Ultraviolet (UV) radiation has affected life at least since the first life forms moved out of the seas and crawled onto the land. Therefore, one might assume that evolution has adapted to natural UV radiation. However, evolution is mostly concerned with the propagation of the genetic code, not with a long, happy, and fulfilling life. Because rickets is bad for a woman giving birth, the beneficial effects of UV-radiation outweigh the adverse effects like aged skin and skin tumors of various grades of malignancy that usually only afflict us at older age. Anthropogenic damage to the stratospheric ozone layer and frighteningly high rates of melanoma skin cancer in the light-skinned descendants of British settlers in Australia piqued interest in the health impacts of UV radiation. A changing cultural perception of the beauty of tanned versus light skin and commercial interests in selling UV-emitting devices such as tanning booths caught public health experts off-guard. Counseling and health communication are extremely difficult when dealing with a “natural” risk factor, especially when this risk factor cannot (and should not) be completely avoided. How much is too much for whom or for which skin type? How even measure “much”? Is it the (cumulative) dose or the dose rate that matters most? Or should we even construct a more complex metric such as the cumulative dose above a certain dose rate threshold? We find there are still many open questions, and we are glad that this special issue offered us the opportunity to present many interesting aspects of this important topic. We were thrilled when the journal invited us to serve as guest editors for a special issue about ultraviolet (UV) radiation. We are three Austrian scientists: Stana Simic (SS) as a meteorologist has long-standing experience in UV research as a coordinator of the Austrian UV monitoring network ,2 and asWe soon realized that meteorologists and public health experts talk different languages. We also learned that health professionals have a somewhat simplified concept of UV radiation . They knExceptionally high rates of melanoma skin cancer in the light-skinned descendants of British settlers in Australia set the stage for intensive public health debate about individual protection measures against UV radiation . DestrucLifetime risk for melanoma skin cancer is enlarged by exposure to natural and artificial UV light and reduced by sun protection. Thus, disease prevention is feasible simply and cost-effectively by appropriate photo-protection and sun avoidance. Increasing melanoma incidence and mortality rates worldwide create human suffering and a vast economic healthcare burden. To tackle this important global public health issue, costly skin cancer prevention programs have been initiated. These health campaigns strive at enhancing both knowledge and awareness regarding the potential dangers of UV radiation from natural and artificial sources. To supplement the clinical perception of skin disease diagnosis and treatment, we implemented the concept of public (skin) health as an umbrella term for conceptual and pragmatic research in the field of skin health promotion and cancer prevention.Austrian melanoma incidence and mortality rates are constantly rising with higher rates in males. With Austria being a predominantly mountainous country, our ecological study found that melanoma incidence rates increased, whereas mortality rates decreased with altitude of place of living . The obsWe further aimed at investigating prevailing sun exposure and photo-protective practices influencing skin health among the general Austrian population. When exploring gender-specific aspects of recreational skin health habits, we identified a male factor, suggesting higher prevalence of sun exposure and poorer sun protective behavior among males ,14,15.Among the Austrian population, print media and television are perceived as the two most relevant sources for skin health information, thus ranking as sources before physicians ,17,18. CDespite media campaigns on the harmful effects of excessive sunlight and sunbed exposure, we found a high prevalence of self-reported sun exposure and sunbed use among Austrian citizens ,20. SociWe are pleased that we were able to invite additional papers dealing with this aspect .From a public health point of view, the beneficial health effects of UV exposure are also of relevance. Additionally, the positive impact of physical outdoor activity in spite of and in conjunction with solar UV radiation cannot be neglected . In the Human perception, cultural norms, and health behavior are often strange and unpredictable. Tanning is now perceived by many as a cosmetic measure enhancing good appearance . There a


Reduced levels of physical activity and increased levels of fatigue are commonly reported in prostate cancer patients treated with androgen-deprivation therapy (ADT)  that in Exercise has been shown to be effective for improving surgical outcomes, reducing symptom experience, managing side effects, improving psychological health, maintaining physical function, and reducing fat gain and muscle and bone loss in cancer patients  and hencResistance exercise improves muscle strength and function and has been shown to be an effective intervention against sarcopenia . This exImprovements in muscle mass, such as those seen by Galvao et al. , are impStudies employing aerobic training only interventions have primarily utilized breast cancer patients, with promising outcomes reported in physical function, fatigue mitigation, and quality of life –27. Of tper se. High cardiorespiratory fitness levels have also been found to attenuate the increased arterial stiffness in patients with metabolic syndrome. Increases in arterial stiffness, independent of age and blood pressure, have been reported in men receiving ADT (With regard to non-cancer patients, it is well established that cardiorespiratory fitness attenuates the mortality risk associated with metabolic syndrome in healthy men, independent of body mass , indicatving ADT –33 highlAlthough there are studies that have investigated the effects that resistance training programs and aerobic training programs have on prostate cancer patients undergoing treatment, very few have utilized a combined aerobic and resistance training intervention with prostate cancer patients undergoing ADT. Culos-Reed et al.  were oneGiven the recent attention that ADT and the associated CVD risk have received, it is clear that exercise interventions specifically targeting CVD risk outcomes are required. Previous studies have targeted resistance training or aerobic training alone and have reported positive outcomes specific to the training modality. What is now needed are exercise interventions that apply sound aerobic and resistance training principles in combination to prevent the development of CVD in men undergoing ADT for the treatment of prostate cancer.BW is responsible for all aspects of this opinion piece.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Bees are amazing little creatures; while some of them live solitary lifestyles, many bee species form large colonies, or hives, and function as a superorganism. Scientific interest in bees covers many different angles. Some researchers are interested in how bees learn and communicate as part of the superorganism. Others study how bees fly and recognize objects during flight—skills that have intriguing implications for development of manmade drones. And, as we are all sadly aware, there is intense research on bee pathogens and the contribution of those pathogens to colony collapse. In this Open Highlights article, I will discuss some of the recent advances in our understanding of these fascinating insects.PLOS Biology [While one bee is small, a colony is mighty, and colonies are capable of extremely complex behaviors. How bees communicate and pass on knowledge has interested researchers for decades. In a recent paper in  Biology , the autPLOS ONE paper unearths new insights into learning and memory by developing an operant conditioning test whereby bees push a cap to uncover a food source [Apis cerana is often attacked by hornets (Vespa velutina), and authors of another PLOS ONE paper [Bees can be trained in other non-natural tasks, and a d source . Bee leaNE paper  find thaPLOS Biology article [Apis cerana can not only warn nest-mates of a predator, but can tell them how big a threat the colony is facing. The ‘stop signal’ identified by the authors is a brief vibrational pulse that informs the nest of the level and context of the danger . Bees receiving these signals behave differently, either avoiding a food source, remaining in the nest, or attacking the invading hornet by forming a ball of bees that kills the attacker by heating it to death.In addition to alarm pheromone, bees have evolved other mechanisms to warn their nest-mates of danger. In a second  article , the autPLOS ONE article, the authors provide evidence that Asian giant honeybees (Apis dorsata) engage in collective respiratory behavior to ventilate their hives for thermoregulation and freshness [PLOS Genetics paper [Communication within bee colonies is extremely complex. One of the primary mechanisms is through the famous “waggle dance,” which occurs on the dance floor as a means of signal amplification. But bees also engage in other types of collective behavior. In another reshness . Howevercs paper  compare PLOS ONE article [PLOS Computational Biology paper [As mentioned above, another facet of bee research is into their mode of flying and information processing during flight. Authors of a  article  investiggy paper , the autScientific Reports article [Nosema apis. After four days of infection, the bees performed more flights of shorter duration, indicating a trade-off between foraging activities and the immune response. Another article published in Scientific Reports [Nosema infection caused short flights, but interestingly, the bees were still able to use the optimal search strategy, suggesting that search strategy is robust to physiological effects of pathogen infection. Related to these studies is one published in Behavioral Ecology and Sociobiology [Nosema and investigated whether these infections altered the task allocation of bees within the colonies. Bees use an age-related division of labor, known as the temporal polyethism schedule. The authors found that the pathogens accelerated this schedule, but didn’t change the host behavioral repertoire, though they did see pathogen-specific changes in behavioral alterations.Another aspect of bee flight studied is how it changes due to pathogen infection. In this  article , the aut Reports  also looobiology . In thisPLOS Pathogens paper performed a large-scale controlled trial to determine how combinations of stressors impacted colony health [Varroa destructor, a bee mite that not only steals nutrients from larvae but is also a vector for bee viruses. From data collected in this study, the authors build a predictive model to understand how the combination of stressors leads to colony collapse. Further studies on individual pathogens and their effects in combination will be needed to truly understand, and hopefully prevent, further loss of bee colonies.Pathogens are one of the key stressors that are blamed for the colony collapse disorder plaguing regions like the United States. Since nearly one-third of the North American food supply is reliant on insects for pollination, the observed rise in colony collapse is highly concerning. However, it seems that a combination of stressful factors may be contributing to colony collapse. The authors of a y health , measuriFor more detailed reading please see the associated PLOS Collection .


Fundamental metabolic processes determine homeostasis of neuronal and glial networks at the molecular, cellular, and systems levels. Metabolic resilience promotes brain health and has the potential to prevent or reverse brain disease. A renewed and increasing interest in the relationship between metabolism and homeostasis is evident across multiple disciplines and has the potential to spawn new insights and therapeutic targets. The striking lack of effective treatments in disorders such as brain cancer, Alzheimer's disease, epilepsy, and autism spectrum disorder (ASD) highlights the limitations of conventional, discipline-specific pharmacological approaches.Boison). A molecular link to basic biochemical mechanisms is further provided in an original research article that ascribes a specific role of the methionine cycle-associated enzyme enolase phosphatase 1 in apoptotic response mechanisms triggered by oxidative stress . The link between metabolic homeostasis and neuronal activity is evident in the relationship between ion homeostasis and energy demand of fast neuronal network oscillations associated with higher brain functions—including sensory perception, attentional selection, and memory formation and requiring timed synaptic excitation and inhibition with glutamate and GABA, respectively . Fast neuronal network oscillations are characterized by high oxygen consumption and significant changes in the cellular redox state, indicating rapid adaptations in glycolysis and oxidative phosphorylation. A second review article highlights the complex role of glycogen and its role in brain energy and particularly synaptic plasticity . Exquisite sensitivity to metabolic stress is essential for adaptation and plasticity and confers vulnerability of higher brain functions to injury and disease.For this Research Topic authors were encouraged to submit basic research on homeostasis and excitability as well as metabolic mechanisms associated with neurological diseases and novel treatment approaches based on metabolic and homeostatic interventions. This special issue features several papers examining molecular mechanisms involved in neural network homeostasis and higher brain function. From an evolutionary perspective, “early” metabolites such as adenosine  and glycine (the simplest amino acid) assumed multiple functions as structural building blocks of cellular systems, as biochemical metabolites involved in energy and carbon homeostasis, as epigenetic modulators, and finally  as receptor ligands and signaling molecules. Not surprisingly, dysregulation of those key metabolites is implicated in virtually every neurological condition, whereas therapeutic reconstruction of biochemical homeostasis has potential for disease prevention and cure . An excitatory/inhibitory “imbalance” and excess excitability can have many causes: Westmark et al. delineate the homeostatic role of amyloid-β protein precursor (APP) and its metabolites in fragile X syndrome in humans and in the Fmr1KO mouse model. APP seems to serve as a rheostat where too much or too little causes hyperexcitability—suggesting that normalizing APP levels can address aspects of this pathophysiology.Advances in sequencing technologies led to the discovery of amino acid-recoding RNA editing in many gene transcripts. In this context, recent advances in A-to-I and C-to-U RNA editing are reviewed. This mechanism points to the systemic relevance of the neurotransmitter receptor for glycine (GlyR) and possible clues to disease mechanisms. C-to-U RNA editing of GlyR-coding transcripts is increased in the hippocampus of patients with intractable temporal lobe epilepsy and can provoke completely different symptoms depending on the neuron type that is affected . An analysis of post-traumatic brain injury cerebrospinal fluid finds that mortality at 6 months can be predicted by levels of cortisol and BDNF, particularly in younger people, and suggests a regulatory role for cortisol . Several articles look at changes mobilized by a metabolic therapy used to treat epileptic seizures for nearly 100 years: the ketogenic diet . In an original research paper, anxiolytic behavioral effects of ketone-based metabolism—mobilized by administering a ketone ester to induce nutritional ketosis—are reported in two rat strains . A second original paper compared ketosis induced by exogenous ketones vs. a ketogenic diet and found similar biochemical changes but more robust behavioral effects of the diet . Laboratory and clinical evidence is reviewed regarding the prevalence of dysfunctional mitochondria and altered metabolism in ASD alongside current limited but positive data on the role of ketogenic diets and metabolic therapy in reducing ASD symptoms and common comorbidities—potentially via adenosine or other mechanisms . An original research article demonstrates that enhancing adenosine in brain through pharmacological blockade of the enzyme adenosine kinase prevents radiation-induced cognitive impairment in rats .Regarding translational and clinical research, a study of the healthy human brain indicates the existence of specific metabolomic profiles in different brain regions . Metabolic therapy with a ketogenic diet is highlighted as a multifaceted therapy for glioma, particularly glioblastoma, and clinical and basic research is reviewed indicating that a metabolic approach may both limit tumor growth and augment the efficacy of chemotherapy and radiation . Finally, hypometabolism is a hallmark of Alzheimer's disease, and regional glucose hypometabolism is also found in patients at risk for Alzheimer's disease and may be a presymptomatic marker. However, hypometabolism is reversed by administering ketones as an alternative fuel—suggesting that a selective problem with glucose metabolism may underlie the pathophysiology of early onset Alzheimer's disease, and that a metabolic therapy may prevent or delay the disorder .Finally, the role of metabolic factors and the promise of metabolic therapy in brain cancer and Alzheimer's disease are implicated directly in several articles: an original research article reveals a critical role of the proneural basic helix-loop-helix transcription factor human achaete-scute homolog 1 (hASH1) in neuroblastoma. This study shows that hASH1 suppresses neuronal differentiation by inhibiting transcription at the retinoic acid receptor element, highlighting hASH1 as a key determinant of neuroblastoma resistance to differentiation therapy (Taken together, this research topic provides a cross-cutting perspective of the relationship between metabolism and homeostasis and showcases novel metabolic therapies to restore molecular and biochemical networks. The direct and potentially imminent clinical implications of several of these articles will be exciting to follow as the field moves forward. While a range of topics and mechanisms is featured herein, there is room for much more.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Streptomyces encompasses transitions from vegetative mycelial forms to reproductive aerial hyphae that differentiate into chains of single-celled spores. Whereas their mycelial life – connected with spore formation and antibiotic production – is deeply investigated, spore germination as the counterpoint in their life cycle has received much less attention. Still, germination represents a system of transformation from metabolic zero point to a new living lap. There are several aspects of germination that may attract our attention: (1) Dormant spores are strikingly well-prepared for the future metabolic restart; they possess stable transcriptome, hydrolytic enzymes, chaperones, and other required macromolecules stabilized in a trehalose milieu; (2) Germination itself is a specific sequence of events leading to a complete morphological remodeling that include spore swelling, cell wall reconstruction, and eventually germ tube emergences; (3) Still not fully unveiled are the strategies that enable the process, including a single cell’s signal transduction and gene expression control, as well as intercellular communication and the probability of germination across the whole population. This review summarizes our current knowledge about the germination process in Streptomyces, while focusing on the aforementioned points.The complex development undergone by  Actinomyces, Streptomyces, and Micromonospora, differentiate into dormant fungi-like uninucleoid spores (arthrospores or exospores). Arthrospores significantly differ from the endospores of Bacilli and Clostridia in morphology and function. The endospores exhibit striking resistance to a wide range of environmental stresses, such as heat, desiccation, and ultraviolet radiation  and extremely stable small spore proteins  that bear individually constricted conidiospores , widely resistant forms. Several bacterial clades living in soil, such as adiation . Their aadiation . The welproteins . All theiospores . Both, siospores , protectiospores . Spores Their complex life cycle and the described similarities with eukaryotic fungi make streptomycetes unique organisms within the bacterial kingdom. However, comprehensive information about the diverse features of spore germination in this antibiotic-producing clade is still missing. This review attempts to fill this gap.Streptomyces. Some species (mainly S. viridochromogenes and S. granaticolor) exhibit fast and robust germination with nearly all spores germinating. That is also why this organism was subjected to many initial germination experiments (S. coelicolor and S. venezuelae) germinate more slowly with a fraction of spores that does not germinate at all. These exhibit more complex germination behavior and possess a fraction of germlings that stop growing soon after germination, probably due to produced inhibitory compounds, such as germicidins and hypnosins, that affect their development  offers many clues for understanding the readiness of spores for successful germination. The life cycle of Streptomyces, similarly as in the other arthrospore-forming bacteria, encompasses a development of a network of branched hyphae that grow into the substrate thus creating a vegetative mycelium. The subsequent development of aerial hyphae and spores is considered to be the cell’s response to nutrient depletion. The sporulation-specific regulon is activated after repression of sporulation-specific genes by the BldD-c-di-GMP complex is released , a system somewhat similar to the elongasome of rod-shaped bacteria , they germinate remarkably faster and more synchronously. On the other hand, the fully maturated spores exhibit less viability and longer lag-phase in conditions suitable for germination . These dbacteria . Membersbacteria . Maturatelicolor . After melicolor  and cellelicolor .S. avermitilis (suspended in Tris-HCl) are able to oxidize atmospheric H2 to supply maintenance energy  that guided by chemotaxis  are temporarily able to rapidly swim  of dipicolinic acid  over the experimental period. This result suggested that there is also a pool of stable mRNAs, functional ribosomes, and translational apparatus that have been preserved during spore maturation .S. coelicolor, several hydrolases that might take their part in the cell envelope reconstruction  were shown to be stored throughout spore dormancy and not synthesized de novo during germination .Germination is associated with a complete reconstruction of the cell that involves highly accelerating metabolic activity, morphological changes that start with uncoating, and reconstitution of the cellular content. Spore germination is a sequential process and thus can be divided into three distinctive steps (defined by (a)Darkening is associated with cell wall reconstruction2+, Mg2+, Mn2+, Zn2+, and Fe2+   revealed a highly impaired germination, the strain was able to germinate within 12 h. This suggests that the Rpf hydrolase family is highly important but not essential for a smooth germination. The Rpfs family could probably be substituted by other cell wall hydrolases. Three Streptomyces cell wall lytic enzymes (SwlA to SwlC) are examples of such possible candidates that may be responsible for the proper thickness of the dormant spore wall ensuring its heat resistance   whose into RfpE) . Althougsistance . In this(b)Enzymatic activities are recovered during swellingS. griseus during spore swelling  are constitutively expressed throughout the germination course suggesting that their presence is constantly necessary The vegetative growth starts with germ tube emergenceS. coelicolor one or two germination tubes appear after 180 min of germination and elongate by apical tip extension. At this developmental point two or three DNA replisomes were demonstrated . ATP is essential not only as an energy source for the basal metabolism  or the crp gene were deleted exhibited a similar, dramatic defect in germination. The germination defect caused by the missing or inactive Crp system can be explained by the subsequent absence of several members of the affected Crp regulon that play a crucial role in germination. Other than ATP synthase, the Crp regulon encompasses the cell wall hydrolases and chaperones . Germicidin A is known as an autoregulatory germination inhibitor of Streptomyces and other bacteria  are known to be bound on the spore envelopes and released into the environment during germination. These antibiotics protect the germinating spores against environmental challenges before the internal biosynthetic pathways are re-activated. Some antibiotics, such as cephamycin C and clavulanic acid both synthesized by S. clavuligerus are known to be produced soon after germination (Several streptomycete antibiotics produced during sporulation, such as neomycin in  griseus , or actimination .Streptomyces represents an exceptional study model of bacterial cell differentiation that presents a complete transformation of cellular morphology and the restoration of all physiological processes. More detailed knowledge about the structure of dormant spores may provide clues for understanding their readiness to trigger metabolic activity and cell reconstitution.Spore germination in An interesting area that deserves our attention is the probability of germination and germination control. As discussed in this review, the cell awakening is launched in an aquatic milieu; the probability of awakening differs, possibly depending on the accessibility to nutrients and on other biotic and abiotic factors. Stochastic germination seems to be a widespread strategy of spore-forming organisms that has evolved to ensure the survival of whole populations. From the one-cell perspective, spores represent a safe but non-reproductive state, whereas germination is a risky and irreversible process. From the point of view of the whole population, early germinating pioneers take advantage by occupying vacant niches whereas a hesitant strategy is preferable when conditions become harsh. Therefore, one may assume that the onset of germination is subject to various controlling mechanisms that respond to external signals and activate or suppress the process as is needed. The characterization of these signals and their sensors has not been established to date. The transferred signals are eventually reflected in complete cell reconstruction. This requires the activity of specific genes whose expression is directed by a unique set of transcriptional factors. Characterizing these factors and clarifying their regulons would shed more light on the process by which dormant spores are awakened.JB wrote the whole manuscript, MČ analyzed the knowledge about metabolic activities of germinating spores, KŠ analyzed the knowledge about transcriptional activities of germinating spores.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 induced pluripotent state represents a decade-old Nobel prize-winning discovery. Human-induced pluripotent stem cells (hiPSCs) are generated by the nuclear reprogramming of any somatic cell using a variety of established but evolving methods. This approach offers medical science unparalleled experimental opportunity to model an individual patient’s disease “in a dish.” HiPSCs permit developmentally rationalized directed differentiation into any cell type, which express donor cell mutation(s) at pathophysiological levels and thus hold considerable potential for disease modeling, drug discovery, and potentially cell-based therapies. This review will focus on the translational potential of hiPSCs in clinical neurology and the importance of integrating this approach with complementary model systems to increase the translational yield of preclinical testing for the benefit of patients. This strategy is particularly important given the expected increase in prevalence of neurodegenerative disease, which poses a major burden to global health over the coming decades. Medicine has evolved a sophisticated taxonomic repertoire that is based upon particular constellations of predominantly clinical and macroscopic/imaging features. Although such an approach has clear utility in medical practice, it leaves unresolved to some extent the cellular and molecular basis of disease. It follows that a complementary taxonomic (re)classification to reflect underlying—and potentially therapeutically targetable—molecular mechanisms may serve to strengthen both our diagnostic and therapeutic capacities. In order to first gain accurate insight into the molecular basis of human disease, it is crucial to employ an integrated approach that recognizes inherent limitations in each model system when used in isolation. Animal models and human non-neuronal cell lines have provided invaluable insight into developmental and translational neuroscience. Yet their success in identifying novel and clinically impactful therapies has been underwhelming, perhaps reflecting an inability to capture the true complexity of human neurological disease by using these approaches in isolation. Advances over the last decade have transformed the landscape of mechanistic evaluation and drug discovery in neurodegenerative disease, with new technologies permitting the study of previously inaccessible human cellular subtypes. The induced pluripotent state represents a Nobel prize-winning discovery made in the laboratory of Shinya Yamanaka in Kyoto, Japan, in 2006 and 2007  the ability to self renew and (ii) the capacity to differentiate into any of the cell types comprising the organism from which they are derived. However, with this potential comes the complexity of directing differentiation into highly refined and regionally specified subtypes of neurons and glia . This strategy promotes data sharing and comparison. Further attributes including integration-free lines, equal male and female line representation, and the prospect of intensively characterized cryopreservable differentiated precursors make such stem cell repositories an attractive prospect. Such non-profit initiatives also stand to benefit from close collaboration with industry.Generating isogenic controls, standardizing optimal differentiation protocols, and reproducing mutation-dependent phenotypes Drug development is expensive and time-consuming, and those therapeutics that do emerge from preclinical studies have a low conversion rate into successful disease treatments due to limitations with either safety or efficacy. This failure of translation is particularly evident in the field of neurodegeneration, where only a very small percentage of drugs that reach the development phase are actually ever marketed  would further improve scalability of cultures for high-content cell-based screening approaches. High-throughput screening has been used to identify compounds that can optimize directed differentiation of hiPSCs . Within defined phenotypes at a particular disease phase, it is important to experimentally resolve the crucial pathogenic event(s) in order to guide therapy development around such validated targets specifically.The approach of screening compound libraries is important to inform which mechanistic phenomena are therapeutically manipulable. Important issues to address in the future  include screening compounds on enriched populations of specific cell types in mono- and co-culture. Furthermore, systematic approaches to optimizing the duration of therapy, drug concentration, and timing of initiation relative to disease phase are all important considerations. Integrated medicinal chemistry expertise is then crucial to optimize the compound for clinical trial use. To this end, it is essential to ensure that any potential compound is safe in humans, which highlights another role for hiPSC derivatives as a predictive cell-based model for toxicity assessment. HiPSCs themselves do not faithfully capture the physiological attributes of clinically relevant somatic cell types  and thus cannot serve as appropriate model for predictive toxicity assessment. However, using ontogeny-recapitulating directed differentiation of hiPSCs to desired cell types allows more accurate toxicity assessment in a relevant cellular context see Fig. . Drug deStrategies for generating patient-specific neuronal and glial subtypes—through either reprogramming and directed differentiation or direct conversion methods—have fuelled excitement about the prospect of cellular therapy to restore structure and function in neurodegenerative diseases. Issues of safety are paramount in this context and broadly include rigorous tumorogenicity and immunogenicity testing, recently reviewed elsewhere  primate model, which exhibits a characteristic loss of midbrain dopaminergic neurons in the substantia nigra and phenocopies the human condition. Transplantation of human fetal neural stem cells into this model was found to ameliorate the disease phenotype. Noting that there is a proven relationship between graft survival and amelioration of the disease course , the findings within the same study of only a small minority of graft TH+ve donor cell survival required further explanation. Indeed, >95% remained as neural precursors and hence the mechanism of functional improvement was likely not to be exogenous cellular replacement, but rather influences of the graft on endogenous cellular function , which may be required to achieve clinically evident disease modification. Crucially, clinical trials need careful design including predefined end points, rigorous safety assessment, reproducible cellular derivation, tumorogenicity assays, and demonstration of preserved efficacy in the context of immunosuppression. To realize cellular therapies for neurodegenerative disease, it is clear that transparent international collaboration will be a key driving force.HiPSCs hold tremendous promise for translational research in neurological disease (Connick et al. In future, we envisage diagnostic and therapeutic integration of patient-specific hiPSCs into clinical management. As a first step, this might involve rapid reprogramming and differentiation of patient-specific cells followed by a personalized regimen of drugs selected through high-throughput screening with concurrent toxicity assays. How soon this future can become a reality depends not only on scientific advances but also on practical and financial feasibility. The prospect of automating the majority of hiPSC culture is crucial to ensure scalability and reproducibility across experiments. This would also reduce cell culture demands on researchers and the risk of infection. Such technologies are now available, although wider usage is likely limited by cost. Clinically impactful advances in the hiPSC field will undoubtedly be realized sooner through cohesive international consortia and the closer collaboration/co-location of industry with both academic and clinical colleagues, in order to drive drug discovery and translational neuroscience towards an era of precision medicine.


Rising temperatures during growing seasons coupled with altered precipitation rates presents a challenging task of improving crop productivity for overcoming such altered weather patterns and cater to a growing population. Light is a critical environmental factor that exerts a powerful influence on plant growth and development ranging from seed germination to flowering and fruiting. Higher plants utilize a suite of complex photoreceptor proteins to perceive surrounding red/far-red (phytochromes), blue/UV-A , and UV-B light (UVR8). While genomic studies have also shown that light induces extensive reprogramming of gene expression patterns in plants, molecular genetic studies have shown that manipulation of one or more photoreceptors can result in modification of agronomically beneficial traits. Such information can assist researchers to engineer photoreceptors via genome editing technologies to alter expression or even sensitivity thresholds of native photoreceptors for targeting aspects of plant growth that can confer superior agronomic value to the engineered crops. Here we summarize the agronomically important plant growth processes influenced by photoreceptors in crop species, alongwith the functional interactions between different photoreceptors and phytohormones in regulating these responses. We also discuss the potential utility of synthetic biology approaches in photobiology for improving agronomically beneficial traits of crop plants by engineering designer photoreceptors. After seed germination in the soil, etiolated growth enables the germinated seedling to grow toward the soil surface in search of light. Upon exposure to light, the seedling undergoes photomorphogenesis characterized by de-etiolation, chlorophyll synthesis and development of chloroplast all of which enable the seedling to establish itself as an independent autotroph. Quality as well as quantity of incident light influence the developmental and growth of plants . ResearcPlant growth and development involves complex signaling networks which are tightly regulated by genetic and environmental factors. These factors influence a plant’s ability to germinate, adapt, survive, and reproduce in natural conditions. In agriculture, the genetic constitution of different crop species have been altered via various crop breeding programs for enhancing their survival and productivity under different environmental conditions . RegulatFigure 1). Such responses include stimulation of elongation growth, coupled with reduced leaf development, increased apical dominance, and a reduction in branching , play an essential role in regulating seed germination and seedling establishment in agriculturally important crops such as rice and tomato , while iranching . While sranching .PHYA and PHYB, two of the more functionally important phytochrome genes in plants, show extreme SAR  is a key component of the radiation environment that is utilized by plants as a signal for UV acclimation and survival in sunlight . The dist stages . In adult stages , Plants t stages  alongwitt stages . Converst stages . Furthert stages , which ct stages , which it stages .GmZTL3 a homolog of Arabidopsis ZTL has also been suggested to function as a photoreceptor controlling timing of flowering  photoreceptors referred to as ZEITLUPE/FLAVIN-BINDING KELCH REPEAT, F-BOX1/LOV KELCH PROTEIN2 (ZTL/FKF1/LKP2) having both photoreceptor and F-box protein activities within the same protein . Intereslowering , a critiTable 2). These interactions become especially relevant in the field where plants are subject to uncontrolled environmental conditions of light, temperature, moisture, etc. A detailed understanding of such functional interactions between photoreceptors would further enable researchers to utilize the information for enhancing productivity of crop plants for food and non-food applications.Since natural light is composed of different wavelengths, higher plant growing under natural conditions will invariably have activation of more than one photoreceptor at the same time. Such simultaneous activation could thus result in signaling networks where action of one photoreceptor can be affected by the activity of other photoreceptors. While some developmental responses in plants are specifically triggered by activation of a single photoreceptor, there are several instances where signaling networks downstream of light perception of more than one photoreceptor of the same or different family are co-ordinately activated to ensure proper growth and development. Such developmental processes include seedling germination , photomoLight is an important signal that functions as a developmental switch in germination and photomorphogenesis. Seedling emergence from soil and subsequent photomorphogenic development involve a vast array of photoreceptors which enable the establishment of emergent seedlings. Activation of these photoreceptors by light results in a range of signaling events which co-ordinate plant growth and development that direct seedling emergence from soil and establish them as autotrophs. There is growing evidence that most of these signaling cascades involve interaction of light and phytohormones signaling pathways . Since tPHYB or PHYC cause moderate alteration in flowering while lines carrying mutations in PHYA coupled with mutations in either PHYB or PHYC show very early flowering . Broadly, flowering plants are categorized into those that flower when length of daylight exceeds a particular length  or long-day plants, those that flower when length of daylight is below the critical length or short-day plants and those that flower independent of the critical length or day-neutral plants. phyA, phyB, and cry2 were the first photoreceptors reported to be involved in regulating the timing of flowering in Arabidopsis as well as in crop plants. In rice, mutations in lowering . Under llowering . A studyynthesis , all of ynthesis . Of theslowering . While totropism ,b as welotropism . Howeverynthesis  and alsoynthesis . The invynthesis  is furthynthesis , the overipening  implyingFigure 2). As the mechanisms of signal integration of light and hormone signaling pathways are starting to become clearer, we will be in a better position to understand how light signaling interacts with hormone signaling to regulate traits of agronomic interest in plants.In plants, while the effect of light on photomorphogenesis and photosynthesis has been known for a long time, it is now becoming increasingly evident that light signaling is also an integral component in determining the outcome of plant-pathogen interactions . SeveralThe myriad developmental processes regulated by light suggest that the manipulation of genes involved in light signaling pathways could be a viable tool for crop improvement . Rapid aGene targeting via site-directed mutagenesis is a technique that is commonly used in molecular biology to introduce mutations in defined site(s) on the genome. Apart from its utility in studying gene function, the versatility of these techniques also enables researchers to produce gene knockouts or point mutations in plants which can be used for molecular breeding purposes. For a more detailed summary of the various gene targeting strategies in higher plants via site-directed mutagenesis, the reader can refer to Table 3). As gene editing techniques become more precise, the modulation of photoreceptor activity by engineering designer photoreceptors provides novel opportunities for improving productivity of crop plants. While different engineered photoreceptor systems may require different designs for optimal function (For many centuries, humans have been constantly modifying plants that are beneficial to them. With advancements in crop improvement practices, modification of plant characteristics that were beneficial especially in terms of yield, were favorably targeted. For many decades, traditional breeding practices along with mutation breeding programs have been instrumental in modifying agricultural traits in crop plants. However, a growing global population coupled with altered weather patterns, present multifaceted challenges to future agricultural production both for food and non-food applications. Synthetic biology has emerged as a viable technology for rapid, precise, and robust engineering of organisms for useful societal purposes . Synthetfunction , such phTable 1, alterations in gene function arising due to mutations or altered expression levels of photoreceptors can produce agronomically desirable traits in crops. While research on crops is gaining momentum, the rapid pace of research in Arabidopsis and other established model species is continually contributing large amounts of information on photoreceptor signaling which is yet to be translated to research in crops. However, the information gained from such studies can assist researchers to engineer photoreceptors via genome editing technologies to alter expression or even sensitivity thresholds of native photoreceptors for targeting aspects of plant development that can confer superior agronomic value to the engineered crops. While genome editing in crop plants may have perceived safety concerns (Genomic studies have shown that light induces extensive reprogramming of gene expression patterns in plants . The emeconcerns  which woconcerns , the myrEK designed and directed the study, OM and EK carried out the study, EK wrote the manuscript. All authors read and approved 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.


Studies on the relationship between feedback and creative performance have only focused on the feedback-self and have underestimated the value of the feedback environment. Building on Self Determined Theory, the purpose of this article is to examine the relationship among feedback environment, creative personality, goal self-concordance and creative performance. Hierarchical regression analysis of a sample of 162 supervisor–employee dyads from nine industry firms. The results indicate that supervisor feedback environment is positively related to creative performance, the relationship between the supervisor feedback environment and creative performance is mediated by goal self-concordance perfectly and moderated by creative personality significantly. The mediation effort of goal self-concordance is significantly influenced by creative personality. The implication of improving employees’ creative performance is further discussed. The present study advances several perspectives of previous studies, echoes recent suggestions that organizations interested in stimulating employee creativity might profitably focus on developing work contexts that support it. The employee’s creative performance is the main source of promoting innovation, enhancing competitiveness, and getting competitive advantage of enterprises . CreativThe reasons that researchers conclude about inconsistent results between feedback and creative performance are: first, according to valence, source, and style, feedback is taken a dyadic approach to study its role in creative process, and that it is focused on how isolated feedback interventions impact creative performance  and compIn order to fully understand how feedback affects work-related outcomes, researchers should not only consider single feedback interventions, but also consider the broader psychological feedback context in which these feedback interventions take place . ResearcWith respect to motivation mechanism, in the realistic work environment, purely intrinsically motivated behaviors are limited and rare . In contIn regard to individual difference, because employee’s individual characteristics can influence the responses in a particular environment , the oneThe main purpose of this research is to solve these problems by analyzing how feedback environment impacts creative performance via self concordance and analyzing the moderating role of creative personality.First, the primary literature has shown that some dimensions of the feedback environment influence the employees’ creative performance. For instance, with regard to feedback delivery, research has indicated that if feedback is delivered supportively, then the purpose for informing employees about their contribution is more apparent; thus, the likelihood of improving creative performance is increased . RegardiSecond, an upstanding feedback environment is both supportive and incentivizing , which iHypothesis 1: Supportive supervisor feedback environment will relate positively to creative performance.In view of the SDT , goal seFirst, goal self-concordance refers to a broad continuum of goal-based motivations, which integrates the internal and external motivations, assesses the degree to which internalization of work goals arrive, and assimilates the extent of self-goals. SDT acknowledges that an individual’s behavior is not purely motivated by intrinsic elements , and it Second, SDT suggests that feedback could promote the internalization of employees, followed by goal self-concordance . The feeAt last, employees could not only appreciate the messages to finish tasks but also sense its significant meaning in the favorable feedback environment. This type of supportive and encouraging behavior includes the following actions: offering useful suggestions, monitoring the employees’ feelings when receiving supervisor feedback, letting the employees know that their work is acknowledged, and responding rapidly . In shorHypothesis 2: Supportive supervisor feedback environment will relate positively to goal self-concordance.Previous studies have shown that employees’ level of goal self-concordance is related to their happiness, job satisfaction, and performance . Bono anFirst, as Furthermore, it is easier for individuals to find some alternatives to solve problems when they pursue self-concordant work goals, such as using non-traditional approaches to solve their work problems, which leads to more creativity . For exaBuilding on the arguments for the above two assumptions and the empirical evidence about how self-concordance affects creative performance in contextual factors , goal seHypothesis 3: Goal self-concordance mediates the relationship between employees’ perceptions of the supervisor feedback environment and creative performance.According to Field theory, behavior is a function of the individual and the psychological environment, and the mechanism of how the feedback environment impacts creative performance should consider individual differences. Creative personality is an integrated structure that unifies intelligence factors and non-intellectual factors, which determines people’s creativity. Prior research has shown that creative personality and context factors interact to influence the creative performance of the staff . Oldham Hypothesis 4: creative personality will moderate the strength of the mediated relationship between supervisor feedback environment and creative performance via goal self-concordance, such that the relationship will be stronger when employee is high creative personality than low.Figure 1).We have developed moderated mediation hypotheses for supervisor feedback environment and build up our research model  and their supervisors (25), on average one supervisor evaluated nearly seven employees. Employees and their supervisors provided data on separate questionnaires and on different occasions.To avoid common method bias, data were collected from two sources: the employees and their supervisors. The employees filled out a questionnaire that included items measuring the independent variables, mediation variables, demographics, his or her name and supervisor’s name. In a separate questionnaire, each employee’s supervisor rated the employee’s creativity. The supervisors assigned to complete the rating forms were those who had plenty of opportunity to observe their employees’ creative performance.We assigned an identification number to each employee and his or her supervisors to match the employee questionnaires with the responses of their supervisors. They completed the questionnaires during their work hours and then returned them. One hundred and sixty-two usable dyads were returned, giving a response rate of 94%. Demographic information indicated that there were 95 male employees (58.6%) and 67 female managers (41.4%) in the sample. More than half of the employees were 20-30 years of age, 95% of the participants were under 40 years old; 56% of the participants held a bachelor’s degree or above; 63% of the participants worked for less than 3 years, 81% had worked for less than 5 years.This study was reviewed and approved by of American Psychological Association Ethics Committee Rules and Procedures, APA Ethics Committee with written informed consent from all participants. All participants gave written informed consent in accordance with the Declaration of Helsinki.The measure items used in the present study were primarily developed in English; thus, to ensure cross-linguistic equivalence, we translated all scale items into Chinese and then translated them back into English by means of two bilingual (English–Chinese) professional translators .We measured the supervisor feedback environment using We measured goal self-concordance by using The 30-item Creative Personality Scale  of the AConsistent with prior studies, we used supervisor ratings to assess employees’ creative performance . Using 1Consistent with previous creativity research e.g., , we contTable 1), indicating that the four variables show a good discriminant validity. In summary, the CFA results suggest that the respondents could distinguish clearly the constructs under study.To examine the convergent and discriminant validity of the key variables, we employed structural equation modeling to conduct the discrimination validity of confirmatory factor analysis (CFA) using AMOS 21.0. We assessed overall model fit by goodness-of-fit indices including the goodness fit index (GFI), normalized fit index (NFI), relative fit index (RFI), comparative fit index (CFI), incremental fit index (IFI), and root mean square error of approximation (RMSEA). A reasonable model fit is indicated when the CFI and IFI are above 0.90 and the RMSEA is below 0.08 . AccordiTable 2 presents the means, standard deviations, and correlations among the study variables. An inspection of the correlations reveals that the supervisor feedback environment  is positively related to self-concordance and also positively related to creative performance . The results also indicate that goal self-concordance is positively related to creative performance  and also positively related to creative personality . In addition, creative personality related positively to goal self-concordance  and creative performance . The results of correlation analysis generally supported the positive effects of supervisor feedback environment on creative performance.Table 3, after controlling for the effect of participants’ demographics , supervisor feedback environment significantly predicted goal self-concordance .Further analyses were conducted to better estimate the overall contribution of supervisor feedback environment in predicting outcome variables as well as the mediation role of goal self-concordance. To examine whether goal self-concordance served as a mediator for the relations between supervisor feedback environment and creative performance, we adopted the procedure proposed by Table 2, supervisor feedback environment severed as the significant predictor of creative performance . When adding goal self-concordance to the model, goal self-concordance also significantly predicted employment status career adaptability , but the effect of the supervisor feedback environment on creative performance  became non-significant. To calculate the indirect effects, we adopted the SPSS micro PROCESS  demonstrated that the indirect effect was significant . Bootstrap results confirmed the Sobel test, with bootstrap 95% confidence interval of 0.02–0.12 around the indirect effect not containing 0. Taken together, Hypothesis 1-3 received full support.Logistic regression was conducted to predict creative performance. As showed in  PROCESS . ResultsTo test the moderated mediation (Hypothesis 4), we examined four conditions : (a) sigTable 3 presents moderated regressions results of creative personality on goal self-concordance and creative performance. It shows that the interaction term for supervisor feedback environment with creative personality was significant in predicting goal self-concordance . To further understand the moderating effect, we plotted the interaction effect using one standard deviation above and below the mean of creative personality  than low creative personality (1 standard deviation below the mean).The results for Hypothesis 3 supported Condition 3, in which goal self-concordance was positively related to creative performance. Hence, results based on the first three conditions indicate that creative personality could moderate the mediation of goal self-concordance for the supervisor feedback environment–creative performance association. z statistic for the conditional indirect effect (Condition 4). More specifically, we operationalized high and low levels of creative personality as one standard deviation above, moderate level and below the variable’s mean score. Results in Table 5 show that the conditional indirect effect of supervisor feedback environment was stronger and significant in the high creative personality  and in moderate level of creative personality , but was stronger and not significant in the low creative personality condition . Taken together, Hypothesis 4 was supported.To further validate findings of moderated mediation relationships, we used The present study contributes to the literature on the feedback-creativity relationship by highlighting employees’ perceptions of the broader feedback environment as a new avenue for enhancing employee creative performance. Our results show that employees’ perceptions of a supportive supervisor feedback environment indirectly influence their level of creative performance through the internalization of work goals. In addition, we indicate that creative personality moderates this mediation, such that the more creative personality employees are at work, the stronger this relationship is.Regarding relevant research on supervisor feedback environment, a positive supervisor feedback environment provides useful information to help employees in completing their work . TherefoThe present study advances several perspectives of previous studies. First, our exploration of the impact on burnout of feedback as a multi-dimensional variable helps resolve the inconsistencies of previous studies resulting from only considering feedback from single dimension. Our assumption that employees’ perceptions of the expanded feedback environment indirectly influence their creative performance emphasizes the relevance of studying more aggregate psychological feedback context within the creativity domain. Traditionally, the literature on the feedback-creativity relationship has focused on the effect of specific feedback components, such as feedback valence and feedback delivery, on creative performance . The shiSecond, our results add to the creativity literature by identifying goal self-concordance as a mediating mechanism between perceptions of a favorable supervisor feedback environment and creative performance. While prior theorizing within the creativity and the feedback–creativity domain has focused on intrinsic motivation as a motivational mechanism between contextual factors and creative performance , empiricThird, by introducing creative personality as a moderator of the mediated feedback-creativity relationship, this study sheds light on an important boundary condition that strengthens the relationship between feedback and creativity. While these findings are in line with previous research by Finally, The results also have some contribution to SDT. SDT proposes that people who are high in the autonomous causality orientation tend to be more autonomously motivated in a particular situation and to show positive performance and well-being outcomes, but rarely research test whether this orientation would influence creative performance through goal self-concordance. Different goals need different trains. In the creativity literature, Our study echoes recent suggestions that organizations interested in stimulating employee creativity might profitably focus on developing work contexts that support it. As discussed by Our results also suggest that if creative performance is the organization’s goal, there is value in stimulating effective feedback exchanges by focusing on the supervisor–employee relationship. In the enterprise management practice, it is essential not only to achieve flow of top-down feedback but also ensure the feedback in parallel communication. In the enterprise practice, if an employee needs complete creative task, the supervisor can choose an employee who has a high creative personality.Although our findings have made some contribution to answering several recent questions in the feedback-creative performance literature, this study has several limitations.One limitation is the sample. The small sample size reported here may have affected the current results. However, this small sample size coupled with the significant results suggests that the current findings are reliable. our data were from an organization in China, and therefore the external validity of our findings may not be accurate. Our analysis does not preclude different interpretations in other settings since organizational or cultural difference may influence employees’ attitudes and behaviors. Future studies should add more samples, which will make the results more specific and representative. To improve the generalizability of our results, future research should replicate our model employing multi-organization and cross-national samples.Second, this study relies on cross-sectional data; therefore, no causal relationships of the studied variables can be unambiguously established, because the longitudinal research design may have other explanations. It may be that some of the relationships we found may operate in reverse. For example, it may be that a favorable feedback environment does not promote internalization of work goals, but that when employees pursue self-concordant work goals and thus demonstrate high levels of ownership with regard to their work goals, supervisors are more likely to provide them with well-construed and high-quality feedback and to be receptive and available when these employees seek feedback. To ascertain causality, future studies can start from similar experimental designs or from time-series designs to collect longitudinal data that clarifies the causal relationships among the studied variables.Third, prior studies have demonstrate that supervisors engaged in close monitoring and unsupportive coworkers , rewardiLast, the coworker feedback environment is also very important. In a work field where employees usually have a lot of contact with coworkers, the coworkers’ feedback environment may play a different role in affecting creative performance. By incorporating coworkers as well as supervisors as important feedback sources, some study recognized and found support for the importance of coworker feedback with regard to creative performance. By showing that employees’ perceptions of a favorable coworker feedback environment stimulate them to be creative throughout their goal striving, in future not only we should focus on supervisor feedback and feedback as a generic construct , but alsJZ provided substantial contributions to the research conception and design. ZG and SZ analyzed and interpreted the data. ZG, SZ, and YZ wrote the paper, JZ provided critical revisions of the paper. ZG and SZ both attended to the revision of the paper. JZ and ZG both approved of this version of the paper to be published.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.


Habronattus jumping spiders, males frequently court heterospecifics with whom they do not mate or hybridize; females are larger and are voracious predators, posing a severe risk to males who court indiscriminately. In this study, we examined patterns of misdirected courtship in a natural community of four sympatric Habronattus species . We used direct field observations to weigh support for two hypotheses  to explain how these species reduce the costs associated with misdirected courtship. We show that, while the four species of Habronattus do show some differences in microhabitat use, all four species still overlap substantially, and in three of the four species individuals equally encountered heterospecifics and conspecifics. Males courted females at every opportunity, regardless of species, and in some cases, this led to aggression and predation by the female. These results suggest that, while differences in microhabitat use might reduce misdirected courtship to some extent, co-existence of these four species may be possible due to complex communication . This study is the first to examine misdirected courtship in jumping spiders. Studies of misdirected courtship and its consequences in the field are limited and may broaden our understanding of how biodiversity is maintained within a community.Male courtship display is common in many animals; in some cases, males engage in courtship indiscriminately, spending significant time and energy courting heterospecifics with whom they have no chance of mating or producing viable offspring. Due to high costs and few if any benefits, we might expect mechanisms to evolve to reduce such misdirected courtship (or ‘reproductive interference’). In  In many animals, courtship displays have evolved to facilitate successful mating, often by providing information about a potential mate’s location, sex, species, or quality as a mate (reviewed in ). Yet, cconspecific courtship is risky; if heterospecific courtship never results in offspring, we might expect strong selection on males to avoid it. Despite a growing body of literature addressing misdirected courtship in animals, few studies have considered the potential cost of predation from the female that is being courted  are an excellent group in which to examine mechanisms that reduce heterospecific courtship because, for male jumping spiders, the consequences of courting a female of the wrong species can be severe. Females of most salticid species are generalist predators and thus courting males, even of the same species, can become either a potential mate or prey item; as such, cannibalism from conspecific females and predation from heterospecific females is an important risk (reviewed in ). Even cted . Such indiscriminate male courtship behavior may be responsible, in part, for driving the patterns of hybridization seen among some Habronattus species that overlap in the field . GroS1 FigH. hirsutus with a completely black face (a) and a male H. hirsutus with a bright red facial patch (b). Over 95% of the males observed in our focal population at the Rio Salado Habitat Restoration Area (RSHRA) population were the black-faced form but occasionally males with bright red facial patches were found. All of the focal H. hirsutus males used for our study were the black-faced form.(a) Male (TIF)Click here for additional data file.


This articles serves as a guide to using cost-effectiveness analysis (CEA) to address health equity concerns. We first introduce the "equity impact plane," a tool for considering trade-offs between improving total health—the objective underpinning conventional CEA—and equity objectives, such as reducing social inequality in health or prioritizing the severely ill. Improving total health may clash with reducing social inequality in health, for example, when effective delivery of services to disadvantaged communities requires additional costs. Who gains and who loses from a cost-increasing health program depends on differences among people in terms of health risks, uptake, quality, adherence, capacity to benefit, and—crucially—who bears the opportunity costs of diverting scarce resources from other uses. We describe two main ways of using CEA to address health equity concerns: 1) equity impact analysis, which quantifies the distribution of costs and effects by equity-relevant variables, such as socioeconomic status, location, ethnicity, sex, and severity of illness; and 2) equity trade-off analysis, which quantifies trade-offs between improving total health and other equity objectives. One way to analyze equity trade-offs is to count the cost of fairer but less cost-effective options in terms of health forgone. Another method is to explore how much concern for equity is required to choose fairer but less cost-effective options using equity weights or parameters. We hope this article will help the health technology assessment community navigate the practical options now available for conducting equity-informative CEA that gives policymakers a better understanding of equity impacts and trade-offs. Health equity has risen to prominence on policy agendas in the wake of the universal health coverage movement In recent years there have been a number of methodological advances in this area, which have been developed into practical tools, including extended cost-effectiveness analysis and distributional cost-effectiveness analysis Implicitly or explicitly, all CEA studies already incorporate social value judgments about equity—for example, in scoping and methodologic decisions about the relevant policy options and comparators, which costs and effects to measure, how to compare costs and effects of different kinds, how to aggregate costs and effects for different people and organizations, how to value future costs and effects, and so on We focus on two general categories of policy concern for health equity, which can both be used to address a wide range of more specific concerns: 1) reducing social inequalities in health and financial protection from ill-health; and 2) prioritizing the severely ill. Within the first category, our illustrative examples focus mainly on distributional impacts according to socioeconomic, ethnic, and sex groups, although the methods described are applicable to other differences in health-related outcomes that policymakers may consider unfair, including differences by geographical location, disability, mental illness, and other social variables.First, we introduce two key concepts that underpin the economic approach to health equity analysis: 1) health equity trade-offs and 2) net equity impact. We then describe two approaches to conducting equity-informative CEA: 1) equity impact analysis, which quantifies the distribution of costs and effects by equity-relevant variables; and 2) equity trade-off analysis, which quantifies trade-offs between improving total health and other equity objectives.The policy objective underpinning conventional CEA can be thought of as a health equity objective: the quasi-utilitarian objective of maximizing total health in the general population Population-level health gain is simply the unweighted sum total of all individual health gains, based on the standard value judgment that “a QALY is a QALY.” This also allows the calculation of an incremental cost per QALY gained, or per DALY averted, of one policy option compared with another. A cost-increasing policy option can be considered cost-effective if its cost per unit of health gain compares favorably with alternative ways of using resources. This recognition of opportunity costs—that resources used in the provision of a program would have generated value if used elsewhere—is fundamental to CEA.Every benefit attributed to a program must be assessed relative to those displaced when resources are diverted from alternative activities. In a public health system with a fixed budget, the displaced activities will comprise alternative health programs that would have produced alternative health benefits. Cost-effectiveness can then be defined as a test of whether a program will improve total health. A cost-effective policy will have a positive net health impact because its health gains will outweigh the health losses that result from shifting expenditure away from other health programs. By contrast, a cost-ineffective policy will have a negative net health impact because the health losses that result from shifting expenditure away from other health programs will outweigh the health gains.CEA can thus help decision makers to choose cost-effective investments that increase total health and avoid cost-ineffective investments that reduce total health. This interpretation of opportunity costs in terms of forgone health benefits is more problematic if there is no fixed health budget. Opportunity costs then may fall instead on household consumption (via increased taxes or insurance premiums) or on reductions in public expenditure on programs not primarily designed to improve health. Regardless, thinking about trade-offs between cost-effectiveness and health equity is useful even if the test of cost-effectiveness, or value for money, is not interpreted in terms of health maximization.The health equity impact plane in The horizontal axis shows the net health equity impact of the program. This refers to the net impact on the alternative health equity objective, again after allowing for program opportunity costs as well as program benefits In Many policies do indeed fall into quadrants I and III. In low- and middle-income countries, for example, investments in high-cost hospital treatments may fall into the “lose-lose” quadrant of being neither cost-effective nor likely to improve health equity insofar as they deliver small health gains per unit of cost and disproportionately benefit well-off groups In some cases, however, socially disadvantaged groups may gain less than advantaged groups from a decision to fund a particular medical technology as a result of factors such as unequal access to or quality of health care. As a case in point, access costs may be relatively high and health care coverage relatively low in remote, rural areas that lack well-resourced health facilities. In such cases, there may be trade-offs between cost-effectiveness and health equity. Policy makers may wish to consider redesigning delivery strategies to increase utilization and quality in disadvantaged communities, and may even wish to consider equity-oriented strategies that are less cost-effective than standard delivery strategies and lie in the “lose-win” quadrant.Equity trade-offs can also arise in relation to preventive health interventions that seek to change behavior—including participation in screening and vaccination campaigns, as well as changes in smoking, diet, physical exercise, and other lifestyle behaviors—insofar as it may be more challenging and costly to change behavior in relatively disadvantaged communities, so preventive interventions may have more success in improving health in advantaged communities This health equity impact plane provides a simple illustration for understanding when trade-offs are necessary. It can also be operationalized to present this information to decision makers, which has been done in two recent examples from the United Kingdom When assessing equity impacts, both the distribution of benefits and the distribution of opportunity costs are important. The forgone health benefits that could have been generated through the next-best alternative may be unequally distributed, and this distribution is required to estimate the net distributional health impact of a program The potential health equity implications of alternative sources of funding are illustrated in Cost-effectiveness analysis can be used to examine the distribution of benefits and opportunity costs from alternative policy options, broken down by one or more variables of concern to policymakers from an equity perspective. At the request of the UK health minister, for example, Holmes et al. Disease Control Priorities, third edition (DCP-3) project (http://www.dcp-3.org) In low- and middle-income countries, a common approach to equity impact analysis is extended CEA (ECEA), developed by the As an illustration of ECEA, Verguet et al. ECEA has now been applied to the study of about 20 policy interventions in different low- and middle-income countries, producing breakdowns of costs, health benefits, and financial risk protection benefits by socioeconomic quintile group Another framework for equity impact analysis is distributional CEA (DCEA), developed by the University of York. This approach focuses on the distribution of health effects and pays careful attention to the distribution of health opportunity costs from displaced expenditure within a fixed health care budget. Asaria et al. DCEA allows multiple inequality impacts on different social groups to be combined in the same analysis and compared in magnitude. It also aggregates all costs and effects into the common metric of net health benefits as well as presenting findings in a disaggregated form. This allows the construction of summary measures of net health equity impact that can be plotted on the horizontal axis of the equity impact plane, rather than reliance on judgments based on disaggregated data on the distribution of costs and effects. If required, this equity impact metric can then be weighed against the cost-effectiveness metric  on the vertical axis using an overall equity-weighted index of social welfare that combines concern for both equity and cost-effectiveness. As discussed later, we do not propose using an index of this kind as an all-purpose algorithm for decision making. Rather, we recommend sensitivity analysis using different equity weights to explore the implications of alternative views about the appropriate trade-offs between improving total health and reducing health inequity. A limitation of DCEA is that, like conventional CEA, it does not examine effects on financial risk protection. However, this limitation may be less important in countries like the United Kingdom where few people suffer impoverishment as a result of medical costs Equity impact analysis can also be conducted outside the context of CEA and the aforementioned ECEA and DCEA frameworks. Bajekal et al. Another form of distributional impact analysis that is typically conducted outside the context of CEA is known as benefit-incidence analysis. This analysis looks at the benefits of public health care spending as a whole for different social groups. It generally examines only health care consumption and coverage rather than health outcomes, and looks at the average benefits of current expenditure rather than the marginal benefits of potential future changes in expenditure. Some recent benefit incidence analyses, however, have used data on subnational variation and change in expenditure and outcomes to estimate the health outcomes of marginal changes in spending in a way that could be used more directly to inform priority setting Equity trade-off analysis examines trade-offs between improving total health and other equity objectives not usually addressed by CEA. The two main approaches to equity trade-off analysis—equity-constraint analysis and equity-weighting analysis—are described below.A simple approach to equity trade-off analysis is to count the cost of choosing fairer but less cost-effective options. This can be thought of as an equity constraint analysis because equity is treated as a constraint on the pursuit of health-maximizing cost-effectiveness. For example, Cleary et al. Cleary et al. The health loss associated with choosing the more “equitable” option gives an indication of the value the decision maker places on this equity constraint When programs fall in the “win-lose” or “lose-win” quadrants of the health equity impact plane, decision makers face difficult trade-offs between equity and cost-effectiveness. Equity-weighting analysis can be used to help policy-makers assess these trade-offs by quantifying how much concern for equity is required to choose cost-ineffective options that improve equity (programs in the “lose-win” quadrant) and cost-effective options that harm equity (programs in the “win-lose” quadrant). This can be done using “equity weights” for health benefits that apply to people with different characteristics or using an “equity parameter” that quantifies the degree of concern for reducing health inequity versus improving total health.Different characteristics of health policies and the people affected by them can be used as the basis for setting equity weights, and several different equity-weighting systems have been proposed Equity-weighting analysis also requires that all costs and effects be aggregated into a common metric to which weights can be applied, such as annual mortality risk, life years, QALYs, or DALYs. In addition, if decision makers are interested in impacts on relative inequality  as well as absolute inequality , then an estimate of the baseline distribution of health will be required because relative inequality impacts depend on the baseline levels as well as the absolute changes.In response to growing policy concerns about health equity, the tools of economic evaluation are being refashioned to provide useful evidence about health equity impacts and trade-offs. This article has introduced the key concepts that underpin the use of CEA to address health equity concerns. This article has also reviewed the main practical tools available for analyzing who gains and who loses from policy interventions  and for assessing equity trade-offs between improving total health and other health equity objectives not usually addressed by CEA . These approaches can also be thought of as a type of multicriteria decision analysis with two decision criteria—improving total health and improving health equity—and could be embedded within a wider multicriteria decision analysis that encompasses further decision criteria The methods we describe can be used to address most but not all of the equity concerns that routinely arise in HTA, including 1) concern for reducing inequalities in health-related outcomes by income, ethnicity, geographical location, disability, sex, and other social variables; and 2) concern for prioritizing severely ill patients, including “end-of-life” patients. “Fair innings”–type concerns to reduce lifetime inequalities can be addressed under both headings 1) and 2) by using lifetime health metrics. These methods, however, do not address other issues sometimes discussed in relation to equity  and have not yet been extended to analysis of inequality between current and future generations or the dynamics of social mobility Aligning the methods of CEA to address equity concerns is only one facet of the much larger question of how to design fair processes of decision making that appropriately address equity concerns More fundamentally, robust institutional structures, processes, and incentives are needed to ensure that decision makers take appropriate steps to reduce inequities in health. Analysis of the health equity implications of decisions cannot help to improve decision making if, for example, the analysis is poorly conducted or communicated, or based on the idiosyncratic value judgments of a narrow group of experts rather than the broader community of stakeholders, if policy advisers lack sufficient training to understand the findings, or if the conclusions are disregarded by decision makers who merely pay lip-service to health equity concerns.Using CEA to analyze equity impacts and trade-offs requires the same basic analytical skills needed for standard CEA. It is more demanding, however, in terms of data requirements because it requires social distributions of key parameters rather than population average values. Data limitations can be particularly severe in low-income countries that lack basic health information systems, such as vital statistics on births and deaths and hospital and primary care administrative data. As the DCP3 project has amply demonstrated, however, equity-informative CEA can successfully be performed in low- and middle-income countries using existing survey-based data sets, such as the demographic and health surveys, which include information disaggregated by socioeconomic status and geographical setting.An important frontier for future research is to provide better estimates of the distribution of opportunity costs. Work is ongoing to examine this distribution in England, drawing on existing research on variation in health expenditure and outcomes at a subnational level In the past, some authors have taken a skeptical view of the value of equity-weighting analysis due to the difficulty of securing consensus on an equity “algorithm” or “tariff” that rigidly prespecifies particular equity weights—for example, differential weights for individual health gains according to disease type , health characteristics  or social characteristics  Thus, we do see a role for equity-weighting sensitivity analysis as an aid to deliberation in the context of specific decisions in light of information on who gains and who loses. For example, the Dutch use sensitivity analysis around severity weighting in the economic evaluation evidence used to support decisions on inclusion in their basic health benefits package Unlike the methods of severity weighting, the methods of ECEA and DCEA for analyzing who gains and who loses from decisions are not yet widely known among the HTA community and are not yet widely used to inform decision making. These methods are now starting to be applied, however, and are gradually becoming more sophisticated


Animal research suggests that neural reward activation may be systematically modulated by sleep and circadian function. Whether humans also exhibit sleep and circadian modulation of neural reward pathways is unclear. This area is in need of further research, as it has implications for the involvement of sleep and circadian function in reward-related disorders. The aim of this paper is to describe the protocol for a pair of systematic literature reviews to synthesise existing literature related to (1) sleep and (2) circadian modulation of neural reward pathways in healthy human populations.A systematic review of relevant online databases  will be conducted. Reference lists, relevant reviews and supplementary data will be searched for additional articles. Articles will be included if (a) they contain a sleep- or circadian-related predictor variable with a neural reward outcome variable, (b) use a functional magnetic resonance imaging protocol and (c) use human samples. Articles will be excluded if study participants had disorders known to affect the reward system. The articles will be screened by two independent authors. Two authors will complete the data extraction form, with two authors independently completing the quality assessment tool for the selected articles, with a consensus reached with a third author if needed. Narrative synthesis methods will be used to analyse the data.The findings from this pair of systematic literature reviews will assist in the identification of the pathways involved in the sleep and circadian function modulation of neural reward in healthy individuals, with implications for disorders characterised by dysregulation in sleep, circadian rhythms and reward function.PROSPERO CRD42017064994The online version of this article (10.1186/s13643-017-0631-3) contains supplementary material, which is available to authorized users. There is a growing interest in moderators of the human reward system, with biological rhythms (sleep and circadian function) being a particular focus because of their potential interplay in mental disorders. Sleep and circadian function have been shown to be important in numerous reward-related disorders  but iThere is substantial evidence from animal research that circadian and sleep function modulates neural reward pathways. For example, Sleipness, Sorg and Jansen , 13 demoIn humans, neuroimaging methods, particularly commonly used functional magnetic resonance imaging (fMRI) paradigms, have potential to illuminate the putative sleep and circadian modulation of neural reward pathways. In fMRI, neural activity is inferred from changes in the blood-oxygen-level-dependent (BOLD) signal, premised on regional blood flow. A common approach to investigating neural reward functioning in fMRI is via presentation of reward stimuli within a task-based protocol . Reward Any synthesis of fMRI studies of reward must attend to the multiple methodological dimensions on which studies may differ. One advantage of using task-based imaging is that it allows for event-related and block-based tasks to temporally distinguish between these reward components. Block designs employ blocks of similar trial types which give higher power across many trials; event-related designs can distinguish between trials in a block, and separate out components within a trial . Reward The aim of this study is to synthesise existing research on the putative modulation of neural reward pathways by sleep and circadian function. An initial scoping of the literature strongly suggested that (a) these two modulation propositions would be best investigated separately to minimise heterogeneity and facilitate synthesis, and (b) there were sufficient studies in each area to support two separate systematic reviews. Therefore, the objective of this study is to conduct a pair of systematic reviews, driven by the following questions.What evidence is there for modulation of neural reward pathways by sleep?What evidence is there for modulation of neural reward pathways by circadian function?This systematic review will be written using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines Study methods. Studies will be included if they use naturalistic designs or experimental designs  to manipulate sleep or circadian function to examine neural reward functioning through fMRI. In addition, articles must be written in English and published in a peer-reviewed journal.(ii)Study participants. Studies will be eligible for inclusion if they include samples of human subjects of any age. In the sleep systematic review, studies that include insomnia, symptoms or disorders will be included if these quasi-experimental groupings formed the predictor variable, compared to another sleep comparison group. So too, in the circadian systematic review, delayed or advanced sleep-wake phase will be included if these symptoms or disorders are related to another circadian function comparison group. In both reviews, clinical samples with psychological or physical illnesses that may affect reward will be excluded. Studies using samples with neurological or physiological disorders that have a pronounced effect on sleep  or circadian function  will be excluded from both reviews. Studies that use pharmacological, acupuncture, transmagnetic stimulation or administered reward-related substances  will be excluded, as this intervention may affect both the sleep or circadian predictor variable and the neural reward activation outcome variable. Individuals who have diagnoses of disorders known to affect the reward system  will be excluded. Studies investigating altered reward response specific to a population  will also be excluded, on the grounds that they effectively add an additional interaction term to the two broad relationships of interest in this systematic review.(iii)Search strategy for study identification. Relevant health and neuroscience electronic databases  will be searched for articles from the database inception until October 2017. Reference lists of selected articles, relevant reviews and meta-analyses and supplementary data files will be examined to identify any additional articles. The search strategy includes examining the article title, abstracts and keywords for relevant criteria  and measure circadian phase through preformed chronotype  groups or use more endogenous markers of circadian function such as circadian genes, melatonin or cortisol levels.As seen in Tables Search term 2 identifies studies collecting data on the neural basis of reward, while search term 3 identifies reward stimuli that may be used in imaging studies. Neural reward activation as measured by fMRI will be the outcome variable of both the planned systematic literature reviews. Reward functioning can be examined as an outcome of reward tasks, or through resting state scans that examine brain regions or neuronal activity associated with rewards. Search terms will be broad, including terms for reward stimuli, neural reward regions of interest and whole-brain analyses in fMRI studies. Search term 4 identifies fMRI paradigms, with search term 5 excluding commonly used animals in sleep and circadian research, and limits to full articles that are already in press (search term 6). Search term 7 aims to identify studies that have searched for or identified neural reward regions or used an imaging paradigm with reward-based stimuli.Articles will be screened in two stages. Stage 1 (titles and abstract) will screen for inclusion and exclusion criteria  sleep systematic review and (2) the circadian systematic review  qualityAs we expect the studies to be heterogeneous in both the sleep and circadian systematic reviews and the operationalisation of reward variables, the main data analysis will follow a narrative synthesis of articles in both cases. Popay et al.’s  four-steCurrently, no systematic literature reviews have considered the impact of either sleep or circadian function on neural reward pathways. This is an important gap in knowledge, because recent empirical and theoretical evidence e.g. –36) have have36])We expect that the primary limitation of these systematic literature reviews will be heterogeneity across identified studies. The measurement of neural reward activation has not been standardised across studies, with different designs using different types of reward stimuli, and varied focus between reward stages (anticipation and outcome). In addition, some studies will investigate neural reward through stimuli-response paradigms while others use resting state data to speak to a neural preparedness to engage in reward behaviour. While all these studies may speak to a sleep and circadian modulation of neural reward activation, differences in study paradigms will be important qualifications on any synthesis. On the basis of the results of the narrative synthesis, however, we expect to be able to identify which protocols may best illuminate the sleep and circadian modulation of neural reward activation in future research.A final potential limitation of the literature is that few studies are expected to speak to both sleep and circadian function, which are known to be deeply interdependent. As such, this pair of reviews will emphasise that while it is scientifically important to examine sleep and circadian functioning separately, practically, these two studies will be confounded by the respective sleep or circadian process. As a result, these two systematic reviews can help inform future research ofsome of the ways that neuroimaging may better manage the interplay between sleep and circadian rhythms in their joint determination of neural reward functioning.Additional file 1:PRISMA-P  2015 checklist: recommended items to address in a systematic review protocol*. (DOC 60 kb)Additional file 2:Article Selection. (XLSX 8 kb)Additional file 3:Data Extraction. (XLSX 11 kb)