-conjugated antioxidants trigger a mitophagy-mediated resistance mechanism . The rolm reported in aggressive cancer cells leading to sustained mitophagy [The pharmacological control of mitophagy could in turn be tested as a way to improve the therapeutic efficacy of chemotherapy. Hitherto, few selective non-toxic inducers of mitophagy have been developed, i.e. Urolithin A  and the itophagy . The autitophagy . InteresThis work re-invigorates the field of mitophagy in the progression and management of tumours. Discovering whether mitophagy induction is a feature of less aggressive cancer cells could unveil the culling of non-abiding mitochondria as a mechanism to reprogram cells towards metastatic tendencies. Conclusively, this research brings into focus mitochondrial life-cycle modulation as a key effector in cancer cell divergence and reveals therapeutic implications for the pharmacological fine-tuning of mitophagy to overcome chemotherapy resistance .


Whilst associations between polygenic risk scores (PRSs) for schizophrenia and various phenotypic outcomes have been reported, an understanding of developmental pathways can only be gained by modelling comorbidity across psychopathology, something no studies have done to date. We examine how genetic risk for schizophrenia relates to a broad range of adolescent psychopathology using a latent modelling approach, and compare this to genetic risk for other psychiatric disorders, to gain a more comprehensive understanding of development pathways at this age.PRSs for schizophrenia, major depressive disorder, neuroticism and bipolar disorder were generated for individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariate linear regression was used to examine relationships of these PRSs with psychopathology factors modelled within i) a correlated factors structure, and ii) a bifactor structure.The schizophrenia PRS was associated with an increase in factors describing psychotic experiences, negative dimension, depression, and anxiety, but once modelling a general psychopathology factor specific effects above this persisted only for the negative dimension. Similar factor relationships were observed for the neuroticism PRS, with a (weak) specific effect only for anxiety once modelling general psychopathology.Psychopathology during adolescence can be described by a general psychopathology construct that captures common variance as well as by specific constructs capturing remaining non-shared variance. Schizophrenia risk genetic variants identified through genome-wide association studies mainly index negative rather than positive symptom psychopathology during adolescence. This has potentially important implications both for research and risk prediction in high-risk samples.