It has been shown that hepatocyte-like cells (HLCs) can be generated from iPSCs. Furthermore, human iPSCs (hiPSCs) can provide an unlimited source of human hepatocytes and hold great promise for applications in regenerative medicine, drug screening and liver diseases modelling. Despite steady progress, there are still several major obstacles that need to be overcome before iPSCs will reach the bedside. This review will focus on the current state of efforts to derive hiPSCs for potential use in modelling and treatment of liver disease.Tens of millions of patients are affected by liver disease worldwide. Many of these patients can benefit from cell therapy involving living metabolically active cells, either by treatment of their liver disease, or by prevention of their disease phenotype. Cell therapies, including hepatocyte transplantation and bioartificial liver (BAL) devices, have been proposed as therapeutic alternatives to the shortage of transplantable livers. Both BAL and hepatocyte transplantation are cellular therapies that avoid use of a whole liver. Hepatocytes are also widely used in drug screening and liver disease modelling. However, the demand for human hepatocytes, heavily outweighs their availability by conventional means. Induced pluripotent stem cells (iPSCs) technology brings together the potential benefits of embryonic stem cells (ESCs) ( Liver transplantation, the ultimate cell therapy, is presently the only proven treatment for many medically refractory liver diseases including end-stage liver disease and many inherited liver diseases. However, there is a profound shortage of transplantable donor livers. Regenerative medicine, which focuses on innovative approaches to repairing and replacing cells, tissues and organs, is undergoing significant revolution do to the unprecedented world-wide demand for organs. Many of the liver disease patients can benefit from cell therapy involving metabolically active cells. Cell therapies, including hepatocyte transplantation and bioartificial liver (BAL) devices, have been proposed as therapeutic alternatives to the shortage of transplantable livers. BAL is an extracorporeal supportive therapy developed to bridge patients with liver failure to liver transplantation or to recovery of the native liver. Hepatocyte transplantation is best suited for patients with metabolic liver disease for which smaller number of cells (<10% of liver mass) may be curative. Both BAL and hepatocyte transplantation are cellular therapies that avoid use of a whole liver. Hepatocytes are also widely used in drug screening and liver disease modelling. However, conventional methods of obtaining hepatocytes cannot meet clinical demand because of the shortage of donor livers from which high quality hepatocytes can be isolated. Furthermore, hepatocytes are not easily maintained in culture over extended periods of time. Moreover, hepatocyte propagation is minimal h factor . The demin vitro disease modelling, as these cells are easily accessible. iPSC technology brings together the potential benefits of embryonic stem cells (ESCs)  and addresses major ethical and scientific concerns of ESCs: (1) iPSCs bypass the ethical concerns of embryo destruction since they are produced from somatic cells in vitro without embryonic tissues or oocytes; (2) the immune-compatibility issues since they are generated from patient-specific cell types. The field of iPSCs has undergone tremendous growth, and differentiated cell types produced from a patient’s iPSCs have demonstrated many potential therapeutic applications, including their use in tissue replacement and gene therapy. It was shown that HLCs could be generated from iPSCs. Our previous study [in vitro. Therefore, in theory, hiPSCs could provide an unlimited source of human hepatocytes and hold great promise for applications in regenerative medicine, drug screening and liver diseases modelling. More recently, investigators have reported that HLCs differentiated from hiPSCs of patients with the inherited metabolic conditions may be used to model inherited liver diseases [The recent discovery that human induced pluripotent stem cells (hiPSCs) can be derived from human somatic cells through forced expression of defined transcription factors such as OCT4 (O), SOX2 (S), KLF4 (K), and c-MYC (M)  or O, S, NANOG (N) and LIN28 (L) , has renewed hopes for regenerative medicine and us study  and othediseases . Transplin vitro that possess some of the properties of mature hepatocytes. Song et al. [i.e., dimethyl sulfoxide (DMSO), dexamethasone) have been shown to extend the hepatic differentiation of iPSCs. The characteristics of pluripotent stem cell derived HLCs produced from various differentiation protocols have been critically reviewed [et al. induced efficient generation of highly differentiated HLCs from mouse iPSCs by a combination of cytokines and sodium butyrate [We will first address the hepatic differentiation of iPSCs. The term HLCs refers to cells produced g et al.  first dereviewed . Zhang ebutyrate . To prombutyrate . A limitbutyrate  reportedThe applications of iPSCs in liver diseases will be outlined in the vivo transplantation of HLCs to reverse lethal fulminant hepatic failure [iPSCs-Derived HLCs from normal individuals can be used in the establishment of cell banks for applications in regenerative medicine. Results from various studies have demonstrated the therapeutic potential of iPSCs-derived HLCs in liver diseases. Examples of the therapeutic potential of iPSC-derived HLC’s in rodent models include  failure , both th failure , reduced failure , and sta failure . DiseaseThe incidence of ALF is approximately 2500 cases per year in the United States and is much higher worldwide . The shoin vitro. Porcine hepatocytes are limited by immunogenic reactions resulting from the xenogenicity of porcine hepatocyte products and the possibility of xenozoonotic retroviral infection of patients with porcine endogenous retrovirus (PERV). However, the BAL membrane mitigates these concerns (the risk has never been quantified since no cases exist). Also of concern, immortalized cell lines lack essential functions, particularly the loss of urea cycle activity and lack of CYP enzyme expression [To date, the various cell types that have been used in BAL devices have included primary human hepatocytes, primary porcine hepatocytes, immortalized human cell lines, fetal liver cells, and stem cell-derived cells. Primary human hepatocytes are not available in sufficient amounts needed for clinical usage of BAL, exceeding 200 grams per treatment. Furthermore, primary hepatocytes are limited by the short duration that they retain functionality and viability pression . Transfepression . AlternaThe Fox group has reported an implantable BAL device containing HLCs derived from ESCs in a murine model of liver failure . They diex vivo gene therapy and cell transplantation has been considered [The liver is affected by many types of diseases, including inherited metabolic disorders. A major indication for hepatocyte transplantation is inherited metabolic liver diseases in children. The liver is a vital organ that represents a promising target for cell therapy, because of its ability to functionally integrate transplanted hepatocytes. Hepatocyte transplantation has been performed as a treatment for inherited liver diseases, either for bridging to whole organ transplantation or for long-term correction of the underlying metabolic deficiency . Howevernsidered ,32.in vitro and subsequently corrected A1AT in vivo. Transplantation of these iPSC-derived HLCs into immunodeficient mice was able to produce albumin and provide functional A1AT protein. This approach is significantly more efficient than other gene-targeting technology currently available, and does not require homologous recombination that leaves residual sequences in the targeted genome, and which leads to unintended consequences. These studies provide the first proof of principle that combining genetic correction in hiPSCs will generate clinically relevant cells for autologous cell-based therapies. iPSC-based gene/cell therapies have been applied in several animal models of liver-based metabolic disorders, with encouraging results. Yusa performed targeted gene correction of A1AT deficiency in iPSCs . Mutatioet al. [in vitro. Hence, their work describes an attractive model for studying the pathogenesis of WD that is valuable for screening compounds or gene therapy approaches aimed to correct the abnormality. This approach may be used for other diagnosis and correction of diseases susceptible to gene therapy. Genetically corrected, characterized lines of patient-specific iPSCs can be obtained in 4–5 months [Wilson’s disease (WD) is an autosomal recessive inborn error of copper metabolism. Mutations in the ATP7B gene (located in chromosome 13) are responsible for WD with a prevalence of 1 in 30,000–100,000 . Zhang eet al.  describe5 months .Liver tissue from patients is difficult to obtain and only reveals the disease aftermath, so several genetic disorders have been modeled in rodents and large animals . AlthougDisease modelling and drug screening are two immediate applications of the reprogramming technology and the resulting iPSCs differentiated cells. hiPSCs offer the ability to produce host-specific differentiated cells and thus have the potential to transform the study of infectious disease. HLCs derived from hiPSCs are particularly important for patients with liver diseases who cannot undergo surgical biopsy for the isolation of hepatocytes for transplantation. Disease modelling using iPSCs has been achieved for a variety of genetic diseases . in vitro. Thus, alternative models have been used. In vitro models using animal hepatocytes, human HCC cell lines, or in vivo transgenic mouse models have contributed to understanding the pathogenesis of HBV and HCV [Research on HBV or HCV has been hampered by difficulty in culturing human primary hepatocytes, which tend to dedifferentiate and lose hepatic function after a limited time  and HCV . Howeverin vitro models of hepatocytes for the study of HCV infection. Schwartz reported that hiPSC-derived HLCs support the entire life cycle of HCV [HCV is a prototypic pathogen for which host genetic factors have been implicated in modulating disease natural history and treatment response but whose functions remain poorly understood because of the lack of robust experimental systems. Yoshida  group ine of HCV , includiin vitro. iPSCs generated from patients who have monogenic inherited liver diseases and HLCs derived from iPSCs can be used as instruments to study the pathogenesis, disease mechanism(s) and possible cures for inherited liver disorders.Monogenic metabolic disorders of the liver are an ideal platform to explore the complexity of gene–environment interactions and the role of genetic variation in the onset and progression of liver disease. The use of human hepatocyte cultures may circumvent the problems of animal models of human diseases in some sense. Many traditional cell-based models have been used to study pathogenesis and to screen for candidate drugs. However, none has used symptom-relevant human cell types since these cells are difficult to obtain, and under monolayer culture conditions hepatocytes lose their liver specific functions within a few days. Disease-relevant cell types could accurately reflect disease pathogenesis in vitro disease model using iPSCs from WD patients [Current animal models of WD, including the toxic milk mouse, ATP7B2/2 mouse and Long-Evans Cinnamon rat, have provided very useful representation concerning its pathogenesis. However, physiological differences in phenotype between species limit the conclusions. As mentioned earlier, Zhang reported establishment of an patients . Recently, several liver-specific disease iPSCs, such as familial hypercholesterolemia (FH), glycogen storage diseases (GSD), Crigler-Najjar syndrome, A1AT deficiency and FH have been launched ,20. Theset al. demonstrate the possibility of modeling groups of diseases whose phenotypes are a consequence of complex protein dysregulation within adult cells. They derived iPSCs from the skin fibroblasts of patients with A1AT deficiency, GSD type 1a, FH, Crigler-Najjar syndrome type 1 and hereditary tyrosinemia. These iPSCs were then differentiated into HLCs, and characterized with special attention to the phenotypic properties specific to the corresponding diseases [et al.’s results demonstrated that hiPSCs-derived HLCs can be generated from multiple patients of varied genetic and disease backgrounds. Their system has proved to be an efficient methodology for screening of early-stage safety and therapeutic effect of liver-targeted compounds of potential relevance to the pharmaceutical industry. Rashid diseases . Rashid Ghodsizadeh  derived in vivo without losing their depth and breadth of specialized functions, and their limited availability, inter-donor differences, variable viability following isolation and rapid dedifferentiation of the hepatocyte phenotype in culture, particularly in the loss of CYP enzyme expression, impede their use. The pluripotent nature and the indefinite proliferative potential of ESCs are two major detractions of using ESCs in safety research in the fields of pharmacology and toxicology. However, directed differentiation of human ESCs to mature hepatocyte phenotypes in vitro could provide a readily available source of hepatocytes for early stage safety testing. Today, approximately 70% of the top 20 pharmaceutical companies utilize stem cells in their research and among these, 64% use human ESCs or their derivatives. Human ESCs and their derivatives do not encompass all the variances within a population or between ethnicities. Alternatively, ideal cells for drug screening could be obtained from iPSCs-derived HLCs. Since cells from patients with many different metabolism phenotypes must be tested to establish safety, hiPSCs-derived HLCs from this wide range of patients are expected to improve the drug discovery process [et al. used patient-specific iPSCs, screened the clinical-ready drug library (the JHDL), and identified and validated several hits for novel treatment of A1AT deficiency. With emerging new tools and technologies for gene manipulation, such as transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPRs), the feasibility of iPSC-based large-scale drug screening and highly efficient gene correction are anticipated. Integration of patient-specific iPSC-based screening in early stages of drug development will help to more accurately predict drug effects in humans, thereby significantly shortening the timeline and reducing the costs associated with clinical trials and high failure rates [in vitro systems based on hiPSCs [in vitro [in vitro.An added benefit of iPSCs is that they can be used for drug screening. Adverse drug reactions continue to pose a major problem to the clinician, the pharmaceutical industry and the regulatory authorities. Amongst the different types of adverse drug reactions, drug-induced liver injury (DILI) is the most prominent cause of patient morbidity and mortality. Thus, a multitude of new drugs need to be efficiently screened every year to assess their potential for toxicity. A major challenge for drug discovery is to develop appropriate preclinical models. Human primary hepatocytes have become a major liver model for hepatotoxicity tests. Unfortunately, as mentioned above, there is also a shortage of primary hepatocytes, and it is difficult to culture the hepatocytes  process ,21 and m process . Choi etre rates . In viewn hiPSCs . Moreovein vitro ,25. For A major technical hurdle that must be overcome before iPSCs can be implemented clinically is scalability, referring to the reproducible production of cells and their differentiated progeny on a large scale. All of the iPSCs lines established thus far have been generated and expanded under static tissue culture protocols, which are time-consuming and suffer from batch-to-batch variability. Additionally, monolayer culture provides limited numbers of iPSCs, only sufficient for research. Therefore, large scale systems for rapid expansion and maintenance of iPSC’s and their differentiated progeny are required for further research as well as future clinical applications.in vitro and in vivo. Chen described the use of microcarriers (MCs) in suspension culture bioreactors for iPSCs cultivation [Shafa reported expansion and long-term maintenance of iPSCs in a stirred suspension bioreactor (SSB) . Their stivation . Such a in vitro. Researchers have then termed such populations of cells derived from iPSCs or ESCs as hepatocyte-like cells or “HLCs”. HLCs indicates that only some of the properties of mature hepatocytes are present. In general, HLCs demonstrate lower rates of albumin production, incomplete urea cycle activity, lower CYP activity, immature mitochondria and lower oxygen consumption than primary hepatocytes [Prior to clinical application, HLCs derived from iPSCs must be compared to primary liver-derived cells and shown to have similar morphology and functional properties such as nutrient processing, detoxification, plasma protein synthesis, and engraftment after transplantation into a suitable animal model. While a wealth of studies highlight the promise of iPSC-derived HLCs for transplantation therapies, several obstacles remain. So far, neither ESCs nor iPSCs can differentiate to fully mature hepatocytes atocytes . HLCs alatocytes . MoreoveTo address the issue of maturation of HLCs from iPSCs, Ogawa  used a min vitro. The second class enhanced hepatocyte functions and promoted the differentiation of iPSCs-derived HLCs toward a more mature phenotype than what was previously obtainable. Gene expression profiles showed that HLCs treated with small molecules more closely resembled mature hepatocytes. Marked increases in the amount of albumin and CYP3A were seen with treated cells vs. untreated cells. Of particular interest, AFP was largely absent in treated cells. The identification of these small molecules may have an impact on several areas of research, including maturation of other iPSCs-derived cell types, expansion of other “terminally” differentiated cell types, and the translational potential of these cell types. Shan  used a set al. [Zhang et al.  directlyet al. demonstrated the direct induction of functional HLCs (named as iHep cells) from mouse tail-tip fibroblasts. Direct induction was accomplished by single step transduction of Gata4, Hnf1a and Foxa3, and inactivation of p19Arf. iHep cells show typical epithelial morphology, express hepatic genes, and perform hepatocyte functions. Notably, iHep cells showed an expression profile and hepatic function very similar to mature hepatocytes. Donor iHep cells repopulate the livers of FAH-deficient mice and rescued almost half of recipients from death by restoring liver functions. More importantly, iHep cells did not form tumors in immunodeficient mice. Their study provides a novel strategy to generate functional HLCs for the purpose of liver regenerative medicine [The induction of HLCs from iPSCs is a complicated process that will eventually be replaced by less complex technology. Huang medicine .et al. [Under current situations, transplantation of differentiated iPSCs into patients is risky as the residual undifferentiated iPSCs may retain the possibility of tumor formation. Therefore, the safety of clinical cell transplantation using differentiated hiPSC derivatives is contingent on novel methods to remove the undifferentiated iPSCs . To dateet al.  generateet al. . The EpCet al. ,51. Theret al. [in vitro applications such as drug screening. The present strategy should also be suitable for the purification of a broad range of cell types derived from either iPSCs or adult stem cells.Yang et al.  reportedin vitro is currently best tested by transplantation into immunodeficient rodent models. However, low efficiency of engraftment and proliferation of transplanted cells into the host parenchyma is a limitation that must be considered. Alternatively, a selective growth advantage of donor cells over endogenous cells may address this limitation. For example, in some models, the survival and/or proliferation of native hepatocytes is impaired by a genetic or inherited inability to regenerate, as in fumarylacetoacetate hydrolase (FAH)-deficient mice and urokinase (Alb-uPA) transgenic mice [Functionality of human cells differentiated nic mice ,54. Thesnic mice . Even winic mice . These rBesides the high variability and efficiency of differentiation, the pluripotent nature of ESCs and iPSCs results in production of cells types from different germ layers in most differentiation protocols. Thus, it is difficult to produce pure monolineage cultures of a desired cell type from iPSCs . An effein vivo step-wise developmental processes. Therefore, hiPSCs-derived hepatic progenitor-like cells (HPCs) might exist at an appropriate time point during similar in vitro differentiation steps. Yanagida reported that after differentiating with defined cytokines, HPCs from hiPSCs can be highly purified using cell surface markers CD13 and CD133. Further investigation revealed that hiPSCs-derived HPCs exhibit a long-term proliferative potential and maintain bipotent differentiation toward hepatocytic cells and cholangiocytic cells [in vitro expansion system of HPCs may contribute to regenerative therapies of liver diseases using functional human hepatic progenitor cells and hepatocytes. As noted earlier, differentiation from iPSCs toward hepatic lineage cells mimics ic cells . Their het al. [in vitro and in vivo. EP cell lines provide a powerful reagent to study gut tissues from a common multipotent endodermal progenitor and to optimize monolineage differentiation. Moreover, creation of EP cells from ESCs/iPSCs may represent a strategy to optimize the production of pure, non-tumorigenic cells for tissue replacement therapies.Recently, Cheng et al.  generatei.e., albumin secretion after implantation). This novel enrichment strategy provides a new platform for generating HLCs, and it may open new windows in the clinical and pharmaceutical application of these cells.Large scale production of HLCs is needed for their clinical application. As mentioned earlier, generation of HLCs from iPSCs is very time consuming under monolayer culture conditions. Vosough  reportedIt has been shown that the efficient function of multiple cell types, including hepatocytes and islet hormone-producing cells, is dependent on matrix-producing cells and endothelial cells that provide a 3D support structure and sufficient vascularization ,61,62. Tet al. transferred wild-type mouse iPSCs into the embryos of FAH-deficient mice to generate chimeric mice. These mice demonstrated the ability of iPSCs to develop into hepatocytes in vivo. Furthermore, recipient FAH-deficient mice were protected from developing hepatic failure [Because even a small number of undifferentiated cells can result in teratoma formation, a goal of iPSCs differentiation is to avoid production of undifferentiated cells. To date, no iPSCs-derived differentiation protocol has succeeded in yielding high purity HLCs that fulfill both functional engraftment and response to proliferative stimuli in the diseased liver. Alternative strategies are needed to obtain mature hepatocytes. To exclude compensation by hepatocytes not derived from iPSCs, Espejel  failure . Zhao al failure , which cTakebe and his team grew bioengineered liver tissue from hiPSCs by reprogramming human skin cells to an embryo-like state. The researchers first placed the iPSCs on growth plates in a custom medium. After nine days, the mature cells were characterized by biochemical markers as hepatocytes. Umbilical endothelial cells and mesenchymal cells were then added to the culture system to induce formation of blood vessels and stroma, respectively. Two days later, 3D tissues of 5 mm width were observed, which the researchers described as a “liver bud” at an early stage of liver development . The liv4-induced liver injured mice [in vivo. Chan reported that they directly transplanted iPSCs into CClred mice . They foin vivo hepatocyte incubator [ex vivo cell therapies depends on novel techniques to provide an abundant, high quality supply of functionally normal hepatocytes.Other possibilities for large scale expansion and maturation of HLCs include a genetically engineered large animal model  to servencubator . Prior sncubator . Exposurin vitro modeling, in vivo modeling of diseases, drug development, tissue engineering, and development of BAL devices. iPSCs also provide novel opportunities for autologous cell therapies and cell transplantation without risk of immune rejection. However, there are still several obstacles that need to be overcome before iPSCs reach the bedside. These include: (i) improved efficiency of iPSCs generation without viral integration; (ii) avoidance of animal feeders to culture hiPSCs; (iii) novel differentiation protocols for more efficient and economical production of mature cell types whose functionality are comparable to their in vivo counterparts; (iv) rapid differentiation protocols for emergent usage; and (v) enrichment of desired (mature) cells and removal of undesired (undifferentiated) cell types that have the potential for tumor formation in vivo. A recent report [iPSCs present exciting possibilities for the study and treatment of liver diseases. Areas of study and treatment include t report  that undA thorough preclinical assessment of iPSCs in suitable large-animal models is prudent to ensure that the proposed treatment with iPSC-derived cells is both safe and effective before testing in humans. It has reported recently that transplantation of undifferentiated iPSCs demonstrated T-cell-dependent immune response in recipient syngeneic mice due to the abnormal expression of antigens following genetic manipulation . Therefo


Sleep/wake disturbance is a feature of almost all common age-related neurodegenerative diseases. Although the reason for this is unknown, it is likely that this inability to maintain sleep and wake states is in large part due to declines in the number and function of wake-active neurons, populations of cells that fire only during waking and are silent during sleep. Consistent with this, many of the brain regions that are most susceptible to neurodegeneration are those that are necessary for wake maintenance and alertness. In the present review, these wake-active populations are systematically assessed in terms of their observed pathology across aging and several neurodegenerative diseases, with implications for future research relating sleep and wake disturbances to aging and age-related neurodegeneration. Over the course of healthy human aging, many aspects of sleep are significantly altered. Some of these alterations include decreased slow wave sleep (stages 3 and 4), changes in delta power, decreased homeostatic sleep responses, phase shifts, increased instances of sleep-disordered breathing, periodic limb movements, and sleep and wake fragmentation Bliwise RoennebeOhayon eFoley etConte et. Sleep fWake-active neurons are neurons that fire action potentials with high frequency during waking and very low frequency during sleep; these cells include orexinergic (de Lecea and Huerta Alzheimer’s Disease (AD) is the most common age-related neurodegenerative disease in the world, and it is the leading cause of dementia , the second most common neurodegenerative disease, is characterized primarily by a loss of movement and postural control resulting from decreased dopaminergic neurons in the area substantia nigra (SN). Degeneration in SN and other areas is accompanied by accumulation of Lewy Bodies, intracellular aggregates of α-synuclein  , degeneration of lower motor neurons leads to muscle weakness, paralysis, and eventual death Rowland . Up to 5Frontotemporal Lobar Degeneration (FTLD), a broad term encompassing a wide range of pathologies that all involve degeneration of the frontotemporal region, accounts for 10% of all instances of dementia  releases the neuropeptides orexin-A/hypocretin-1 and orexin-B/hypocretin-2, which coordinate wakefulness and alertness through direct communication with other wake active brain areas including locus coeruleus (LC), tuberomammillary nucleus (TMN), dorsal raphe nucleus (DRN), and ventral periaqueductal gray (vPAG)   called the Nucleus Basalis of Meynert (NBM) provides the primary source of cholinergic input to regions throughout the cortex -dependent increase in adenosine release from BF neurons   nuclei synthesize the neurotransmitter serotonin (5-HT) and send extensive projections through the telencephalon, brainstem, and cortex. The DR receives inputs from all other wake active neuronal populations . These cells have strongly increased c-fos expression during wakefulness, and their depletion causes an increase in total sleep time in rats (Lu et al. per se.Very little has been reported regarding changes to the vPAG during healthy aging, despite extensive attention paid to other dopaminergic systems such as SN and VTA. Based on its recently discovered role in sleep-wake cycle maintenance (Lu et al. Regarding disease, loss of vPAG cells (Benarroch et al. Although it is widely documented that sleep fragmentation and EDS are strongly correlated with both aging and neurodegenerative disease, it has proven difficult to define the causal relationships among these features, and the topic remains controversial (Klerman and Dijk Several animal studies have now provided plausible mechanistic bases for effects of sleep disturbance on neurodegenerative disease onset or progression as well. For instance, it was recently reported that in mice, interstitial fluid levels of β-amyloid are increased with both orexin administration and sleep deprivation (Kang et al. Each neurodegenerative disease exhibits unique pathology, symptomology, genetic risk factors, and environmental correlates, but sleep disturbances are the one feature common across a wide range of diseases. This highlights a role for sleep in neurodegenerative onset as one of the most parsimonious explanations for emergence of disease, and the failure of wake-active neuronal populations following prolonged sleep disruption provides a mechanistic framework to bolster the likelihood of such a model. As the sleep and neurodegeneration fields begin to foster greater collaboration, we expect to see more studies in both animals and humans to determine whether improving sleep may ameliorate the high disease risks faced by the elderly population.


Oryza sativa) is used here as an example to highlight mechanisms and genes for adaptation of crop plants to drought stress.Plants in their natural habitats adapt to drought stress in the environment through a variety of mechanisms, ranging from transient responses to low soil moisture to major survival mechanisms of escape by early flowering in absence of seasonal rainfall. However, crop plants selected by humans to yield products such as grain, vegetable, or fruit in favorable environments with high inputs of water and fertilizer are expected to yield an economic product in response to inputs. Crop plants selected for their economic yield need to survive drought stress through mechanisms that maintain crop yield. Studies on model plants for their survival under stress do not, therefore, always translate to yield of crop plants under stress, and different aspects of drought stress response need to be emphasized. The crop plant model rice ( The sheer diversity of plant species grown across climatic regions that include extreme dry conditions suggests that, in nature, plants have evolved to endure drought stress with an array of morphological, physiological, and biochemical adaptations3. ‘Drought resistance’ (DR) is a broader term applied to plant species with adaptive features that enable them to escape, avoid, or tolerate drought stress4. ‘Drought escape’ is the ability of a plant species to complete its life cycle before the onset of drought. Thereby, plants do not experience drought stress, as they are able to modulate their vegetative and reproductive growth according to water availability, essentially through two different mechanisms: rapid phenological development and developmental plasticity5. Rapid phenological development involves rapid plant growth, producing a minimal number of seeds before the soil water depletes, and these plants are considered not to have any special morphological, physiological, or biochemical adaptations. Plants with mechanisms of developmental plasticity show little growth during the dry season, with very few flowers and seeds, but in wet seasons they grow indeterminately, producing a large amount of seed. ‘Drought avoidance’ is the ability of plants to maintain (relatively) higher tissue water content despite reduced water content in the soil4. This is achieved through a variety of adaptive traits involving the minimization of water loss (water savers) and optimization of water uptake (water spenders). Water spenders achieve higher tissue water status by maintaining the water uptake through increased rooting, hydraulic conductance, etc. under drought stress. In contrast, water savers use water effectively through reduced loss of water by reducing transpiration, transpiration area, radiation absorption, etc. under drought stress. ‘Drought tolerance’ (DT) is the ability of plants to endure low tissue water content through adaptive traits. These adaptive traits involve maintenance of cell turgor through osmotic adjustment and cellular elasticity, and increasing protoplasmic resistance6.Drought stress is the most prevalent environmental factor limiting crop productivity8 which possess strong drought escape mechanisms. Resurrection plants can be exposed to severe drought for months, extending up to years, forcing them to optimize their growth for survival, but not for seed production, in the long term9. Therefore, the DR mechanisms that enable plants to merely survive longer lead to subsistence yield, which is much lower than that which is observed under normal conditions. Crop plants, on the other hand, are grown by humans in environments under conditions for high agricultural production and will be exposed to only a random short-term drought stress of days to weeks, from which they must quickly respond to limit the damage caused by short-term drought stress while they continue to grow and yield in the stressful environments. Therefore, bringing in the drought adaptive mechanisms from plants adapted to grow in extreme dry conditions may not be a feasible option, as it may result in growth and/or yield penalty in crop plants under drought as well as normal conditions.Improvement of yield and maintaining yield stability of crops, under normal as well as drought stress conditions, is essential for the food security of the growing global population. It is difficult to resolve the role of different components of DR in the stability of the crop yield as the major objective. However, there exist a variety of different mechanisms for drought escape, avoidance, or tolerance in natural populations that can improve DR and maintain grain yield in crop plants. In nature, extreme DR is found in resurrection plants11. Looking forward in crops, the effective drought improvement approach should be selection for yield and its component traits under reproductive-stage drought stress12. Additionally, little importance has also been given to simultaneous improvement of grain yield under normal and drought conditions. Selection for DT has been suggested to have a yield drag under normal conditions. It has been proposed that the yield potential of crop plants should be simultaneously selected for under favorable and environmental stress conditions, as there is a positive correlation between yield potential under normal and drought stress conditions13. Combining high yield potential under normal conditions with good yield under drought stress is the ideal trait. Identification of mechanisms, traits, and genes regulating yield under drought stress that are free from yield drag under normal conditions should be the focus. For example, regulation of yield under normal as well as drought stress conditions has been shown for three NAC family transcription factors (TFs). Transgenic plants expressingOsNAC5,OsNAC9, andOsNAC10 TFs showed an increase in grain yield of 5-26% under normal conditions16. Nevertheless, in these studies, yield under normal conditions has been overlooked with more emphasis given to yield under drought stress. Two of our recent studies show the potential of simultaneously improving and stabilizing grain yield, both under normal as well as drought stress conditions, using two regulatory genes, namelyGUDK andHYR in rice18. These studies indicate that it might be advantageous to identify mechanisms and genes for increasing grain yield that are also stable or maintained under drought stress conditions.Although plant survival is very critical in the early growth stages, the mechanisms have little relevance to increasing grain yield directly. The emphasis to improve DR of crop plants should therefore be based on stability of yield components and not on plant survival alone. So far, most of the efforts to improve grain yield under drought stress were focused on secondary traits such as root architecture, leaf water potential, osmotic adjustment, and relative water content at the vegetative stage, which are often not highly correlated with grain yield20. Adaptation through DR mainly involves morpho-physiological alterations. These alterations in adaptive processes are controlled by molecular mechanisms that regulate the expression of genes21. There exists a large diversity in drought adaptation within a crop species, as some genotypes are able to cope with drought better than others. Genotypes that differ in drought adaptive mechanisms serve as an important resource to study the variation in drought adaption in crop plants. This natural variation needs to be exploited to simultaneously improve DR and yields of cultivated varieties through better understanding of the underlying mechanisms and to aid in selection for these traits22. In the following sections, we describe the widely known morpho-physiological processes and recent molecular advances in regulating these drought-adaptive processes leading to increased yield in crop plants.Despite the complexity of DR, tremendous progress has been made in understanding the drought-adaptive mechanisms of plants23. Continued photosynthetic light reactions during drought stress under limited intercellular CO2 concentration results in the accumulation of reduced photosynthetic electron transport components, which can potentially reduce molecular oxygen, resulting in the production of reactive oxygen species (ROS). ROS can cause severe damage to the photosynthetic apparatus24. The adaptive responses that plants have developed to reduce drought-induced damage to photosynthesis include thermal dissipation of light energy, the xanthophyll cycle, the water-water cycle, and dissociation of the light-harvesting complexes from photosynthetic reaction centers27. The metabolic impairment during drought stress is mainly caused by changes in photosynthetic carbon metabolism24. The biochemical efficiency of photosynthesis under drought stress mainly depends on ribulose-1,5-bisphosphate (RuBP) regeneration and the activity of ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO)29. Considerable progress has been made in improving the stomatal components for CO2 diffusion, photosynthetic light reaction, and metabolic changes, including the expression of photosynthesis-related genes to regulate photosynthesis under drought towards the improvement of grain yield30.Drought stress is known to reduce photosynthesis by decreasing both leaf area and photosynthetic rate per unit leaf area. Reduced photosynthetic rate is mainly through stomatal closure or metabolic impairment31. However, many important crops—including rice, wheat, soybean, and potato—use the C3 pathway of photosynthesis. Although the transfer of the C4 pathway into C3 crops is underway, so far its contribution to increased grain yield is very limited32. Photosynthetic adaptation of plants to drought stress involves a complex interaction of hormones, ROS, sugars, and other metabolic events33. Combinations of computational models, which integrate the physiological and metabolic processes with gene expression data, along with modern breeding and transgenic technologies hold promise in improving photosynthesis and hence crop yield under normal as well as drought stress conditions.The C4 pathway of carbon assimilation has been suggested to be the major adaptation of the C3 pathway to limit water loss, reduce photorespiration, and improve photosynthetic efficiency under drought stress17, and on overexpression in rice enhanced photosynthesis under normal conditions as well as under drought and high temperature stress. HYR regulates several morpho-physiological processes leading to higher yield under normal and environmental stress conditions. Our study showed that HYR is a master regulator of photosynthesis, directly activating photosynthesis genes, cascades of TFs, and other downstream genes involved in photosynthetic carbon metabolism, resulting in improved yield.In recent studies, we used a rice gene regulatory network to identify a TF termed HYR (HIGHER YIELD RICE), which was highly associated with primary carbon metabolism34. Upon exposure of plants to drought stress, ABA is the major hormone synthesized in roots and translocated to leaves to initiate adaptation of plants to drought stress through stomatal closure and reduced plant growth35. However, modulating the ABA-induced drought adaptation of plants for better yield remains a greater challenge because of the potential inadvertent reduction in carbon gain upon stomatal closure and ABA-induced senescence, especially if the drought occurs at the reproductive stage36. There are ABA signaling genes, such asOsNAP,OsNAC5, andDSM2, which promote improved yield under reproductive drought40. These ABA-induced non-stomatal adaptations of plants under drought stress can be exploited to improve grain yield under reproductive drought , cytokinin (CK), gibberellic acid (GA), auxin, and ethylene, regulate diverse processes which enable plant adaptation to drought stressdrought .isopentenyltransferase (IPT), a CK biosynthetic pathway gene, leads to stress adaptation by delaying drought-induced senescence and an increase in yield42. Generally, auxin has been shown to negatively regulate drought adaptation in plants. Decrease in indole-3-acetic acid (IAA) content was shown to be associated with up-regulation of genes encoding late embryogenesis abundant (LEA) proteins, leading to drought adaptation in plants44. Recently, theDEEPER ROOTING 1 (DRO1) gene determining a quantitative trait locus (QTL) controlling root growth angle was shown to be negatively regulated by auxin. Higher expression ofDRO1 in a shallow-rooting rice cultivar resulted in drought avoidance and high yield under drought45. GA is suggested to positively regulate plant adaptation to drought stress. A rapid decline in levels of endogenous GA was observed in plants subjected to drought stress, resulting in growth inhibition46. The role of GA in regulating grain yield of crop plants is thus an important area that can be further explored. Ethylene is a negative regulator of drought stress response by promoting leaf senescence and inhibiting root growth and development, shoot/leaf expansion, and photosynthesis51. Ethylene can also directly affect yield by increasing embryo and grain abortion and reducing the grain-filling rate52. In addition to the major hormones, other hormones such as brassinosteroids, jasmonic acid (JA), salicylic acid (SA), and strigolactone also have an equally important role in plant growth and development. However, their function under drought stress is relatively less characterized. Tillering in rice has been suggested to be the outcome of an interaction among three hormones, CK, auxin, and strigolactone, with CK promoting branching and the other two inhibiting it54, suggesting that all hormones do not act in isolation but instead interact and modulate each other’s biosynthesis and responses. Therefore, the net outcome of the drought stress response is regulated by a balance between hormones that promote and those that inhibit the trait, rather than individual hormones.Under drought stress, CKs are known to delay premature leaf senescence and death, adaptive traits very useful for increasing grain yield. An increase in the endogenous levels of CK through expression of2 and nutrient uptake, and hence alters metabolic pathways such as photosynthesis55. Plants growing in dry areas have developed xeromorphic traits to reduce transpiration under drought stress. Reduction in transpiration under drought stress conditions can also be achieved through leaf shedding (i.e. deciduous species in drought) as well as decrease in leaf number, leaf size, and branching. Another adaptation to counter drought stress is sclerophylly, where plants form hard leaves that will not suffer permanent damage due to wilting and can be restored to full functionality when normal conditions resume56. Recent research has shown that decreased stomatal conductance in response to drought stress is related not only to reduced expression of aquaporin genes but also to anatomical traits leading to reduction of chloroplast surface area exposed to intercellular space per unit leaf area58. Several other factors, including leaf developmental stage and light availability, are also known to interact with drought in modulating mesophyll and chloroplast differentiation, ultimately affecting conductance and photosynthetic capacity58. Reduction in stomatal size and number on exposure to drought is another adaptation for survival under drought conditions. Previous studies have shown that while there is an increase in stomatal density under mild drought stress, there is a decrease during severe drought59. Thus, all these adaptations in plants reduce the negative impacts of drought stress on photosynthesis and thereby have a positive effect on water use efficiency (WUE), which in turn will result in high yield potential and high yield60. Such an adaptation was shown in rice by overexpression of the Arabidopsis AP2/ERF TFHARDY that improved WUE (the ratio of biomass produced to water used) by enhancing photosynthesis and reducing transpiration61. The above reported traits therefore exemplify adaptive mechanisms in plants to survive under drought stress without loss of productivity or yield.The immediate response of plants on being exposed to drought stress is stomatal closure. However, stomatal closure not only diminishes water loss through transpiration but also reduces CO62. Although the growth of the primary root is not affected by drought stress, the growth of lateral roots is significantly reduced, mainly by suppression of the activation of the lateral root meristems63. The Arabidopsis R2R3-type MYB TFMYB96 has been shown to regulate activation of lateral root meristem through an ABA signaling cascade, with an activation-tagged mutant showing enhanced DR with reduced lateral root formation64. The plant microRNA miR393 has also been shown to play a role in root-mediated adaptation to drought stress response through attenuation of auxin signaling65. In addition to the lateral roots, the presence of small roots is also considered as an adaptive strategy to increase water uptake by providing more absorptive surface. Presence of specialized tissues like rhizodermis, with a thickened outer cell wall or suberized exodermis, or reduction in the number of cortical layers are considered an adaptive advantage for drought stress survival. Hydrotropism is another adaptive measure taken by plants to counter stress, where studies have shown that degradation of amyloplasts in the columella cells of plant roots on exposure to drought stress increases hydrotropism67. Hormonal cross-talk mediated by auxin, CK, GA, and ABA has been implicated as a potential chemical signal in response to water stress to modulate root system architecture68.In many agriculturally important crops, drought stress is perceived first by the root system, which continues to grow underneath the soil even though shoot growth is inhibited under these conditions69. More lateral root and root hair formation was found in lines possessing a QTL, qDTY12.1, only when under drought70. Such traits, which are expressed only under drought stress, have higher potential to increase grain yield under drought. Moreover, it has also been shown that drought stress triggers a wide variety of anatomical traits expressed to different levels and patterns in different species and even in different cultivars within species73. For example, suberization and compaction of sclerenchyma layer cells were shown to decrease in rice under drought, which increases retention of water under drought stress71.The expression of enzymes related to root morphology (e.g. xyloglucan endotransglucosylase) is induced upon mild drought stress, while other structural proteins are down-regulated, which is strongly correlated with root growth and hence an augmentation in the surface area for water uptake. The alterations in the expression of these proteins correlate positively with lateral development that in turn also affects photosynthesis74. Cell enlargement and growth in plants is highly dependent on water availability and helps in maintaining the turgor. Turgor measurement in growing regions of plants, especially the leaves and stems, shows little or no reduction, though cell enlargement is inhibited during drought stress and is believed to be due to OA76. Under conditions of drought stress, OA has been implicated in maintaining stomatal conductance, photosynthesis, leaf water volume, and growth77. At times of drought stress, in addition to the reduction in water content, there are also other associated changes, such as increases in salt concentration and mechanical impedance78. Inorganic cations, organic acids, carbohydrates, and free amino acids are the known predominant solutes that accumulate in response to water stress. Previous studies have shown that drought-resistant wheat varieties, with yield stability under drought stress, have a greater capacity for osmoregulation than less resistant varieties76. The accumulation of compatible solutes such as proline and glycine betaine help in protecting the plants from detrimental effects of drought stress not only by OA but also by detoxification of ROS, protection of membrane integrity, and stabilization of enzymes or proteins79. Enzymes such as betaine aldehyde dehydrogenase (BADH), pyrroline-5-carboxylate reductase (P5CR), and ornithine δ-aminotransferase (OAT) have been shown to play major roles in OA. Overexpression of ArabidopsisEDT1/HDG11 was shown to increase DT of poplar and cotton through increased accumulation of solutes such as proline and soluble sugars and also increase the yield of cotton in the field80. However, there are some plants in which sugars are the main osmolytes that play a significant role in OA, including sucrose, trehalose, glucose, and fructose. Previous studies have shown that overexpression of thesucrose:fructan-6-fructosyltransferase (6-SFT) gene fromPsathyrostachys huashanica in tobacco and the trehalose-6-phosphate phosphatase geneOsTPP1 in rice confers abiotic stress tolerance82. Researchers have also identified a QTL for OA on chromosome 8 in rice that is homeologous with a segment of wheat chromosome 783.Osmotic adjustment (OA) is defined as a process of solute accumulation in dividing cells when the water potential is reduced, and thereby helps in maintaining the turgor85. Drought stress affects the source-sink relationship by reducing the source strength, leading to yield reduction. Sufficient sugar supply through photosynthesis, transport, and conversion of sugars is regarded as the most critical component in determining the viability of reproductive organs in rice88. Drought stress dramatically affects pollen viability due to abnormal starch accumulation89. Insufficient starch synthesis and arrested pollen development have been linked to reduced invertase activity under drought stress88. In addition to invertases, active grain filling involves other key enzymes, such as sucrose synthase, ADP glucose pyrophosphorylase (AGPase), and starch synthase as well as starch branching and debranching enzymes, which are also affected by drought stress88. Therefore, enhancing rice yield through source-sink relationships involves not only sugar metabolism but also the regulated mobilization of metabolic resources from source to sink tissue.Source-sink relationships largely determine the grain yield of cereal crops, with developing grains being primary sinks while the top two leaves, the flag leaf in particular, are the primary source90. Comparative omics analyses between the diverse germplasm could aid in bettering our understanding of the variety of crop adaptations to drought stress. In addition, analysis of specific genes focussed on increasing DR while stabilizing the yield is crucial for understanding the broad basis of complex traits such as DR91. The development of high-yielding resilient crops74 that maintain yield stability under drought and other environmental stresses due to climate change is also currently needed. Drought-resistant plants should combine a better root system, stomatal regulation, WUE, and hormonal balance while avoiding the negative effects on grain yield under both normal and drought stress conditions. Therefore, a holistic crop improvement strategy should involve the deployment of high crop yield potential and the utilization of a combination of morpho-physiological, biochemical, and anatomical adaptive responses to drought stress.Improving DR in crop plants is a challenge for plant breeders and crop physiologists, as it is a complex genetic trait with multiple pathways involved. Effective development of drought-resistant crop plants thus requires the pyramiding and interaction of many mechanisms, traits, and genes that are appropriate to individual crops and their growing environments. Success in this direction not only extends the growing area of crop plants but also achieves stable yield in drought-prone areas. Identifying genetic variation for DR is the first step towards development of drought-resistant crop plants. Such variation is often present in wild species and adapted genotypes that have evolved under natural selection and these are the best source of DR traits. Evaluation of these resources through an integrated phenotyping and genotyping approach under field conditions alongside identification of traits that are directly associated with yield is key to improving DR


Platelets are anucleate blood cells that play a crucial role in the maintenance of hemostasis. While platelet activation and elevated platelet counts (thrombocytosis) are associated with increased risk of thrombotic complications, low platelet counts (thrombocytopenia) and several platelet function disorders increase the risk of bleeding. Over the last years, more and more evidence has emerged that platelets and their activation state can also modulate innate and adaptive immune responses and low platelet counts have been identified as a surrogate marker for poor prognosis in septic patients. Viral infections often coincide with platelet activation. Host inflammatory responses result in the release of platelet activating mediators and a pro-oxidative and pro-coagulant environment, which favors platelet activation. However, viruses can also directly interact with platelets and megakaryocytes and modulate their function. Furthermore, platelets can be activated by viral antigen–antibody complexes and in response to some viruses B-lymphocytes also generate anti-platelet antibodies. All these processes contributing to platelet activation result in increased platelet consumption and removal and often lead to thrombocytopenia, which is frequently observed during viral infection. However, virus-induced platelet activation does not only modulate platelet count but also shape immune responses. Platelets and their released products have been reported to directly and indirectly suppress infection and to support virus persistence in response to certain viruses, making platelets a double-edged sword during viral infections. This review aims to summarize the current knowledge on platelet interaction with different types of viruses, the viral impact on platelet activation, and platelet-mediated modulations of innate and adaptive immune responses. From an evolutionary perspective, the cellular mediators of hemostasis and immune defense have not always been separated. In invertebrates, a cell type called hemocyte protects the host from invading microbes and the same cell also prevents “blood”  loss upon injury by triggering coagulation , 2. In hFor decades, these two systems were thought to act independently, but this concept has recently been challenged. Emerging evidence suggests that the boundaries between coagulation and immune defense are actually not as clear-cut as originally supposed. A new concept of involvement of immune cells in hemostasis, termed immunothrombosis, has been recently proposed, which assumes a function of innate immune cells in thrombosis . On the In 1882, Bizzozero discovered platelets as the third morphological element in blood and elucidated the function of these cells in hemostasis and thrombosis . ConsequThus, platelet activation does not only occur in response to injury and is not only limited to hemostatic processes but also modulates host response and virus survival , 10–12. To date, the role of platelets in response to invading pathogens is not fully understood. Platelet–microbe interactions seem to be beneficial for the host due to up-regulation of immune responses. However, platelet interaction with invading pathogens is also speculated to benefit virus or bacteria, as platelets provide shelter against leukocytes, antiviral agents, and antibiotics. Moreover, the stickiness of platelets might attenuate microbe–endothelial interactions and facilitate infection by similar mechanisms to those recently described for platelet interactions with circulating tumor cells .This review aims to summarize the current knowledge on platelet interaction with different types of viruses, the viral impact on platelet activation, and platelet-mediated modulations of innate and adaptive immune responses.Platelets are, after erythrocytes, the second most abundant cell population in the blood. Normal platelet counts range from 150,000 to 450,000 platelets per microliter. Thrombocytopenia, which represents a drop in platelet count caused by either decreased platelet production or increased platelet destruction, is associated with an increased bleeding risk. Thrombocytopenia is frequent following viral infections and viruses use a variety of distinct strategies to decrease the levels of circulating platelets. The different mechanisms of how virus infection can interfere with platelet production and might trigger platelet destruction are summarized in the first chapter and Figure Platelets are produced in the bone marrow by megakaryocytes, which develop from hematopoietic stem cells. Megakaryocytes first undergo linage commitment, followed by endomitosis resulting in polyploidy . PolyploViruses can modulate platelet production at various steps of development. They are able to influence the cytokine profile of the host, resulting in altered TPO production in the liver. Examples of this include: simian immunodeficiency virus (SIV), which triggers TPO production via up-regulation of tumor growth factor (TGF) β ; human hSome viruses also directly interfere with TPO production by destruction of liver tissue as shown for hepatitis C virus (HCV) . The resHuman immunodeficiency virus (HIV), cytomegalovirus (CMV), and HCV are known to replicate in megakaryocytes –24 and mWhile thrombocytopenia induced by decreased platelet production is observed at later stages of infection, rapidly induced thrombocytopenia in response to viral infections is mediated via enhanced platelet destruction.The most rapid way of platelet destruction occurs via direct interaction between platelets and viruses. Platelet–virus interaction can occur via a variety of receptors and are mainly mediated by integrins, surface lectins, and TLR , 31, 32 Rotavirus utilizes the collagen receptor GPIa/IIa to bind to platelets , 34, whi13 directly binds to the cytoplasmic domain of GPIIIa and promotes ligand binding to GPIIb/IIIa  interaction with platelets occurs via complement receptor 2 (CR2) . HIV andIn addition, platelets express the Coxsackie virus-specific Coxsackie-adenovirus receptor (CAR)  and HCV These direct interactions often result in platelet activation and adhesion of activated platelets to leukocytes. Platelet binding to neutrophils triggers phagocytosis of platelets , 47 and However, platelets are not only activated by direct interactions with viruses. Host defense mechanisms in response to viral infections can also lead to platelet activation. For example, many viral infections lead to systemic inflammation, which in turn triggers platelet activation and decreases platelet life span . Among oPlatelets can be activated by these cytokines, leading to platelet–leukocyte interactions, which foster leukocyte and endothelial activation, further amplifying platelet activation and enhancing their clearance by splenic macrophages or Kupffer cells in the liver . MonocytSeveral virus infections activate the coagulation cascade via induction of tissue factor (TF) expression in target cells. Generation of thrombin by the activated coagulation cascade causes platelet activation and subsequent clearance via protease activating receptor (PAR) signaling . PARs on2 (TxA2) feedback mechanisms to cause platelet aggregation, which is further enhanced by CXCL4 . Further, gp120 interacts with CD4, which is expressed by immature megakaryocytes, which also express CCR5, and leads to their infection  or Junin virus results in thrombocytopenia and decreased agonist-induced platelet responses in mice , 69. As ignaling , inductiignaling , and decHantavirus can directly interact with and activate platelets via GPIIb/IIIa  and infeViruses also possess enzymes, which can modulate platelet functions. For example, Influenza virus exhibits neuraminidase , which hydrolyses the terminal sialic acid residues from host cell receptors and thereby decreases the life span of platelets by targeting platelets for rapid clearance in the liver and spleen . As anotDespite its effects on TPO generation, direct interaction of the non-human SIV with platelets results in platelet–monocyte aggregate formation, which promotes monocyte differentiation into a more inflammatory phenotype. Furthermore, platelet activation triggers clearance of platelets , 77 as pIt is currently unclear if, and to what extent, viruses or the host could benefit from thrombocytopenia. It has been suggested that down-regulation of hematopoiesis, for example, in dengue virus infection might have a protective role for the microenvironment to limit injury during elimination of infected cells .in vitro studies. The interactions leading to platelet activation do not only result in enhanced platelet clearance, the elimination of virus-laden platelets also contributes to the clearance of virus particles . CXCL4 is released into the blood stream upon tissue injury, inflammation, oxidative stress, or pathogen stimulation such as platelet–virus interactions. CXCL4 has been identified as a broad-spectrum HIV-1 inhibitor and suppresses HIV-1 infection of T-lymphocytes via steric inhibition by binding of CXCL4 proximal to the CD4 binding site on gb120 , 82.Other important chemokine released during viral infections in host defense are CCL5 and CCL3 . CCL5 anCCL5 is further involved in viral lung diseases . It reprUpon activation, platelets release β-defensins, which have been shown to neutralize a variety of viruses . PlateleThe highest amounts of serotonin in blood are stored in platelet dense granules, which are also released upon platelet activation. Serotonin was found to be an important mediator of liver regeneration , 94 and Platelet degranulation further results in surface expression of P-selectin, which is part of the inner α-granule membrane, which fuses with the outer platelet membrane upon granule exocytosis. P-selectin interacts with its counter-receptor P-selectin glycoprotein ligand-1 (PSGL-1), which is constitutively expressed on the surface of leukocytes . PlateleIn response to CMV and EMCV, platelet–virus interaction results in stimulation of TLRs, which trigger platelet degranulation and rapid direct interaction of platelets and neutrophils , 33. Of Platelets recruit dendritic cells to sites of injury or infection  and prodPlatelet–leukocyte interaction and modulation of leukocyte functions can be further accelerated by CD40 ligand (CD40L/CD154) binding to CD40. Platelets express and secrete (soluble) CD154, thereby triggering host responses and boosting inflammation.Platelets directly interact with T-lymphocytes and B-lymphocytes and modulate their function via direct cell–cell interaction as well as soluble mediators . PlatelePlatelets additionally enhance T-lymphocyte-mediated germinal center formation  and theyBinding of IgG-coated viruses causes platelet expression of CD154 and CCL5, which in turn primes protective T-cell-mediated immunity . PlateleIn hepatitis virus B (HBV) infected mice, platelets were shown to be responsible for the intra-hepatic accumulation of virus-specific cytotoxic T-lymphocytes  and to mTo date, it remains unclear if platelet–virus interactions are beneficial for the host or for the virus. Potential adverse effects of platelets in viral infections are summarized in Figure Virus-mediated activation of platelets and subsequent platelet-derived cytokine release not only protects the host but may also have unwanted implications for the host. While several reports indicate that CXCL4 is a broad-spectrum suppressor of HIV infection, one report indicates that platelet CXCL4 can also facilitate human macrophage infection with HIV-1 and potentiates virus replication . FurtherPlatelet-derived serotonin results in a delayed entry of activated cytotoxic T-lymphocytes into the liver, which slows down virus control and supports virus persistence in the liver . This reMegakaryocyte infection and subsequent modulation of platelet function by CMV have been speculated to be a reason for graft failure in allergenic bone marrow transplantation .Arenaviridae , Bunyaviridea , Filioviridae , and Flaviviridae .Primary and secondary hemostasis work tightly together. Imbalances of either system result in impaired function of the other. Activation of the coagulation cascade has been observed in various virus infections, including HIV, dengue, and Ebola virus infection, and might provide a host defense mechanism to limit pathogen dissemination . ChangesOf note, it was recently shown that a reduction in platelet count of more than 85% is necessary for hemorrhages to occur, indicating that a very low percentage of platelets are sufficient to maintain vascular integrity . In an LAlthough thrombocytopenia is frequently observed in patients with dengue infections, bleedings are rare. However, if bleedings do occur they are associated with high mortality risk. Of note, in dengue virus-infected patients, platelet count does not predict bleeding risk. However, systemic platelet activation might contribute to the pro-coagulatory state in these patients, which frequently develop DIC . Moreove2 production, has been hypothesized to have worsened the incidence and severity of the influenza pandemics in the 1910s , HIV, CMV, HCV, EBV as well as influenza DNA, and/or protein has been found in atherosclerotic plaques , 121. LaIn animal studies, CMV increased T-lymphocyte influx into plaques  and neutThere is some discrepancy regarding the strength of data regarding HSV infection and cardiovascular disease and despite its pro-inflammatory responses, a negative association between EBV infection and cardiovascular disease has been observed.Moreover, the association between HIV infection and cardiovascular disease remains controversial and anti-retroviral therapy itself alters platelet function  and reprPlatelets and their released products have been reported to directly and indirectly suppress infection but also to support virus persistence in response to certain viruses, making platelets a double-edged sword during viral infections. Platelets are involved in a variety of complications in response to viral infection but also fulfill a pivotal role in retaining adequate host responses. Thrombocytopenia is a common complication in several viral infections and viruses exert various strategies to mediate platelet decay. The question, if thrombocytopenia is a viral strategy to evade immune responses or if it also has host protecting functions, seems to depend on the virus variant and the underlying pathology. Further studies are warranted to fully understand the role of platelets in viral infections and to gain a clear understanding of the effects of anti-platelet therapies in viral infections. These studies will help us to predict the benefit or drawback of platelets and their inhibition during viral infections.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.


Whales receive underwater sounds through a fundamentally different mechanism than their close terrestrial relatives. Instead of hearing through the ear canal, cetaceans hear through specialized fatty tissues leading to an evolutionarily novel feature: an acoustic funnel located anterior to the tympanic aperture. We traced the ontogenetic development of this feature in 56 fetal specimens from 10 different families of toothed (odontocete) and baleen (mysticete) whales, using X-ray computed tomography. We also charted ear ossification patterns through ontogeny to understand the impact of heterochronic developmental processes. We determined that the acoustic funnel arises from a prominent V-shaped structure established early in ontogeny, formed by the malleus and the goniale. In odontocetes, this V-formation develops into a cone-shaped funnel facing anteriorly, directly into intramandibular acoustic fats, which is likely functionally linked to the anterior orientation of sound reception in echolocation. In contrast, the acoustic funnel in balaenopterids rotates laterally, later in fetal development, consistent with a lateral sound reception pathway. Balaenids and several fossil mysticetes retain a somewhat anteriorly oriented acoustic funnel in the mature condition, indicating that a lateral sound reception pathway in balaenopterids may be a recent evolutionary innovation linked to specialized feeding modes, such as lunge-feeding. The auditory system of cetaceans diverges from its nearest mammalian relatives in two profound ways. First, originating from terrestrial ancestors, the auditory hardware of cetaceans has been completely modified for an obligate aquatic existence . Cetaceaschalltrichter [sound-funnel]” or the “ear trumpet” )th century, along with samples from fisheries by-catch and strandings, which were all archived at the Smithsonian Institution. CT data provided crucial non-destructive insight into fetal stages that are difficult to observe and under-sampled relative to post-natal vouchers that dominate curated collections of cetacean material. Our findings show that the acoustic funnel develops early in the ontogeny of all cetaceans, and then diverges in anatomical orientation and morphology at late fetal stages of odontocetes and mysticetes. We also found that the orientation of the acoustic funnel correlates with previously described sound reception pathways for each clade. The phylogenetic distribution of these traits across living cetaceans  suggests that the acoustic funnel has been present at least since the Eocene-Oligocene transition (~34 million years ago), and that a laterally directed sound reception pathway in rorquals is an innovation likely linked to other cranial and mandibular specializations for lunge-feeding.We investigated the developmental origin of the acoustic funnel in cetacean ears and charted their evolutionary implications by building an X-ray computed tomography (CT) dataset of various developmental stages . These specimens mostly consisted of fluid-preserved, intact vouchers collected in association with commercial whaling operations in the early to mid-20We examined a total of 56 fetal cetacean specimens, including 3 families of mysticetes  and 7 families of odontocetes . All specimens were from the Smithsonian Institution’s National Museum of Natural History ; USNM specimen numbers are listed in The total length (TL) of all intact specimens were measured in ORS along the dorsal curve from the rostrum to the fluke notch , in which the sigmoid process almost reaches the periotic. Overall, the acoustic funnel is not as cone-shaped in balaenopteroid mysticetes compared to odontocetes.The malleus, goniale, and the tympanic annulus are the earliest structures to form in the tympanoperiotic complex of all cetaceans. The tympanic annulus is not as well-ossified as the malleus and goniale in the early, Stage 2 fetuses. The tympanic annulus originates as a U-shaped structure viewed from the ventral perspective, with the open end of the U facing posteriorly. The medial branch of the U-shaped tympanic annulus elongates posteriorly and laterally and gives rise to the posterior process of the tympanic. The lateral branch of the U-shape fuses to the posterior and ventral margin of the malleus, giving rise to the sigmoid process, which is consistent with previous descriptions . In odonIn the earliest fetal specimens, the tympanoperiotic complex is not well-ossified relative to the rest of the skull. However, the ears rapidly ossify during the early fetal period and become the densest element of the skull (based on CT number) by approximately 20% of the newborn length in mysticetes and approximately 40% of newborn length in odontocetes .. Mysticin situ the incipient cetacean acoustic funnel, which is thought to be a critical component of hearing [Our study is the first to identify and depict  hearing , 11, 12. hearing .Aetiocetus weltoni, a small, toothed fossil mysticete from the late Oligocene, also show anteriorly converging tympanic bullae [Janjucetus hunderi, Chonecetus geodertorum, Cetotherium rathkei and Herpetocetus transatlanticus have tympanic bullae that converge anteriorly [In contrast to odontocetes, the malleus-goniale complex in balaenopterid mysticetes faces laterally in later stages. Furthermore, whereas the main axes of the tympanic bullae converge anteriorly in earlier fetuses, just like odontocetes of the same stage, these main axes start to become parallel to the skull in later stages  may have possessed an acoustic funnel; the large mandibular foramen in this lineage would have provided the anatomical space to house intramandibular acoustic fats, providing a lipid conduit to the ears [Remingtonocetus harudiensis [The lack of non-keratinized soft cranial tissue preservation in the fossil record prevents clear identification of the acoustic funnel in extinct cetaceans, but the phylogenetic distribution of tymapanoperiotic traits observed in our dataset allows for several inferences. First, the early development of the acoustic funnel from the goniale and malleus in both mysticetes and odontocetes points to the acoustic funnel being shared in all crown Cetacea; thus, its antiquity is minimally placed near the Eocene-Oligocene boundary (~34–33 million years ago), the likeliest timeframe for the origin of this clade  Fig. 3)Fig. 3). s ramani ), a forwthe ears . Well-prudiensis . Pakicetudiensis , 19, 20,udiensis .Our results have important implications for the evolution of hearing and feeding within crown Cetacea, as discussed above. Ancestrally, crown cetaceans appear to have tympanic bullae whose main axes are converging anteriorly , which oThis study is unique in its broad taxonomic coverage and large number of specimens because CT techniques provide non-invasive ways to examine rare, irreplaceable museum specimens. However, CT has a limited resolution and we were unable to detect early features of the tympanoperiotic complex in specimens with TL < 16 cm. Furthermore, the morphology of structures that are not well-ossified is difficult to see on the CT scans, which rely on differential X-ray attenuation through tissues to create contrast. MicroCT and magnetic resonance microscopy techniques have been applied to at least three very early cetacean fetuses , 32, andWe could not control for any potential preservation artifacts of the fluid-preserved specimens, which may have been fixed in unknown solutions before transfer to ethanol. However, our results are consistent with previous morphological descriptions of equivalent stages and taxa, including data from dissections, cleared and stained specimens, histology, and other non-invasive techniques see .Lastly, tremendous progress has been made in the study of cetacean sound reception over the past several decades . NonetheAetiocetus cotylalveus USNM 25210 and Albertocetus meffordorum USNM 525001 from NMNH Paleobiology collections), and may potentially be inferred in some Eocene stem cetaceans as well.By following ontogenetic series of cetacean fetuses across a broad range of taxa, we found that the unique acoustic funnel into the cetacean ear arises from a V-shaped feature formed by the malleus and goniale early in fetal development. The malleus-goniale complex is a well-ossified, persistent, and conspicuous feature of the fetal cetacean ear. In mature odontocetes, the malleus-goniale complex forms the ventral portion of the cone-shaped acoustic funnel , 12, to We found that the orientation of the acoustic funnel correlates with previously described sound reception pathways for each clade, although cetacean middle ear mechanisms are still debated and key experimental evidence is lacking in mysticetes due to the logistical as well as legal challenges of working with these large marine mammals. The acoustic funnel faces anteriorly in all fetal cetaceans and remain this way in mature odontocetes and balaenids, while the acoustic funnel rotates laterally later in ontogeny in balaenopterid  mysticetes. Fossil cetaceans possess anteriorly oriented acoustic funnels, suggesting that crown cetaceans mainly employ ancestral sound reception pathways inherited from stem cetaceans, except for rorquals and gray whales. The examination of fetal specimens provides insight into the developmental basis for major evolutionary innovations, including the aquatic sound reception pathways of cetaceans.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S1 FigS. attenuata; (d) B. borealis; (e) B. musculus; (f) M. novaeangliae; (g-i) B. physalus. The tympanoperiotic complex is highlighted in yellow and the main axes of the tympanic bullae are approximated by the dashed pink line. Specimens featured in each panel are as follows: a) USNM 504052; b) USNM 504008; c) USNM 504048; d) USNM 504718; e) USNM 268885; f) USNM 267637 (yellow highlight for tympanic only); g) USNM 268884; h) USNM 268883; i) USNM 260585.(a-c) (TIF)Click here for additional data file.S2 FigAll CT scanned specimens are represented in this figure. The relative density of the ears is obtained by dividing the maximum CT number of the tympanoperiotic complex by the maximum CT number of the rest of the skull. TL = total length. The newborn length of each species was obtained from .(TIF)Click here for additional data file.S3 FigRefer to (TIF)Click here for additional data file.S4 FigB. physalus, USNM 269156. (b) Eschrichtius robustus, USNM 593416. Scale bar = 2 cm.(a) (TIF)Click here for additional data file.


Gap junctions mediate electrical synaptic transmission between neurons. While the actions of neurotransmitter modulators on the conductance of gap junctions have been extensively documented, increasing evidence indicates they can also be influenced by the ongoing activity of neural networks, in most cases via local interactions with nearby glutamatergic synapses. We review here early evidence for the existence of activity-dependent regulatory mechanisms as well recent examples reported in mammalian brain. The ubiquitous distribution of both neuronal connexins and the molecules involved suggest this phenomenon is widespread and represents a property of electrical transmission in general. The functions of electrical synapses have recently been of increasing interest within the neuroscience community. Electrical transmission is supported by gap junctions, structures that are formed by plaques of paired and docked connexin-formed hemichannel pores in apposed neuronal cell membranes. These channels form a physical connection between cells, allowing ionic current to flow directly between coupled neurons. Electrical synapses in most mature mammalian neuronal systems are composed of connexin36 (Cx36) –3 and coLike chemical synapses, electrical synapses can vary their gain , 7. ModiMore recent evidence indicates that the strength of electrical synapses is influenced by ongoing activity in neural networks, via interactions with chemical synapses . ‘ActiviMauthner cells mediate escape reflex in fish (and amphibian tadpoles) and receive auditory input from the nerve afferents that terminate as ‘club endings’, a synapse that combines chemical and electrical transmission –18. Elec2+) increase, which activates a Ca2+/calmodulin-dependent kinase (CaMKII) [Several types of stimuli have been shown to induce plasticity of the electrical component within these synapses. Discontinuous bursts of tetanizing stimulation of the VIIIth nerve leads to long-term potentiation of the electrical component of the EPSP , 20, 21 (CaMKII) , and inv(CaMKII) . Brief c(CaMKII) . Thus, b(CaMKII) , suggestTogether, these results indicate a high degree of sensitivity of Mauthner electrical synapses to neuronal activity and signaling. While the sensory stimulus that triggers an escape response is likely multimodal, and combines vestibular and lateral line information , 27, theThe retina has provided the earliest and more numerous examples of regulation of electrical synapses by neurotransmitter modulators. Electrical synapses appear widely across the retina, which contains layered structures of cells that are conserved between fish and mammalian retinas. Variations in electrical synapse strength contribute to tuning the sensitivity of retinal circuits for transitioning between nighttime and daytime visual tasks. In the outer layer, coupling connects both functionally similar (e.g. cone-cone) and dissimilar (rod-cone) types of photoreceptors. Dispersion of voltage signals between cells helps to suppress voltage noise in individual cells. Moreover, the rod pathway informs the cone pathway of light levels at the upper end of its dynamic range. In bright light, rod-cone coupling is reduced and rod input is effectively eliminated from the cone pathway by a dopamine-mediated circadian mechanism , 32. In In addition to the action of neuromodulators, recent data indicates that mammalian retinal electrical synapses are also sensitive to activity of glutamatergic synapses. That is, AII amacrine cell synapses undergo changes in electrical coupling driven by light adaptation , in whicThe olivo-cerebellar network provides the timing signals necessary for precise coordination of motor actions, and for non-motor and cognitive tasks. Within the network, neurons of the inferior olive (IO) provide the powerful excitatory climbing fiber input to Purkinje neurons. The clock of the timing signals in the cerebellum is thought to be provided by subthreshold 5–10 Hz oscillations produced by intrinsic mechanisms within neurons of the IO –39. ElecIO neurons are also influenced by GABAergic input from the cerebellar nuclei in IO glomeruli, where dendrites of neighboring IO neurons are connected via gap junctions  that are2+ and CaMKII activity [Another recent set of work has investigated long-term electrical synaptic plasticity coincident with glutamatergic activity in this structure. Long-term potentiation of electrical synapses between pairs of IO cells results from high-frequency stimulation or NMDA application, an effect dependent on intracellular Caactivity . Conversactivity . The invactivity . NMDAR-dCoupling among IO neurons is highly variable, heterogeneity that was proposed to result from short-term activity-dependent plasticity at individual glomeruli . CouplinThe thalamic reticular nucleus (TRN) forms a dorsolateral shell around the thalamus proper. This structure primarily receives glutamatergic input from the corticothalamic and thalamocortical axons, and projects inhibitory GABAergic synapses to neurons of the thalamus , 51. TogTwo forms of electrical synapse depression have emerged in the TRN. First, tetanic stimulation of cortical afferents to the TRN result in an glutamate-mediated long-term depression of electrical synapses ; activatSynchronous low-frequency bursting activity induced in coupled TRN neurons also leads to depression of the electrical synapses between them  via a yeIn the TRN, depression of electrical synapses generally acts to desynchronize the spiking of active neurons. The TRN is a regulator of thalamocortical spindle rhythms ; plasticThe established role of glutamatergic transmission in promoting activity-dependent plasticity of electrical transmission is consistent with earlier reports in hypothalamus. Glenn Hatton and colleagues , 66 repoFrom the functional point of view, these data suggest that coupling increases following strong sensory inputs associated with behavior that result in increased hormone or peptide release in response to other incoming stimuli.While electrical synapses are known to be the target of the neuromodulatory transmitters, increasing evidence indicates that they are profoundly influenced by the activity of the networks in which they are embedded. This activity-dependent plasticity of electrical transmission has been shown to rely, so far, on interactions with nearby chemical synapses via activation of glutamate receptors. Originally identified in fish Fig. , this foThe distinction between neuromodulator-dependent and activity-dependent plasticity is somewhat arbitrary, and both regulatory processes are likely to interact. For instance, a form of activity-dependent potentiation at goldfish mixed synapses was shown to require activation of mGluR1 receptors that, by promoting the release of endocannabinoids, led to the release of dopamine from nearby varicose terminals, which in turn triggers potentiation via a postsynaptic mechanism , 74.Beyond interactions with chemical synapses, activity-dependent plasticity of electrical transmission is likely to occur via other mechanisms. Interestingly, a recent report indicates that the induction of gap junction plasticity occurred in the absence of chemical synaptic stimulation and was driven by bursting cellular activity , suggest


Global temperature has increased by 0.85°C between 1880 and 2012, with an acceleration during the last decades and many extreme weather events since about 1950 IPCC, . A conseConsequences of climate change on phenology have often been documented by the study of single life stages , PPM is a capital breeder achieving one generation per year (except in case of extended diapause), with winter larval development  and early cold snaps (3b) tend to apply antagonistic constraints on PPM lifecycle (3d). Moreover, PPM is widespread across Europe, North Africa and Minor Asia, with locally differentiated phenologies, except in continental regions where opposing constraints can be too strong to be overcome by phenological responses. Conversely, high phenological variability in processions and flights in the south-western area suggests less stringent climatic conditions due to milder summers and winters Figure . Such phSince the early 2000s, an increasing number of erratic PPM phenologies are being reported in France. The most striking illustration is the co-occurrence of both typical (March-May) and atypical (October-January) processions within the northern area under oceanic influence Boutte,  will favClimate warming can exert opposing pressures on the distribution of insects, not only among species, but also within species due to contrasted susceptibility of life stages and heterogeneous phenologies, ultimately altering local survival. Predicting insect distribution under climate change is thus challenging as models should consider not only common concepts of species spread, but also stage-specific thermal thresholds and inter-populational heterogeneity in phenology, acclimation and physiological adaptation Chuine, . MonitorCR and JR prepared the phenology and climate datasets; CR, ML, JR worked on the data and wrote the paper.This study was supported by PCLIM network funded by metaprogram ACCAF of INRA.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.


Reciprocal altruism implies delayed payoffs by definition. It might therefore seem logical to assume that limited memory, calculation, and planning capacities have constrained the evolution of reciprocity in non-human animals. Here I will argue that this is not the case. First, I will show that the emotional track of past interactions is enough to motivate and maintain reciprocity over longer timespans. Second, I will propose a developmental pathway of this system of emotional bookkeeping. In particular, the neuropeptide modulation underlying mother-infant and pair bonding may have been coopted for emotionally mediated reciprocity. Finally, I suggest that similar rewarding mechanisms may motivate indirect reciprocity and cooperation in larger social networks. Therefore, reciprocity can be ultimately conserved in primate lineages, without the need for individuals to keep a detailed account of benefits exchanged.Observations, experimental studies, and meta-analyses speak for a robust occurring of reciprocity in the social life of primates. An equally robust proximate mechanism, that is emotional bookkeeping can account for that occurrence. In this way, unnecessary assumptions related to delayed payoffs are cut out.Macaca fuscata) preferentially groom and support those individuals that overall supported and groomed them most, grooming and support are weakly correlated in the short-term. In fact, during a whole year, kin were never observed to support each other immediately after grooming , mandrills (Mandrillus sphinx), and olive baboons (Papio anubis) have revealed that short-lived imbalances are tolerated in favor of stable partner preferences   found evidence for long-term but not short-term reciprocity of support in favor of higher-ranking individuals, kin, and preening partners involved in an ongoing conflict (Fraser and Bugnyar, Defining a time frame for immediate reciprocity, within minutes or hours, allows the effects of contingency to be controlled with great precision. However, observational studies have found that reciprocity does not occur during short time frames in primate species. For example, although both kin and non-kin Japanese macaques (When individuals are observed over months, instead of minutes or hours, it turns out that they maximize reciprocal benefits over time on the basis of shared positive experiences. This may be one of the reasons why experiments focused on contingency have failed to show reciprocity in both chimpanzees and cotton-top tamarins (Brosnan et al., Evidence for prolonged rather than immediate exchanges may indicate that reciprocity evolved despite differential cognitive capacities between species. Phylogenetic meta-analyses support this point. A meta-analysis on non-human female primates across 48 social groups, in 22 species and 12 different genera found a significant correlation between grooming given and received, even when controlling for kinship (Schino and Aureli, Lloyd Morgan's canon states that “in no case is an animal activity to be interpreted in terms of higher psychological processes if it can be fairly interpreted in terms of processes which stand lower in the scale of psychological evolution and development” Morgan, , p. 59. As a consequence, there is no reason to assume that reciprocity requires the expectation of future rewards, calculation, and strategic capacities, contrary to what many authors have argued (e.g., Stevens and Hauser, Proximate explanations of behavior require the description of both physiological/psychological mechanisms, such as emotional bookkeeping, and developmental processes that lead to those mechanisms during an individual's lifetime (Tinbergen, The neuroendocrine modulation underlying nurturance and attachment is a plausible candidate process coopted for emotional bookkeeping. Genetic mutations in oxytocin receptors are found more frequently than structural variations in neuropeptides themselves Hoyle, . In humaThe cascade of interactions between different kinds of neuropeptides gives a rich picture of the processes underlying reciprocity. Oxytocin's sensitivity to the quality of relationship suggests that it is involved in keeping track of past affiliative interactions. In chimpanzees, for instance, recent grooming increased oxytocin levels only when partners were kin or non-relatives previously bound (Crockford et al., The extension of prosocial attitudes from dyadic relationships to individuals who helped others appears cognitively demanding. It has been theorized, for example, that indirect reciprocity requires gossip to update the others' reputation (Alexander, This opinion piece offers a parsimonious solution to both the cognitive and evolutionary issues related to reciprocal altruism. The emotional track of past interactions motivates individuals to reciprocate without cognitively demanding expectations of future rewards from others. This cognitively inexpensive mechanism accounts for the long-term exchanges of favors among non-human primates. I have provided some evidence in support of the hypothesis that neuroendocrine systems have been recruited for reciprocity. In addition, I have proposed that over an individual lifespan, reciprocity arises as a consequence of positive, iterated interactions and their immediate benefits. Emotionally mediated reciprocity may also favor the formation of close-knit social networks. As long as bonding is mutually rewarding, its proximate mechanisms facilitate higher-order cognitive processing presumably required by living in larger groups.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.