One way it does so is through control of microbial metabolism. Warming effects on metabolism change with time as physiology adjusts to the new temperature. I here propose that such thermal adaptation is observed in soil microbial respiration and growth, as the result of universal evolutionary trade-offs between the structure and function of both enzymes and membranes. I review the basis for these trade-offs and show that they, like substrate depletion, are plausible mechanisms explaining soil respiration responses to warming. I argue that controversies over whether soil microbes adapt to warming stem from disregarding the evolutionary physiology of cellular metabolism, and confusion arising from the term thermal acclimation to represent phenomena at the organism- and ecosystem-levels with different underlying mechanisms. Measurable physiological adjustments of the soil microbial biomass reflect shifts from colder- to warmer-adapted taxa. Hypothesized declines in the growth efficiency of soil microbial biomass under warming are controversial given limited data and a weak theoretical basis. I suggest that energy spilling (aka waste metabolism) is a more plausible mechanism for efficiency declines than the commonly invoked increase in maintenance-energy demands. Energy spilling has many fitness benefits for microbes and its response to climate warming is uncertain. Modeled responses of soil carbon to warming are sensitive to microbial growth efficiency, but declines in efficiency mitigate warming-induced carbon losses in microbial models and exacerbate them in conventional models. Both modeling structures assume that microbes regulate soil carbon turnover, highlighting the need for a third structure where microbes are not regulators. I conclude that microbial physiology must be considered if we are to have confidence in projected feedbacks between soil carbon stocks, atmospheric CO Numerical models demonstrate that physiological acclimation does not need to be invoked to explain the ephemeral augmentation of soil respiration in response to a fixed and sustained increase in temperature above ambient . That is, the same respiration response as projected by the traditional SOM models, where decomposers are implicit in the model frameworks , faces a number of challenges . One of Section 2 – Clarifying the meaning of the terms thermal acclimation and adaptationSection 3 – Describing mechanisms underlying soil respiration responses to warming that are independent of direct temperature effects on microbial physiologySection 4 – Reviewing direct responses of microbial physiology to warmingSection 5 – Discussing theoretical challenges to incorporating microbes into SOM, ecosystem and Earth System Models.Much of my review focuses on respiratory processes because (a) at the ecosystem-level for soil responses to warming the literature focuses primarily on respiration; and (b) a substantial proportion of physiological work on thermal adaptation has focused on respiration. The caveat, however, is that thermal adaptation refers to a suite of phenomena  and I de2 . These organisms are also primary agents of SOM formation .I concentrate on soil microorganisms that decompose organic matter using extracellular enzymes and/or assimilate low molecular weight organic compounds from the soil environment. These organisms include free-living, heterotrophic microbes in the litter, bulk soil and rhizosphere, as well as those that are plant mutualists, such as ectomycorrhizal fungi. What they have in common is that together they are the primary biotic agents in terrestrial systems regulating the breakdown of organic matter and its eventual mineralization and hence return to the atmosphere as COormation , suggestdirect organism responses to temperature across immediate to multi-generational time-scales that manifest as physiological change. This then permits me to discuss thermal adaptation in soil communities without pretending to know the precise mechanisms underlying the adaptive response, because we simply do not yet know which mechanisms contribute most to thermal adaptation in soil microbial activity. These mechanisms operate across three distinct timescales.The scientific literature is burdened with a variety of uses for the same term. The confusion created hinders discourse across disciplines, presenting an obstacle to the interdisciplinary science demanded by environmental problem solving . The terde novo mutations could take many generations .I use the term “apparent thermal acclimation”  rates are calculated as respiration per unit biomass, making the measurement of individual, population and/or community biomass essential for calculating and discussing thermal adaptation of respiration.Thermal adaptation of respiration involves dampening in the response of mass-specific respiration rates to temperature change. Mass-specific respiration (Rmass to warming is exhibited through a dampening of Q10 (type I adaptation) and/or a change in absolute Rmass rates at any one temperature  are achieved at the cell level through, for example, changes in the inherent properties of enzymes that determine the temperature sensitivity or absolute magnitude of their catalytic rates, respectively. Type II adaptation dampens respiration responses to a sustained temperature change without adjustment of temperature sensitivity. Rmass . Such community shifts have the potential to generate seemingly paradoxical Q10 values; where over the same temperature range warm-adapted communities have elevated (as opposed to dampened) Q10 values. These elevated Q10 values could arise because measured Q10 typically decreases across the temperature range over which respiration is active . I am not aware of this phenomenon of elevated Q10 values being shown for soil microbial respiration, but the same mechanism might explain why soil communities adapted to warmer temperatures have higher Q10 values for growth . This classical test relies on the fact that cold-adapted organisms should have higher Rmass rates, at intermediate temperatures, than warm-adapted organisms because the temperature optimum for the latter has been shifted right . The test needs to be performed under conditions where other factors do not limit respiration. For example, for the soil microbial community one should ensure that soil moisture and substrate availability are non-limiting . The mechanism has both observational and experimental support. For example, labile carbon availability to the microbial biomass is lower in experimentally warmed soils . This dynamic causes the initial stimulation of soil respiration under warming . Gradually, however, the SOM pool of interest decreases in size  and, as it does so, there is a proportional decline in respiration from this pool. At the new steady state , soil respiration rates equal carbon input rates to the soil . Conventional SOM modeling studies have kept carbon input rates equal under ambient and warmed conditions , although faster cycling SOM pools are smaller in warmed soils . These effects of warming appear consistent with our understanding of limiting factors on microbes in mineral soils: SOM decomposers typically exist in an environment where substrate is limiting . Temperature then selects (in the Darwinian sense) for more flexible enzymes when it is cooler and for less flexible enzymes when it is warmer.Enzyme-mediated reactions are generally temperature sensitive. An increase in temperature accelerates reaction rates in the short-term, when all other variables are non-limiting . At high temperatures proteins denature and so enzyme function and hence reaction rates drop precipitously. Long-before reaching denaturing temperatures, however, the rate of increase in an enzyme-mediated reaction decreases. Fundamental trade-offs in enzyme structure and function underlie this deceleration. Essentially, enzymes need to be folded into certain three-dimensional shapes  to bind a substrate and other shapes to release the product. The rate at which they change shape theoretically controls the speed of the reaction the enzyme catalyzes. At lower temperatures, these shape changes are faster for more flexible enzyme structures. At warmer temperatures, however, a flexible enzyme spends less time in shapes that bind substrate, which decreases the affinity of the enzyme for substrate and hence reduces the relative rise in reaction rate with increasing temperature . An isoenzyme (aka isozyme) is an enzyme with the same function but a different structure. In environments where temperature varies markedly in the short-term, such as the day-night cycle during the growing season in temperate forest, a broad suite of isoenzymes might be expressed but the relative contribution to catalysis of any one isoenzyme will change with the daily temperature cycle . Across broad latitudinal gradients, however, catabolic responses for communities from lower latitudes appear shifted right along the temperature axis, consistent with expected trade-offs  necessarily underlie apparent thermal acclimation of soil respiration. For example, Most of the biochemical adaptation work on trade-offs in flexibility under temperature has been conducted with enzymes involved in the metabolic pathways that comprise cellular respiration. The CORmass rates will differ if measured under standard conditions  because of physiological adjustments that arise through individual or community responses. There is some evidence for these shifts in functional traits for soil microbial communities and for laboratory-grown heterotrophic microbes  should hold for the traits of cold- and warm-adapted communities, given the fundamental evolutionary trade-offs between enzyme structure and function across temperature. That is, microbes . If we lmicrobes  and for perature . Given tFor functional trait differences to influence soil respiration responses to warming requires Rmass values for warm- vs. cold-adapted organisms when testing for thermal adaptation , however, would not detect thermal adaptation of extracellular enzymes because substrate is supplied in a form not requiring decay prior to assimilation. The test then only examines warming-induced shifts in cellular physiology, such as membrane structure and isoenzyme expression of assimilatory and intracellular enzymes.If microbial activity does regulate how temperature affects the breakdown of SOM stores, the accepted wisdom is that extracellular (not intracellular) biological processes provide the rate-limiting step . SpecifiMicrobial growth is likely much more important than respiration for determining climate-carbon cycle feedbacks. Colonization rates and hence the breakdown of new resources are a function of growth rates, extracellular enzyme production is tied to biomass production, and so are SOM formation rates . MicrobiThat MGEs decline as environmental temperature increases is controversial. For heterotrophic microbial communities in aquatic systems, debate has raged as to whether substrate quality alone vs. temperature explains differences in growth efficiencies . The ideRmass, then conform to a suite of unimodal response curves . Why are individual growth efficiencies unimodal and those for soil communities unresponsive or only negatively affected by warming?Original observations that MGEs in soils declined with temperature were confounded by the complexity of substrates on which the microbial biomass was growing . IncreasThere is no clear answer as to why MGEs of soil communities are temperature insensitive  or, when sensitive , respond only negatively to temperature. It seems that our understanding of how MGEs respond to warming is woefully inadequate. In short, the theoretical basis is a physiological quagmire, arising from the complexity and associated unknowns of metabolism across all forms of life. For example, why do MGEs of whole communities decline with increasing temperature when using substrates that require extracellular decay ? There iFigure 6). For individual organisms, faster growth rates are often even associated with an increase in efficiencies because maintenance costs may be a relatively constant demand whether you are growing or not  is in excess and nitrogen is strongly limiting . That isismissed .Given uncertainties about the physiological mechanisms that determine MGEs, it is unlikely that we will be able to explain in the near term how they might adapt to warming. If energy spilling is beneficial, then under some environments  reductions in MGE might even be adaptive! What seems likely is that substrate quality and availability, nutrient supply and microbial traits all contribute to observed MGEs. Direct warming effects on MGE are uncertain because conventional views of maintenance vs. growth energy demands fall short of explaining changing efficiencies with temperature. This means we may need to be satisfied with black-boxing the efficiency response of the soil microbial community to warming for current SOM modeling studies. The uncertainty also demands that we redress the paucity of observations we have for how warming affects MGEs of soil communities on specific substrates , where cRmass . These unimodal responses are shifted to the right under experimental warming  and plants. These groups of organisms are faced with the same suite of physiological trade-offs in response to warming that heterotrophic microbes are . Physiol but see . Virtual2 evolution from an SOM pool is a function of the pool size, and a decay rate constant that responds positively to temperature and moisture  as a supply driven pool, as in the conventional models; or (b) as a demand-driven pool, as in the new family of microbial SOM models? The primary difference between the two approaches is that the demand-driven approach creates a feedback between SOM turnover and microbial response . In the The conventional and microbial SOM model structures both assume that SOM turnover rates are dependent on microbial activity . A thirdThermal adaptation of organism respiration and growth rates should occur through fundamental evolutionary trade-offs in cellular physiology, such as between the structure and function of both enzymes and membranes. Individuals can adjust their physiology in response to sustained warming by producing warm-adapted isoenzymes and membrane structures, but changes in the physiology of the soil microbial biomass as a whole likely arise through shifts from colder- to warmer-adapted species (or at least genotypes). These physiological responses to warming are consistent with the idea that indirect warming effects, such as substrate depletion, at least partly explain apparent thermal acclimation of soil and ecosystem respiration to prolonged warming. Indeed, I hope that I have demonstrated in this review that thermal adaptation must occur in soil decomposer communities. As such, questions related to the consequences of thermal adaptation for carbon cycling must move from asking whether adaptation occurs, to asking what role adaptation plays in shaping ecosystem carbon stocks and flows in a warming world.The idea that growth efficiencies of the soil microbial biomass decline with increasing temperature should be viewed as controversial. There is little empirical evidence that temperature directly elicits this response in soil communities and the physiological basis for the decline is not resolved. We should explore whether maintenance demands vs. energy spilling is the primary mechanism that uncouples anabolism and catabolism. Energy spilling seems more plausible but how it will adapt to warming is unclear because rather than “waste metabolism,” it likely has many fitness benefits for microbes. Uncoupling in favor of catabolism vs. anabolism causes declines in MGEs, which then prevent warming-induced SOM losses in microbial models and exacerbate them in conventional SOM models. Despite these divergent responses, both model structures assume that microbes regulate SOM turnover, an idea that has recently been questioned. Microbial ecologists thus face two challenges to the explicit incorporation of microbes in ESMs. We need to show conclusively that microbial activity does regulate SOM dynamics, and that adjustments in microbial physiology under warming can be represented in a manner commensurate with observed responses of soil respiration, microbial biomass and SOM stocks.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.


In children with childhood-onset growth hormone deficiency, replacement GH therapy is effective in normalizing height during childhood and achieving adult height within the genetic target range. GH has further beneficial effects on body composition and metabolism through adult life. The transition phase, defined as the period from mid to late teens until 6–7 years after the achievement of final height, represents a crucial time for reassessing children’s GH secretion and deciding whether GH therapy should be continued throughout life. Evidence-based guidelines for diagnosis and treatment of growth hormone deficient children during transition are lacking. The aim of this review is to critically review the up-to-date evidence on the best management of transition patients in order to ensure the correct definitive diagnosis and establish the appropriate therapeutic regimen. The main effect of GH therapy in childhood is to stimulate linear growth: therefore the primary objective of GH replacement therapy in growth hormone deficient (GHD) children is to achieve adult height within the genetic target range. In addition, GH plays a key role in the regulation of body composition and metabolism and its deficiency in adulthood has been associated with reduced lean body mass and bone mineral density (BMD), increased visceral adiposity, abnormal lipid profile, decreased muscle strength, cardiovascular risk, and impaired quality of life   are likely to have permanent GHD, though there may be subjects with MPHD with normal GH response at retesting  has been suggested to have the best efficacy/safety ratio if performed in experienced endocrine units. ITT is considered as the “gold standard” for GHD diagnosis in adults, and allows the assessment of both GH secretion and the hypothalamus-pituitary-adrenal axis function Geffner, . HoweverAn alternative test is the combined stimulation with Growth Hormone Releasing Hormone and arginine (GHRH + Arg). It shows excellent sensitivity and specificity both in childhood and in adulthood, assuming appropriate cut-off limits , sensitivity is poor (about 30%), due to a number of pitfalls which limit reliability and usefulness in clinical practice  is another helpful tool to establish the diagnosis of permanent GHD. It is however worth remembering that not all neuroradiological abnormalities detected at the time of initial diagnosis are indicative of a permanent GH deficiency. While hypothalamic-pituitary disconnections are often associated with persistent deficiency, pituitary hypoplasia (Maghnie et al., Another challenge in the transition phase is to establish the optimal dose of GH for achieving normal adult height and optimal metabolic profile (Clayton et al., Due to the existing conflicting data on both diagnosis and treatment of GHD patients during transition, it has to be pointed out that many of the current approaches are based on arbitrary assumptions rather than on evidence-based medicine. The same definition of transition leaves room to ambiguity. There is no biological basis for considering GHD individuals during a so wide time span under the same label. The different individuals enter puberty at different times; all the more GHD patients have different rates of biological and psychological maturation. Stimulation test cut-offs, GH doses, and responses to GH therapy during transition may be influenced by age, time elapsed from puberty, and underlying diagnoses. It is surprising that in an epoch of individualized medicine and pharmacogenomics, a so simplistic and all-inclusive definition is being still used. Moreover, do we really need that? The diagnosis of permanent GHD should be based on a comprehensive clinical, anthropometric, biochemical, endocrine, and neuroradiological approach rather than arbitrary cut-off laboratory values. Finally, GH dose should be tailored to meet individual requirements for optimizing growth, body composition, bone mineralization, and metabolic homeostasis.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.


These metabolites have been detected in hydrocarbon-contaminated shallow aquifers, offering strong evidence for intrinsic anaerobic bioremediation. Recently, studies have also revealed that alkylsuccinates are present in oil and coal seam production waters, indicating that anaerobic microbial communities can utilize alkanes in these deeper subsurface environments. In many crude oil reservoirs, the in situ anaerobic metabolism of hydrocarbons such as alkanes may be contributing to modern-day detrimental effects such as oilfield souring, or may lead to more beneficial technologies such as enhanced energy recovery from mature oilfields. In this review, we briefly describe the key metabolic pathways for anaerobic alkane  metabolism and highlight several field reports wherein alkylsuccinates have provided evidence for anaerobic in situ alkane metabolism in shallow and deep subsurface environments.Alkanes comprise a substantial fraction of crude oil and refined fuels. As such, they are prevalent within deep subsurface fossil fuel deposits and in shallow subsurface environments such as aquifers that are contaminated with hydrocarbons. These environments are typically anaerobic, and host diverse microbial communities that can potentially use alkanes as substrates. Anaerobic alkane biodegradation has been reported to occur under nitrate-reducing, sulfate-reducing, and methanogenic conditions. Elucidating the pathways of anaerobic alkane metabolism has been of interest in order to understand how microbes can be used to remediate contaminated sites. Alkane activation primarily occurs by addition to fumarate, yielding alkylsuccinates, unique anaerobic metabolites that can be used to indicate  However, documenting that such anaerobic hydrocarbon biodegradation is occurring in fuel-contaminated sites or in fossil energy reservoirs remains a challenge. For example, multiple lines of evidence, both chemical and microbiological, are required to offer support that r et al.  first pr. Beller  proposedin situ anaerobic biodegradation of many hydrocarbon classes. Furthermore, primer sets based on the catabolic gene(s) encoding benzylsuccinate synthase have been developed by several investigators and have been used successfully to indicate the metabolic potential for microbial communities in contaminated field samples to anaerobically biodegrade alkylbenzenes  can be detected in hydrocarbon-contaminated groundwater [see reviews by Beller ; Gieg anIn field bioremediation studies, the biodegradation of BTEX compounds has been a focus because these compounds are highly water-soluble , augmenting the metabolite findings. Primer sets for this gene were also used to probe samples collected from a handful of other hydrocarbon-contaminated aquifers in the US and in Germany, and indeed this gene was detected  heavy oil field in Alberta, Canada (Medicine Hat Glauconitic C field) has been under study for over 5 years to test the effects of nitrate treatment on souring caused by sulfate-reducing bacteria . Detection limits for alkylsuccinates by GC-MS analysis are in the nanomolar range  and high performance liquid chromatography coupled with tandem MS (LC-MS-MS) have generally been used to detect hydrocarbon metabolites in samples collected from contaminated groundwater wells or produced water wellheads of oil or coal reservoirs. Detailed descriptions of these approaches have been described in several previous publications  has been widely been used to garner evidence for the in situ anaerobic metabolism of aromatic hydrocarbons in contaminated aquifers, but has been used to a lesser extent for determining for in situ alkane biodegradation. Since alkanes  comprise substantial components of many fuel mixtures that are spilled into aquifers, looking for their metabolic by-products should be included in more future site assessments to determine the prospects for in situ alkane bioremediation; details on how to look for such metabolites in environmental samples have been described  in subsurface microbial populations along with metabolite profiling offers very strong evidence for the in situ anaerobic biodegradation of alkanes . Of the saturate fraction of fuels, the anaerobic metabolism of 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.


Despite increasing studies targeted at host-pathogen interactions, vector-borne diseases remain one of the largest economic health burdens worldwide. Such diseases are vectored by hematophagous arthropods that deposit pathogens into the vertebrate host’s skin during a blood meal. These pathogens spend a substantial amount of time in the skin that allows for interaction with cutaneous immune cells, suggesting a window of opportunity for development of vaccine strategies. In particular, the recent availability of intravital imaging approaches has provided further insights into immune cell behavior in living tissues. Here, we discuss how such intravital imaging studies have contributed to our knowledge of cutaneous immune cell behavior and specifically, toward pathogen and tissue trauma from the arthropod bite. We also suggest future imaging approaches that may aid in better understanding of the complex interplay between arthropod-vectored pathogens and cutaneous immunity that could lead to improved therapeutic strategies. Through the Looking Glass in her explanation of the nature of Wonderland.“Now, here, you see, it takes all the running you can do, to keep in the same place” – a statement made by the Red Queen to Alice in Lewis Carroll’s In 1973, Leigh Van Valen proposed the metaphor of an evolutionary arms race coined the Red Queen Hypothesis, which suggests that microbial pathogens and their host co-evolve continuously to maintain a state of balance  that resThe skin serves as a primary example of an evolutionary adaptation of vertebrates. As the primary interface between the host’s body and environment, it provides a first line of defense against microbial pathogens and physical insults. Anatomically, the skin can be categorized into two distinct layers separated by a basement membrane: the dermis and the epidermis Figure . The epiDespite the skin serving as a significant barrier, a number of pathogens have evolved to bypass this barrier by hitch-hiking on an arthropod vector. Arthropods form a major group of disease vectors that include mosquitoes, sand flies, ticks, and mites. These hematophagous vectors allow pathogens to be deposited directly into the dermis during a blood meal. Once in the dermis, pathogens must evade the immune response to establish an infection or navigate their way toward the systemic circulation for successful dissemination , 18.in vivo to capture the full sequence of events. Fortunately, the relatively accessible nature of the skin for live imaging has provided us critical information on the fundamental behavior of immune cells  was also shown to mediate intercellular signal relay among neutrophils by amplifying local cell death signals to direct interstitial neutrophil recruitment during the amplification phase  or Bacillus Calmette–Guérin (BCG), dDCs arrested their migratory behavior , we have previously showed that in comparison to the sessile LCs in the neighboring epidermis, dDCs actively crawled through the dermal interstitial space under homeostatic conditions  Figure C. Their behavior . They alL. major as they decreased their motility upon approach  in skin was TLR2 dependent and involved complement factor C3 mediated signaling (in vivo imaging studies have yet to be conducted on arthropod-vectored pathogens, human neutrophils were shown to perform NETosis on Leishmania promastigotes (Plasmodium falciparium (Borrelia burgdoferi (in vivo will thus be of interest in future imaging studies.Neutrophils are recruited to the infectious site and are important for pathogen clearance through phagocytosis and release of microbicidal agents . They adignaling . NETosisstigotes , Plasmodciparium , and Borrgdoferi . The preL. major have evolved to hitch-hike onto the short-lived neutrophil (L. major infection resulted in decreased infection levels.Macrophages are sessile immune cells that serve as obligatory phagocytes and final definitive hosts for replication of some arthropod-vectored pathogens . Upon pautrophil , which autrophil . Similarutrophil . As suchLeishmania parasite. However, the interaction of skin immune cells with many other arthropod-vectored bacteria and viruses, despite being made available for imaging through fluorescent tagging, remain poorly described. In particular, the majority of Plasmodium parasite studies are performed in the liver, as it is the site of transformation from sporozoites into merozoites (Plasmodium parasite was recently shown to linger in the dermis for an unexpected longer period of time and may even be the final destination for differentiation into persistent merozoites (Despite increasing intravital imaging studies on host-pathogen interactions, only a handful are targeted specifically toward arthropod-vectored pathogens and cutaneous immunity through the natural route of infection. Currently, the most well defined arthropod-vectored pathogen in the context of cutaneous immunity is the rozoites . Howeverrozoites . Hence, Leishmania parasite behavior. Nevertheless, it remains challenging to simultaneously define a number of immune subsets without considerable overlap in fluorophores. However, by taking a cue out of the “brainbow” mouse model that allows for the differentiation of up to 90 colors in neurons (Additionally, due to the complex interaction of immune cells in response to pathogen, there is a substantial need to utilize transgenic mice that possess more than one fluorescent cell subset. For example, both monocytes and neutrophils are known to congregate at the locus of the sandfly bite  and such neurons , future 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.


Post-traumatic stress disorder (PTSD) is a debilitating condition that develops in a proportion of individuals following a traumatic event. Despite recent advances, ethical limitations associated with human research impede progress in understanding PTSD. Fortunately, much effort has focused on developing animal models to help study the pathophysiology of PTSD. Here, we provide an overview of animal PTSD models where a variety of stressors  are used to examine the long-term effects of severe trauma. We emphasize models involving predator threat because they reproduce human individual differences in susceptibility to, and in the long-term consequences of, psychological trauma. These sleep disturbances may explain some of the cognitive impairments reported in PTSD , show atypical activity patterns in PTSD. Indeed, results from several functional imaging studies show that reminders of traumatic events activate the amygdala more strongly in individuals with PTSD than in controls  Face validity—does the model reproduce symptoms associated with the human syndrome? (2) Construct validity—does the model measure what it intends to measure ? (3) Predictive validity—can the model predict treatment  outcomes seen in the human syndrome? (4) Discriminant validity—does the model differentiate between those with and without PTSD?  show an immediate and persistent increase in anxiety in the EPM compared to rats that swim without submersion , contrary to what this name implies, actually involves the administration of various stressors . Although SPS does not address the unique contributions of each stressor independently or potential confounds associated with repetitive stress, it is used widely and features some similarities with human PTSD  involves exposing animals to a different stressor daily for 6 days, and this procedure is repeated for several weeks in a row  or their odor  in a proportion of subjects  in Lewis rats is advantageous in many ways. Because random groups of Lewis rats include a nearly equal fraction of susceptible and resilient subjects, fewer rats have to be studied to compare the two groups on any dimension. This is particularly advantageous for labor-intensive studies. Along the same lines, because predator threat induces a bimodal distribution of anxiety-like behaviors, there is no need to eliminate animals from the analyses in order to examine only extreme responders as is sometimes done in other stress models. Furthermore, tests can be conducted before or after exposure of the rats to predators or their odor to determine if differences between susceptible and resilient animals predate or are a consequence of the stressor. In one approach for instance, 1 week following a single 10-min exposure to soiled cat litter, Lewis rats are tested on the EPM  in context A, which results in enhanced fear responses when a single shock is later presented in context B  as well as hippocampal dysfunction. While many models reproduce some aspects of human PTSD, in our opinion, the predatory threat model comes closest to the human syndrome. Indeed, in addition to reproducing avoidance, anxiety, and individual differences in trauma susceptibility, this model mimics the fear extinction and hippocampal processing deficits seen in the human syndrome, 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.


What good are transposable elements (TEs)? Although their activity can be harmful to host genomes and can cause disease, they nevertheless represent an important source of genetic variation that has helped shape genomes. In this review, we examine the impact of TEs, collectively referred to as the mobilome, on the transcriptome. We explore how TEs—particularly retrotransposons—contribute to transcript diversity and consider their potential significance as a source of small RNAs that regulate host gene transcription. We also discuss a critical role for the mobilome in engineering transcriptional networks, permitting coordinated gene expression, and facilitating the evolution of novel physiological processes. The 1983 Nobel Prize for Physiology or Medicine was awarded to Barbara McClintock for her seminal discovery of transposable elements (TEs). McClintock's studies of colour patterns in maize kernels led her to conclude that “controlling elements” that could jump around the genome regulate gene expression . There are only three highly active elements in the human genome: (1) a subset of L1 LINEs, (2) Alu elements that are a family of primate-specific SINEs, and (3) SVA elements , preventing the synthesis of a protein . Indeed,mobilome, have impacted the transcriptome. This includes elements active today as well as those no longer transposition-competent. Although not nearly an exhaustive account, we draw on specific examples from a range of organisms to illustrate the variety of mechanisms through which this can occur. We aim to highlight the importance of the mobilome in shaping both the diversity and regulation of the transcriptome.In this review, we consider how TEs, collectively referred to as the Caenorhabditis elegans: about 20,000 and 19,000, respectively. This was unexpected because of the apparent complexity of humans relative to nematodes; indeed, earlier estimates for the number of human genes ranged from 60,000–150,000. Several factors may account for this discrepancy C. elegansOne surprising finding from sequencing the human genome was that humans have a similar number of genes to the model nematode Alu elements, can introduce novel splice sites Alu elements inserted into a gene can provide both splice acceptor and donor sites, creating new exons Alu-derived exons are alternatively spliced Alu-derived exons are tissue-specific, suggesting TEs contribute to the transcriptome differences that define cell types TEs, particularly L1 and ATRN gene provides a good example of how TE-induced alternative mRNA processing can enable functional diversification of one gene. A subset of ATRN transcripts are cleaved and polyadenylated within an L1 element that has retrotransposed into an intron  mice, in which an ERV intracisternal A particle (IAP) upstream of the Agouti gene provides an alternative promoter than can drive ectopic Agouti expression, producing yellow fur TEs further promote transcript diversity by providing alternative promoters for host genes. Perhaps one of the most elegant examples of this can be found in viable yellow agouti  and small interfering RNAs (siRNAs), may also have evolved as a host defence mechanism, repressing the translation of TE transcripts or promoting their decay. Like DNA methylation, this mechanism has been adopted by the host to regulate endogenous genes. Indeed, TEs are major players in the production of small RNAs that regulate host gene transcripts. For example, TE-encoded piRNAs are required to establish a gradient of maternal Rasgrf1, like Mcts2, is under the control of differential DNA methylation on the two alleles. At this locus, DNA methylation is established in the paternal germline  Stowaway1 regulate tolerance to abiotic stress MAIF1 and stalling growth, a common physiological response in plants to abiotic stresses.These examples from A defensive response to TEs is critical to guard against uncontrolled transposition. Hosts have evolved several mechanisms for tackling this, including transcriptional repression by DNA methylation and posttranscriptional repression by small RNAs. The evolution of these systems has dramatically impacted the transcriptome because they have been adopted for more general gene regulation.Saccharomyces cerevisiae, genes involved in common metabolic pathways are physically clustered in the genome TEs can influence alternative mRNA processing or generate small regulatory RNAs, but these effects on the transcriptome are locus-specific. How is transcription regulated on a global scale, say in response to an environmental cue? In the yeast Kap1 switch more readily to the totipotent state, consistent with the idea that relaxation of ERV repression drives network activation A good example of the importance of TEs in linking genes in a network can be found in embryonic stem (ES) cells. ES cells are pluripotent but can enter a transient phase of totipotency from which they can generate both embryonic and extra-embryonic lineages ATRN. However, by re-wiring networks, the mobilome can facilitate the evolution of complex physiological processes involving gene expression on a global scale. The evolution of pregnancy, the trait that defines mammals, is an intriguing example of this. The hormone progesterone triggers the differentiation of endometrial stromal cells to form the decidua, the maternal component of the placenta Earlier, we discussed how a TE could contribute to the evolution of novel functions at a single gene, such as human syncytin genes, essential for formation of the syncytiotrophoblast layer that mediates fetal-maternal exchange, are derived from ERV env genes and have been independently acquired in the human, mouse, and rabbit genomes An important progesterone-responsive gene is prolactin. In addition to being linked in this network by MER20, the promoter for human prolactin is derived from an independent TE, MER39 Other aspects of the physiological changes required for pregnancy may have evolved by TEs re-wiring networks, such as the tolerance of the maternal immune system to a fetus expressing paternal antigens The impacts of TEs on the host transcriptome are diverse. At the single locus level, a transposition event may result in an alternatively processed transcript that can evolve a new function. At the genome level, TEs may disperse regulatory elements that rewire transcriptional networks. The significance of TEs is becoming increasingly apparent with more widespread application of next-generation sequencing technologies. At first, repetitive elements were a nuisance in the analysis of genome-wide datasets; now new experimental protocols and computational pipelines are being utilised to ask questions specifically about TE distribution Many important questions remain unanswered. For example, what is the extent and biological significance of somatic retrotransposition? What is the contribution of this mechanism to the transcriptome differences between neurons, and how does this influence behaviour? Additionally, inappropriate activation of TEs has been associated with somatic cancers Are the evolutionary benefits conferred by TEs purely accidental? Most point mutations arising in the germline have a deleterious or neutral effect on the host, but some do introduce innovative changes that are beneficial. Likewise, TE insertions may be deleterious but can also provide opportunities for increasing transcript diversity or rewiring the transcriptome. Such advantageous insertion events can be selected for and fixed in a population. This “fine-tuning” of the transcriptome could explain why organisms have evolved mechanisms to regulate TE activity without completely silencing all types.Our understanding of the diverse impacts of the mobilome on the transcriptome has come a long way since the finding that TEs could cause insertional mutations leading to disease. TEs have been fundamental players in evolution and are intimately associated with the regulation of host gene transcription.


Adult T cell leukemia (ATL) is one of the rare human cancers initiated by a transforming retrovirus, HTLV-I. After many years of controversy, it is now accepted that the viral transactivator protein Tax plays a critical role in initiating the leukemic process, because Tax transgenics develop a disease with striking ATL features. However, its role in the maintenance of the lymphoproliferation remains still a matter of debate. Long-term prognosis of ATL patients remains extremely poor. In acute ATL, well conducted Japanese trials demonstrated that although combinations of chemotherapy improved response rate, they failed to achieve a significant impact on survival. Patients with chronic and smoldering ATL have a better prognosis but long-term survival is poor when these patients are managed with a watchful-waiting policy or with chemotherapy. We recently realized a worldwide meta-analysis showing that the combination of zidovudine and interferon-alpha (IFN) is highly effective in the leukemic subtypes of ATL and should be considered as standard first line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as patients with acute ATL and wild type p53. ATL lymphoma patients may benefit from initial induction therapy based on aggressive chemotherapy regimen in addition to or followed by antiretroviral therapy with AZT/IFN. In all patients, in order to prevent the occurrence of resistance and relapse, clinical trials assessing bone marrow transplantation additional targeted therapies such as arsenic/IFN combination or monoclonal antibodies, are mandatory after achieving CR. In that sense, we recently reported that the combination of arsenic trioxide, IFN, known to trigger Tax proteolysis in addition to zidovudine, yielded unprecedented response rates in chronic ATL patients, and may prevent relapses in ATL lymphoma responding patients after chemotherapy. To investigate the molecular mechanism of therapeutic action in vivo, we used Tax transgenic mice that develop a disease with striking ATL features. We demonstrate that the combination of arsenic trioxide and IFN cures Tax-driven murine ATLs through selective targeting of leukemia initiating cell (LIC) activity. Importantly, this effect requires proteasome function. Overall, our findings strongly suggest that in this model ATL LICs are addicted to the iral Tax oncoprotein and open the prospect of new strategies to cure ATL.


When normal subjects fix their eyes upon a stationary target, their gaze is not perfectly still, due to small movements that prevent visual fading. Visual loss is known to cause greater instability of gaze, but reported comparisons with normal subjects using reliable measurement techniques are few. We measured binocular gaze using the magnetic search coil technique during attempted fixation (monocular or binocular viewing) of 4 individuals with childhood-onset of monocular visual loss, 2 individuals with late-onset monocular visual loss due to age-related macular degeneration, 2 individuals with bilateral visual loss, and 20 healthy control subjects. We also measured saccades to visual or somatosensory cues. We tested the hypothesis that gaze instability following visual impairment is caused by loss of inputs that normally optimize the performance of the neural network (integrator), which ensures both monocular and conjugate gaze stability. During binocular viewing, patients with early-onset monocular loss of vision showed greater instability of vertical gaze in the eye with visual loss and, to a lesser extent, in the normal eye, compared with control subjects. These vertical eye drifts were much more disjunctive than upward saccades. In individuals with late monocular visual loss, gaze stability was more similar to control subjects. Bilateral visual loss caused eye drifts that were larger than following monocular visual loss or in control subjects. Accurate saccades could be made to somatosensory cues by an individual with acquired blindness, but voluntary saccades were absent in an individual with congenital blindness. We conclude that the neural gaze-stabilizing network, which contains neurons with both binocular and monocular discharge preferences, is under adaptive visual control. Whereas monocular visual loss causes disjunctive gaze instability, binocular blindness causes both disjunctive and conjugate gaze instability (drifts and nystagmus). Inputs that bypass this neural network, such as projections to motoneurons for upward saccades, remain conjugate. Eye movements evolved to serve vision One important component of gaze control is referred to as the neural integrator for eye movements, because it integrates premotor signals for saccades, pursuit, and vestibular inputs, which are velocity coded, into signals encoding eye position Since vision is used to optimize eye movements, a question arises: What is the effect of loss of vision on the control of eye movements? Prior studies of individuals who have visual loss showed that, during attempted fixation, gaze is unstable due to eye drifts, which may be disjunctive or even in opposite directions e.g., ±10° to the right or left of straight ahead); subjects who have lost vision cannot be expected to do this with precision. Although these studies have provided informative, qualitative records of the eye movements shown by blind eyes, their lack of quantification has precluded any direct comparison with the eye movements of normal subjects.Unfortunately, many prior studies of eye movements in individuals who have visual impairment suffer from a methodological flaw: the calibration of eye movement measurements was either absent or unreliable. With only a few exceptions Fortunately, there is a method to make reliable binocular measurements of eye movements in those who are unable to look at visual stimuli: the magnetic field and search coil technique We studied a group of individuals with variable severity of visual loss and compared their gaze stability and saccades with a group of healthy control subjects. We were primarily interested in the case of monocular visual loss, in which the normal eye serves as a control. In such individuals, the abnormal eye often drifts about its visual target, predominantly in the vertical plane; this is called the Heimann-Bielschowsky phenomenon (HBP) We found that monocular visual loss affected monocular gaze stability more than vertical saccades, pointing to the importance of binocular visual inputs in optimizing the performance of the gaze-holding network. We also found that remarkably accurate saccades could be made to somatosensory cues following binocular loss of vision in adulthood, but not if blindness was from infancy. Some data from one individual with monocular visual loss and another with blindness since birth have been previously reported All subjects gave informed written consent in accordance with Cleveland Veterans Affairs Medical Center Institutional Review Board and the Declaration of Helsinki. The Cleveland Veterans Affairs Medical Center Institutional Review Board specifically approved this study.We studied six subjects with monocular visual loss  and two subjects with binocular visual loss (P7-8); demographic data, etiology, and severity of their visual loss are summarized in Patients and control subjects sat with the head firmly stabilized by supports attached to a chair. We measured eye movements using the magnetic field and search coil technique Horizontal and vertical eye and head position were obtained from coil signals following analog filtering (pass-band 0–150 Hz) and digitization at 500 Hz with 16-bit precision Our first question was whether our healthy CS showed relative gaze instability (evident as a greater SD of position) of the eye under cover during monocular viewing. We found no significant difference between their two eyes in any plane ; median Our next question was whether gaze was less stable in the eye with visual loss than our CS. First we considered the four patients (P1-4) whose visual loss dated from childhood or adolescence. All showed greater instability in the affected eye; an example is shown in Measurements of median speed gave generally similar results , with siA finding that follows from these inter-ocular differences is that their eye movements during attempted fixation were disjunctive – much more so than for the CS; When we compared SD of the position of the affected eye of the two individuals with visual loss in later life due to ARMD  for eye movements, which has been shown to contain component neurons that have monocular firing preference Our findings raise several issues for discussion. First, why is gaze stability in the eye with impaired vision mainly in the vertical plane (HBP)? Second, why is gaze stability of the eye with better vision impaired compared with control subjects, especially when it is covered? Third, why does it take time for these instabilities to develop? Fourth, why does HBP with oscillopsia sometimes persist despite recovery to relatively normal vision?Vergence provides a robust, on-line mechanism to precisely align the eyes in the horizontal plane and, in Patient 1, was preserved, even though he lacked stereopsis. However, vertical vergence mechanisms show more limited range of movement and flexibility, although they are amenable to plastic-adaptive responses to changed visual demands, such as wearing a base-up prism before one eye The finding that gaze stability sometimes improved in the poorer eye when it was required to fix (by covering the good eye) was part of the original report of HBP Third, our studies of bilaterally blind patients stress the importance of the duration and age-of-onset of visual loss. Thus, while our patient who was blind since birth due to Leber’s congenital amaurosis was unable to make accurate saccades, our patient who sustained almost complete vision loss at age 57 years was still able to make accurate saccades to proprioceptive targets three years later . It willFinally, one might ask why the HBP persists despite relatively normal vision (P1 and P2) and oscillopsia. Development of oscillopsia after restoration of vision in an eye with HBP has been described by other groups of researchers


The effects of preterm birth and perinatal events on bone health in later life remain largely unknown. Bone mineral density (BMD) and osteoporosis risk may be programmed by early life factors. We summarise the existing literature relating to the effects of prematurity on adult BMD and the Developmental Origins of Health and Disease hypothesis and programming of bone growth. Metabolic bone disease of prematurity and the influence of epigenetics on bone metabolism are discussed and current evidence regarding the effects of breastfeeding and aluminium exposure on bone metabolism is summarised. This review highlights the need for further research into modifiable early life factors and their effect on long-term bone health after preterm birth. Preterm birth accounts for 5–10% of births in the UK. Worldwide almost 10% of babies are born preterm, representing more than 15 million births every year [Despite these challenges, survival has improved dramatically in the last few years, especially in developed countries. More than 50% of babies born at 24 weeks gestation regularly survive long term with improved nutrition being one potential factor contributing to these improvements. As this cohort of survivors reaches middle age the impact of preterm birth on long-term metabolic outcomes such as bone mineral density will become increasingly important.Osteoporosis is characterised by the depletion of bone mineral mass, combined with bone microarchitecture deterioration and a resultant increased fracture risk . It is oIt is estimated that osteoporosis affects 3 million people in the UK and results in 250,000 fractures annually [We present a review of the current literature regarding early life factors and the impact of nutrition on bone mineral density and bone health after preterm birth, in order to inform further research and highlight current challenges facing the clinicians responsible for this cohort. There is strong evidence linking early life exposures and later peak bone mass in childhood, for example, the contributions of physical exercise both in utero and childhood, cigarette smoking during pregnancy, and diet and endocrine status in childhood , 8. BoneResearch also suggests that some of the predisposition for osteoporosis can be attributed to polygenic genetic inheritance. For example, polymorphisms in vitamin D and oestrogen receptor genes and collagen coding genes have been implicated . It is lThe Developmental Origins of Health and Disease (DOHaD) hypothesis suggest that nutritional imbalance during critical windows in early life can permanently influence or “programme” long-term development and disease in later life . Much ofRecently, research has linked birth weight, birth length, and placental weight to later osteoporosis risk –20. KnowMany of the programming effects may be modulated by epigenetic mechanisms. Epigenetics is the study of mitotically heritable alterations in gene expression potential that are not caused by changes in DNA sequence. The classic examples are DNA methylation and histone acetylation . These pThe preterm population is particularly susceptible to metabolic bone disease for two key reasons: firstly, 80% of fetal bone mineral accumulation occurs during the last trimester of pregnancy, with a surge in placental transfer of calcium, magnesium, and phosphorus to the neonate . A preteSecondly, providing adequate nutrition to preterm infants can be extremely challenging. Most extremely preterm infants (<32 weeks gestation) require support with parenteral nutrition (PN) because of complex factors including metabolic “immaturity” (that may limit nutrient intake) and a delay in establishing enteral feeds. In addition, solubility issues with PN solutions mean it is impossible to provide sufficient mineral via the parenteral route alone. Maternal breast milk is associated with a range of benefits in the short-term  and long-term  but alone will not meet nutrient requirements without fortification. Therefore as well as being born with a mineral deficit, the often stormy neonatal course and nutritional practicalities of providing adequate mineral intake means that many preterm infants develop osteopenia of prematurity.As preterm infants grow, mineral uptake is compromised through the low content in unfortified breast milk  and inefficient absorption due to an under-developed gastrointestinal tract . This reThere is conflicting data regarding the long-term consequences of preterm birth on the skeleton and the potential for peak BMD compared to their term counterparts. Preterm infants are known to have a lower bone mass , BMD 2626 and BMSeveral studies have failed to demonstrate an association between preterm birth and later bone strength, although all of these , 31, 32 Several maternal factors are known to have a negative impact on neonatal growth and skeletal mineralisation in term infants. Although not discussed in detail here, examples are shorter maternal height, low parity, smoking during pregnancy, low fat stores , 34, andThere is conflicting data regarding the influence of birthweight on later BMD. Low birthweight (LBW) is defined by WHO as <2500 g . LBW is n = 201), few measurements were taken after discharge and dual-energy X-ray absorptiometry (DXA) analysis was only taken at 8–12 years. As a result, changes in growth and corresponding bone mass at potentially critical epochs of infancy were not measured. Several studies in infants have shown the influence of early growth on later bone health in those born preterm. In a study by Cooper et al., those who were lightest at 1 year of age had the lowest BMC . In a fuOptimising early growth through nutritional interventions generates positive and lasting effects on bone mineralisation  and it iLieben et al.  and KanaAluminium has no active role in the human body but is inadvertently ingested in the preterm for several reasons. Firstly preterms are exposed to high levels of aluminium in standard parenteral nutrition (PN) regimes. The current trend is for early PN to optimise early growth and associated neurocognitive function. Most aluminium is accumulated through unavoidable contamination via calcium gluconate stored in glass vials. In adults, this aluminium load is probably adequately dealt with by the kidneys, but the premature infant's renal system is relatively immature so accumulation occurs. Adverse effects of aluminium in bone have been seen in uraemic adults and there are now studies showing that infants who received aluminium-depleted PN had significantly higher BMC of the lumbar spine . A direcThere is conflicting evidence as to whether breastfeeding has a protective role in the primary prevention of osteoporosis. In some studies, such as that of Fewtrell et al., breast milk consumption was found to result in higher adult BMD  despite It is difficult for the preterm infant to match the in-utero accretion of minerals. Calcium absorption depends on calcium and vitamin D intakes and phosphorus levels, which affect calcium retention. In clinical practice, very few babies need calcium supplementation if they receive either a preterm formula or breastmilk along with breastmilk fortifier . SuboptiLittle is known concerning the early life control mechanisms for bone development  and the One of the greatest challenges of longitudinal cohort studies, especially in children, is the attritional losses over time. In addition, much of the current data available is from preterm infants recruited to studies in the 1980s, an era pre-dating the widespread use of antenatal steroids and surfactant therapy; two of the key practices that have had the most dramatic effects on long term survival. As cohorts of preterm born adults reach middle age, their risk of osteoporosis and their antecedent risks factors will become increasingly apparent. As survival rates continue to improve, the long term effects of premature birth become increasingly important. Only decades of future follow-up will truly ascertain the risk of osteoporosis and fracture after preterm birth. Because there is no cure for osteoporosis, preventative measures are important to minimise risk in this susceptible population. Genetic and intrauterine environmental factors that influence fetal growth trajectory have long-term consequences on body composition. Clearer identification of risk factors and refinement of biomarkers for later bone health will enable earlier preventative strategies. Reduction of the exposure of preterm infants to aluminium is an urgent research and clinical priority. Breastfeeding along with appropriately formulated breastmilk fortifiers to ensure adequate mineral intake and optimal growth should be strongly encouraged. As early mineral deficiency and metabolic bone disease are often asymptomatic during neonatal period, careful follow-up is required to identify at risk groups. Targeted prevention, early diagnosis and appropriate timely treatment may then significantly reduce the individual, health service, and societal burden of osteoporosis in the future. (i)There are conflicting data regarding the effects of preterm birth and/or LBW on later BMD. (ii)Need for further research into modifiable early life factors and long-term bone health. (iii)Breastfeeding (with appropriate fortifiers) and vitamin D supplementation may have long term benefits on BMD in preterm infants. (iv)Reduction of aluminium exposure in preterm infants is an urgent priority.Key learning points are as follows.


Acute aortic dissection (AAD) is a rare and lethal disease with presenting signs and symptoms that can often be seen with other high risk conditions; diagnosis is therefore often delayed or missed. Pain is present in up to 90% of cases and is typically severe at onset. Many patients present with acute on chronic hypertension, but hypotension is an ominous sign, often reflecting hemorrhage or cardiac tamponade. The chest x-ray can be normal in 10-20% of patients with AAD, and though transthoracic echocardiography is useful if suggestive findings are seen, and should be used to identify pericardial effusion, TTE cannot be used to exclude AAD. Transesophageal echocardiography, however, reliably confirms or excludes the diagnosis, where such equipment and expertise is available. CT scan with IV contrast is the most common imaging modality used to diagnose and classify AAD, and MRI can be used in patients in whom the use of CT or IV contrast is undesirable. Recent specialty guidelines have helped define high-risk features and a diagnostic pathway that can be used the emergency department setting. Initial management of diagnosed or highly suspected acute aortic dissection focuses on pain control, heart rate and then blood pressure management, and immediate surgical consultation. Emergency physicians are especially challenged by diseases that are dangerous, require urgent treatment, and concealed from recognition. No diagnosis better exemplifies these characteristics than aortic dissection, and while the diagnosis is emphasized in Emergency Medicine training and continuing education, aortic dissection is not diagnosed on its initial presentation in 15-43% of cases ; in factAortic dissection is an uncommon disease, with prevalence estimates ranging from 5,000 to 10,000 cases in the United States per year. ,5 Untreanone of the classic features. [dangerous conditions that quite reasonably establish the focus of care but ultimately turn out to be distractors.Approximately 1 in 10,000 ED patients will have aortic dissection, a number so small that emergency providers may only see several cases in their career. Only one quarter of patients with aortic dissection present with a combination of classic features ; 1 in 25 patients diagnosed with aortic dissection has eatures.  Furthermcould be caused by aortic dissection but almost certainly are not; aortic dissection could therefore be said to represent not just a needle in a haystack, but a needle disguised as a blade of hay in a haystack. Physicians evaluating patients whose symptoms may be caused by aortic dissection must therefore understand the clinically relevant risk factors and clinical manifestations of this condition and develop a risk stratification strategy that catches as many patients with the disease as possible without overusing advanced imaging studies. Emergency clinicians are thus confronted with innumerable patients whose symptoms dissecting aortic aneurysm; however this term is discouraged as it is both inaccurate and conflates aortic dissection with aortic aneurysm, a distinct clinical entity. Aortic dissection is thought to result from the hydrostatic pressure accumulated as blood is pumped through the aorta, as well as movement of the aorta itself, with every cardiac cycle. Histologically, aortic dissection is associated with characteristic changes in the vessel wall known as medial degeneration. The former term, cystic medial necrosis, has fallen out of favor as the observed lesion demonstrates neither cysts nor necrosis.Aortic dissection occurs when the innermost layer of the aortic vessel wall is torn, creating a false lumen which transmits a longitudinal column of blood. It is sometimes referred to as a Aortic dissection is more likely to occur in conditions that augment the pressure exerted by blood on the vessel wall, as well as conditions that weaken the vessel and accelerate medial degeneration. These conditions include hypertension, stimulant use , pregnancy, weight-lifting or valsalva, pheochromocytoma, bicuspid aortic valve, aortic valve instrumentation or aortic surgery, syphilitic aortitis, large-vessel vasculitides, and congenital connective tissue disorders such as Marfan, Loeys-Dietz and Ehlers-Danlos syndromes.The Stanford classification designates Type A dissections as lesions involving the ascending aorta, and Type B dissections confined to the descending aorta. Type A dissections are more common and much more dangerous, which drives differences in the therapeutic approach. Variants of aortic dissection include aortic intramural hemorrhage, which is a hematoma completely contained within the vessel wall, and penetrating aortic ulcer, a disruption in the vessel wall that usually leads not to dissection but aneurysm. These lesions are both treated similarly to aortic dissection. Aortic dissection causes morbidity and mortality by several mechanisms. Type A dissections can progress proximally to cause hemopericardium with tamponade as well as acute aortic valve regurgitation. Both types of dissections can breach the outer adventitial layer of the vessel, leading to free rupture into the chest or abdomen. Most sequellae of aortic dissection, however, result from the false lumen extending across ostia of branch arteries, leading to acute ischemia of potentially any organ in the body.Despite the rarity of the disease, good data are available on clinical features of aortic dissection, owing to The International Registry of Acute Aortic Dissection (IRAD).  Pain is Many patients with aortic dissection will present with acute on chronic hypertension, and aortic dissection is one of the cardinal hypertensive emergencies. Hypotension is ominous in the setting of aortic dissection as it often indicates either proximal extension with cardiac tamponade or free or contained rupture. Pseudohypotension–peripheral hypotension with central normotension–may be caused by dissection across the subclavian arteries. Subclavian or iliac artery embarrassment may also lead to the classic (though uncommon) finding of a pulse deficit or blood pressure differential across limbs. The murmur of aortic regurgitation, or signs of cardiac tamponade, may be present. If the dissection involves the left or (more commonly) right coronary artery, acute myocardial infarction and its attendant signs and symptoms can result. A variety of neurologic deficits including weakness or even coma may be caused by aortic dissection, depending on the cerebral branch arteries affected. Distal aortic dissection can cause ischemia to either kidney, lower extremity ischemia, as well as mesenteric ischemia and resulting abdominal pain, back pain, or diarrhea.Routine laboratory testing is not helpful for ruling in or ruling out aortic dissection. Preoperative studies are indicated when sufficient concern for the disease exists, or as soon as the diagnosis is confirmed.The use of serum quantitative D-dimer testing has been proposed as a strategy to rule out aortic dissection. -12 Propo1), the most important being mediastinal widening, which is present in more than half of cases. The absence of suggestive findings on chest xray makes aortic dissection less likely, however, 10-20% of patients with aortic dissection have a normal chest xray; therefore a negative study cannot exclude the disease and should not play a decisive role in the decision to pursue advanced imaging.Plain chest radiography is indicated in all patients with chest pain of uncertain etiology, and whenever aortic dissection is considered. The chest xray is most useful when it provides an alternative explanation for the patient's symptoms. A variety of CXR abnormalities are associated with aortic dissection  poorly visualizes much of the aorta and is limited by patient, operator, and machine characteristics; aortic dissection cannot be excluded by TTE. However, point of care ultrasound by emergency physicians is recommended for all patients with suspected aortic dissection as well as all critically ill patients, and should be considered for all patients with chest or abdominal pain of uncertain etiology. In addition to evaluating alternative diagnoses, an intimal flap at either the aortic root or descending aorta may be distinguished by TTE and is diagnostic. TTE also reliably identifies complications of aortic dissection such as pericardial effusion and aortic regurgitation. -18Transesophageal echocardiography (TEE) is very accurate in both ruling in and ruling out aortic dissection and can be performed in a critical care area as resuscitative efforts are ongoing–a distinct advantage compared to CT and MRI, the two other definitive imaging modalities. However, TEE is uncommonly performed by emergency clinicians and not widely available on a consultative basis in many emergency departments. Invasive echocardiography may play a more prominent role in the emergency evaluation of aortic dissection if the technique sees broader application by emergency providers. Intravenous contrast-enhanced computed tomography reliably confirms and excludes aortic dissection and may elucidate alternative diagnoses, including pulmonary embolism and obstructive coronary artery disease. Contemporary CT scanning is rapid and widely available; CT is therefore the most common definitive imaging study used in patients with suspected aortic dissection. Beyond the concerns raised by moving a potentially critically ill patient to the radiology suite, drawbacks of CT include the risks of IV contrast and ionizing radiation.Magnetic resonance imaging also accurately rules in and rules out aortic dissection,  and is fevaluation pathway that specifically addresses what for emergency and primary care clinicians is the most difficult and crucial element of aortic dissection management: deciding which patients require advanced imaging to exclude the disease.  The pathway hinges on the assessment of pre-test probability of disease using specified high risk features from three risk categories: past medical history, history of present illness, and physical exam. All of these elements are collected on routine emergency assessments, with the exception of blood pressure measurement in both arms.In April of 2010, the American College of Cardiology Foundation and American Heart Association published the first comprehensive, multidisciplinary guideline on the diagnosis and management of patients with thoracic aortic disease, including aortic dissection.  The authPatients with high risk features from more than one risk category are assumed to have aortic dissection until proven otherwise and should be managed accordingly. In this group of high risk patients with a negative definitive imaging study, a second imaging study should be strongly considered.Patients with high risk feature(s) from only one risk category should have an electrocardiogram and chest xray performed promptly. If the electrocardiogram demonstrates evidence of acute myocardial infarction, management should be directed at AMI unless other strong evidence of aortic dissection is present. This recommendation is based on estimates of primary AMI occurring over one thousand times more frequently than AMI resulting from aortic dissection,  and the Patients without high risk features only require aortic imaging if no alternative diagnosis is identified and the patient has unexplained hypotension or widened mediastinum on CXR.The primary concern for emergency physicians managing confirmed or highly suspected aortic dissection is to arrange for immediate surgical consultation. Though Stanford B dissections may ultimately be managed non-surgically, all patients with aortic dissection should receive prompt surgical evaluation regardless of anatomic location. The goal of medical therapy in the normotensive or hypertensive patient with aortic dissection is to reduce the frequency and magnitude of force bloodflow exerts on the aortic wall. Analgesia is the first priority and is easily overlooked. Patients with aortic dissection may have severe pain and anxiety, both of which merit attending to in their own right but also produce a catecholamine response that directly undermines treatment objectives. Fortunately, unlike the underlying lesion, pain and anxiety are easily managed and intravenous opiates should be immediately and aggressively titrated to relief of pain as soon as dissection is diagnosed or strongly suspected.The cornerstone of medical management is beta blockade, titrated to a heart rate of 60 beats per minute. Widely available agents well suited to this purpose include metoprolol and esmolol, with esmolol offering the benefit of minute-to-minute titration; this is particularly advantageous in aortic dissection patients who may experience dramatic swings in blood pressure as the lesion evolves and, for example, causes pericardial tamponade or acute aortic insufficiency. Labetalol is widely recommended and is an acceptable alternative; however labetalol tends to lower blood pressure more reliably than heart rate. ,24 PatieWhen beta blockade has achieved its goal heart rate, blood pressure is the next therapeutic target. If systolic blood pressure is greater than 120 mm Hg, an additional agent should be added to lower blood pressure with a goal of less than 120 mm Hg, ideally titrated to as low a blood pressure as end organs allow. Blood pressure should be measured in both arms and treatments directed at the highest reading. Nicardipine, a parental dihydropyridine calcium channel blocker, has emerged as the first line vasodilator infusion in many emergency departments and is recommended in this context; nicardipine may be replaced on formularies by its ultra-short acting congener, clevidipine, in the future. Nitroprusside is effective and classically used for aortic dissection, but is more difficult to manage and is associated with adverse effects such as cerebral blood vessel vasodilation  and cyanMedical therapies for patients with aortic dissection who are hypotensive are of minimal effect and limited to intravenous crystalloid and vasopressor support, pending surgical management. Pericardial tamponade is a common cause of hypotension in these cases; weak evidence suggests that pericardiocentesis should be avoided in patients not arrested or nearly arrested in favor of expeditious transfer to the operating theater. a priori with surgery colleagues. Patients with diagnosed or strongly suspected aortic dissection require expeditious surgical evaluation, aggressive analgesia, and treatment with rapid-acting, titratable agents to first lower heart rate and then blood pressure to specific targets.Aortic dissection is an uncommon disease that often presents with varied and atypical findings suggestive of more frequently encountered conditions; it therefore poses an exceptional diagnostic challenge to emergency providers. Mortality associated with aortic dissection is significant at presentation and advances with every hour the lesion is left untreated. While the vast majority of patients who have symptoms possibly caused by aortic dissection will not have aortic dissection, key features of the disease including risk factors, pain characteristics, physical examination findings and signs on plain chest radiography allow clinicians to develop a rational approach to diagnostic testing supported by a recently-published multidisciplinary guideline. When the diagnosis is sufficiently likely to indicate definitive testing, the choice among advanced imaging modalities should be guided by institutional capabilities; ideally decided


The interferon-inducible restriction factor tetherin  has emerged as a key component of the antiviral immune response. Initially, tetherin was shown to restrict replication of various enveloped viruses by inhibiting the release of budding virions from infected cells. More recently, it has become clear that tetherin also acts as a pattern recognition receptor inducing NF-κB-dependent proinflammatory gene expression in virus infected cells. Whereas the ability to restrict virion release is highly conserved among mammalian tetherin orthologs and thus probably an ancient function of this protein, innate sensing seems to be an evolutionarily recent activity. The potent and broad antiviral activity of tetherin is reflected by the fact that many viruses evolved means to counteract this restriction factor. A continuous arms race with viruses has apparently driven the evolution of different isoforms of tetherin with different functional properties. Interestingly, tetherin has also been implicated in cellular processes that are unrelated to immunity, such as the organization of the apical actin network and membrane microdomains or stabilization of the Golgi apparatus. In this review, I summarize our current knowledge of the different functions of tetherin and describe the molecular strategies that viruses have evolved to antagonize or evade this multifunctional host restriction factor. Tetherin is trapped in the ER in cells that have defects in the GPI-biosynthetic pathway , suggesting that tetherin is an IFN-inducible gene  to phosphatidylinositol (PI). Subsequently, GlcNAcPI is deacetylated by the ER-resident enzyme phosphatidylinositol glycan anchor biosynthesis, class L (PIGL). Mutations in PIGL cause the CHIME syndrome that is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation, and ear anomalies , tetherin seems to recruit TRAF2 and/or TRAF6 as well as the mitogen-activated kinase TAK1 and TAB, thereby activating the canonical NF-κB pathway . ILT7 forms a complex with FcεRIγ which contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic tail and induces a calcium-dependent signaling cascade that inhibits the release of type I interferons and other proinflammatory cytokines from pDCs  on pDCs . These dimers may either stabilize the Golgi structure or act as a sensor, surveilling the distance between opposing membranes. In this context, Another interesting observation comes from the hamster ortholog of tetherin called Golgi-resident GPI-anchored protein (GREG). As the name suggests, hamster tetherin is preferentially localized to the Golgi apparatus rather than the plasma membrane. GREG is characterized by a stretch of unique EQ tandem repeats serving as a putative Golgi-retention signal that is absent from all other tetherin orthologs . The only non-mammalian tetherin has been identified in the Chinese alligator Alligator sinensis . The sequence homology to mammalian tetherins is, however, only very limited and it remains to be clarified whether this reptile protein really represents a tetherin ortholog.Tetherin orthologs have been described in many mammalian species . Since these five amino acids are also absent from the genomes of the Denisova and Neanderthal, it probably emerged at least 800,000 years ago, before the separation of these ancient hominin species but after the divergence of humans from non-human primates . Some species, however, such as cats, guinea-pigs, horses, or elephants encode only the short isoform or a variant with deletions in the N-terminal part . One well-characterized example is the cat ortholog, which expresses only the short isoform due to a mutation in the upstream start codon  griseimembra encodes a tetherin variant that is not able to inhibit virion release. This lack of restriction could be ascribed to a S164T mutation in the extracellular domain of tetherin  chimpanzee tetherin have been shown to perform this function . AlthougFigure 1A; Sheep, goats, and cows encode two tetherin variants implying a gene duplication event before the divergence of these ruminants . At leasThus, some tetherin functions such as maintenance of the Golgi structure or innate sensing may have evolved relatively recently during evolution and may hence only be found in few species. In contrast, the inhibition of virion release is conserved among diverse mammals suggesting that this is an ancient function of tetherin.Figure 3A; Figure 3A). Mutational analyses revealed that residues within and adjacent to a highly conserved [D/E]xxxLL motif in the C-loop of Nef are critical for its anti-tetherin activity  to antagonize human tetherin  glycoprotein M (gM), the Chikungunya virus non-structural protein 1 (Nsp1) and the Env of SIVtan and equine infectious anemia virus (EIAV), for instance, all reduce the surface expression levels of tetherin . NeuramiFigure 3D; In 2006, tetherin was identified in a screen for factors that are downmodulated by the RING-CH ubiquitin ligase K5 of the Kaposi’s sarcoma-associated herpesvirus  is able to enhance virion release without decreasing the surface levels of the restriction factor (in vivo or have evolved means to inhibit the IFN-mediated expression of tetherin (Thus, viruses may also evolve evasion strategies without directly targeting tetherin. It has for example been suggested that some viruses do not induce IFN production tetherin . Influentetherin . To evadtetherin . Furthertetherin . Some vitetherin . Tetheritetherin . In summThe continuous arms race between viruses and their hosts has certainly driven the evolution of the host restriction factor tetherin. Whereas the ability of tetherin to restrict virion release seems to be an ancient function that is highly conserved among all mammalian orthologs, some species have evolved unique features of this protein. Bovids, for instance, express two tetherin homologs that probably differ in their expression pattern and may thus facilitate adaptation to emerging viral infections . Human aThe AIDS pandemic is an impressive example of this ongoing coevolution between viruses and tetherin. Analyses of different HIV-1 groups revealed that counteraction of tetherin may be a prerequisite for the efficient spread of lentiviruses in the human population : in contA recent publication by in vivo. In contrast to the humanized mouse models described above, these studies focused on the infection of immunocompetent mice with murine pathogens. In a study by in vivo study took advantage of a polymorphism that disrupts the first start codon of tetherin (Several additional mouse studies affirmed a crucial role of tetherin in restricting viral infection tetherin . As a cotetherin .The observation that tetherin knockout mice do not show any obvious developmental or functional defects  argues aThe 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.


Using these cellular components and input characteristics, we found that coherent gamma oscillations could emerge within experimental constraints for particular parameter balances. Here we investigate the effect of appropriately sized and connected networks.From several experimental and modeling studies, it has become apparent that networks of parvalbumin-positive (PV+), fast-firing interneurons play an essential role in generating population gamma rhythms . Many feapplied), which was heterogeneous across cells, and synaptic inhibition from presynaptic interneurons, which had a particular maximal conductance value (gPV). We systematically varied gPV and Iapplied within the experimentally determined ranges, and determined the coherence of the network model population firing and the network frequency for each combination of these values. For each of these network simulation sets, we also varied the connectivity probability as well as network size to explore how these factors affect the network's ability to produce coherent network firing. We find that when our connection probability is similar to what has been found experimentally, our networks exhibit a sharp transition from random firing to network coherence with only a small change in Iapplied. However, as connectivity in the network is increased beyond experimentally estimated values, this sharp transition disappears. Instead, a larger window of coherence is achieved, but with a smooth transition from random to coherent firing. Similarly, decreasing the network size increases the window of coherent firing, and while these sharp transitions remain for changing network sizes, the parameter regimes in which they occur changes significantly when the network size becomes much smaller than experimental estimates. Our work indicates that CA1 fast-spiking PV+ networks are capable of producing gamma population rhythms, and that perturbation in and out of coherent states can occur abruptly given the sharp transitions obtained in our network simulations. Since our simulations approximate a biological context, it may be that gating in and out of coherence is a design property to allow generation of theta/gamma network oscillations.Each cell in the network received excitatory input (I


Women have a higher incidence of stress related disorders including depression and generalized anxiety disorder, and epigenetic mechanisms likely contribute to this sex difference. Evidence from preclinical research suggests that epigenetic mechanisms are responsible for both sexual dimorphism of brain regions and sensitivity of the stress response. Epigenetic modifications such as DNA methylation and histone modifications can occur transgenerationally, developmentally, or in response to environmental stimuli such as stress exposure. This review will provide an overview of the various forms of epigenetic modifications observed in the central nervous system and will explain how these mechanisms contribute to a sexually dimorphic brain. It will also discuss the ways in which epigenetic alterations coincide with, and functionally contribute to, the behavioral response to stress across the lifespan. Ultimately, this review will focus on novel research utilizing animal models to investigate sex differences in epigenetic mechanisms that influence susceptibility to stress. Exploration of this relationship reveals epigenetic mechanisms with the potential to explain sexual dimorphism in the occurrence of stress related disorders. Stress-related disorders such as major depression and generalized anxiety affect over 20% of the American population within their lifetime, and have an annual prevalence approaching 10% . One facWhile females have a higher risk of developing stress-related disorders, males are at greater risk of developing early life social/cognitive behavior-related disorders such as autism spectrum disorders  and atteEpigenetics refers to changes that alter gene transcription in the absence of direct alterations to the genome itself . The terde novo methylation, and therefore can place methyl marks on previously non-methylated DNA [There are a number of epigenetic mechanisms that can modulate sex differences in response to stress. These include DNA methyltransferases (Dnmts), which act directly to suppress transcription or act in concert with methyl-CpG binding domain (MBD) proteins that in turn can recruit histones to modify access of transcription factors to DNA. In addition micro RNAs are another epigenetic mechanism that contributes to sex differences in the stress response and have been reviewed previously in this journal . A classated DNA . Dnmt 2 ated DNA , but theated DNA  and methated DNA ,16 respeThe majority of what is known about the functional role of Dnmts comes from the literature on development. Dnmt 1, 3a and 3b are necessary for normal prenatal development as lethality occurs in the mammalian embryo following constitutive removal of Dnmt 1, Dnmt 3b or combined 3a/3b knockouts -19. DnmtIn addition to acting directly on transcriptional targets, Dnmts work in concert with MBD proteins to alter chromatin structure through recruitment of histone modifiers . The MBDWhereas Dnmt and MBD-modulated transcriptional repression may be long lasting and potentially permanent, in some cases modifications to the histone architecture appear to be a more dynamic epigenetic alteration of the transcriptome. Nucleosomes, which are composed of DNA wrapped around an octamer histone core, are the basic unit of chromatin . Each hiTogether, these epigenetic modifications potentially allow the prenatal or postnatal environment to influence the organism in the absence of genetic alterations. Epigenetic mechanisms can be transferred across generations or can have more immediate effects on the individual. Epigenetics can lead to sex differences in brain and body development  as well Epigenetic modifications lead to sex differences by shaping the neuroanatomy and steroid hormone receptor distribution of the developing brain. The neonatal brain is both masculinized and defeminized by a surge in gonadal hormones including testosterone ,34. ThisOne of the myriad effects of estradiol on the brain is alteration of the expression of estrogen receptor alpha (ERα) distribution in key brain regions linked to male sexual behavior such as the preoptic area (POA) . ERα expActivation of ER during the prenatal period leads to the synthesis of prostaglandin E2 that in turn can permanently masculinize sexual behavior and the synaptic profile of the POA . In addiAdditional environmental factors such as maternal grooming also strongly influence ERα distribution and methylation of ERα promoter CpG islands . MaternaEven though alterations in the histone landscape may be transient, modifications occurring during critical developmental windows can permanently alter the brain. Males and females have different spatiotemporal patterns of histone methylation and acetylation in the cortex and hippocampus on embryonic day 18 and at birth . PrenataBoth histone modifications and DNA methylation have been shown to alter sexually dimorphic brain structures during development. While these patterns of sexual dimorphism have been examined within the context of sexual behavior, there is a paucity of research on their functional role in the formation of sex differences in stress susceptibility. Future research should examine how epigenetic modifications that alter neuroanatomy affect vulnerability to stress in both sexes. Epigenetic modifications are also involved in an individual’s response to stress. This can be through developmental  and tranAnother study examined transgenerational transmission of a stress- susceptible phenotype on the behavioral responses of the offspring of males exposed to repeated social defeat stress . Repeateinvitro fertilization (IVF) techniques on defeated and control fathers. IVF was used to control for levels of maternal care, which can contribute to offspring stress responsiveness through epigenetic mechanisms [Additionally, the authors compared the behavior of offspring bred prior to or post social defeat stress. They selectively found behavioral and hormonal changes in the male offspring bred post defeat. These included anxiety-associated behaviors such as decreased exploration of the open arms in an elevated plus maze, and increased depression-associated behaviors such as anhedonia and decreased latency to immobility in the forced swim test. Similarly, male offspring from defeated fathers had higher basal levels of the stress hormone corticosterone than offspring bred from fathers prior to defeat stress. Female offspring also exhibited some depression and anxiety-like phenotypes, including decreased latency to immobility in the forced swim test, and decreased time spent in the open arm of the elevated plus maze but in the absence of basal hormonal differences. To determine whether transmission of the stress effects occurred via epigenetic mechanisms in the sperm, the authors used chanisms , as the Maternal and paternal stress exposure is transmitted gestationally and transgenerationally through epigenetic mechanisms. Stressful experience by the parent may have a greater impact on stress responses in male offspring than female offspring, although more research is needed to directly test this hypothesis. The current data suggest that female vulnerability to stress changes across the lifespan. Females may be protected from gestational stress compared to males and yet may be more vulnerable to other forms of stress in adulthood -58. HoweAvp) enhancer in the PVN of the hypothalamus was consistently hypomethylated [Avp mRNA expression, along with increased basal levels of CORT and enhanced CORT release in response to stress. Like gestational stress, early life stress may have more robust behavioral and epigenetic effects on male rodents in adulthood [Avp gene in the hippocampus and decreased methylation of the Nr4a1 gene, which encodes a nuclear receptor in the brain and has been implicated in depression and schizophrenia in humans [Early postnatal stress can lead to lifelong changes in numerous behavioral domains as well as stress reactivity, and these alterations are thought to involve epigenetic regulation. Maternal separation is one of the most common methods used to stress animals during early postnatal life . Dependithylated . The hypdulthood . A studyn humans . These sAlthough a number of chronic stressors have been used to induce depression-like behavior in adult rodents, few have been used to examine any associated epigenetic regulation. To date, the majority of studies examining stress in adulthood utilize repeated social defeat stress due to its face, predictive and construct validity. Repeated social defeat stress is not amenable to females, as they are less territorial than males and will not attack an intruding novel animal unless under special circumstances such as when nursing young  or throuDNA methylation of CpG islands along the CRF promoter in the PVN of the hypothalamus also coincides with the behavioral effects of social defeat stress. Animals that were susceptible to social defeat stress displayed higher levels of CRF expression in the PVN than animals that were resilient . SusceptIn addition to DNA methylation, other epigenetic mechanisms contribute to the behavioral manifestations of the social defeat stress. Chronic social defeat stress leads to decreased expression of two brain derived neurotrophic factor (Bdnf) transcripts in the hippocampus that coincides with repressive histone activity along the Bdnf promoter . The beh7 in the adrenal and pituitary glands of young adult rats [Studies have begun to examine other forms of stress during adulthood. Recent work reveals that both social stress and chronic restraint stress alters total methylation of the GR promoter 1ult rats . Methylault rats . These aThere is converging evidence that male animals are behaviorally more susceptible to prenatal and early life stress than females , whereasGiven that epigenetic mechanisms contribute to both sexual dimorphism of the brain and susceptibility to stress, it is likely that there are sex specific modifications that shape responsiveness to stressful experience. As the clinical occurrence of depression is much higher in women, it is absolutely essential for the role of epigenetic modifications in stress related disorders to be examined in both sexes. Findings of significant differences in epigenetic programming between the sexes are rapidly emerging from developmental and transgenerational research that includes female subjects. A greater understanding of the mechanisms by which epigenetic modifications contribute to depression-associated behavior will help to clarify the etiology of mood disorders such as depression and anxiety. Additionally, this work will inform the identification of novel therapeutic targets for drug development. Already, HDAC inhibitors such as Valproic acid exist for the treatment of bipolar disorder. Unfortunately, these treatments are non-specific, and it is important to continue epigenetic research to yield novel treatments with fewer off-target side effects. Given the sex differences already found in epigenetic regulation of behavior, it is vital that any drug trials stemming from epigenetic research programs consider sex at both preclinical and clinical stages.5-hmC: 5-Hydroxymethylcytosine; 5mC: 5-methylcytosine; Avp: Arginine vasopressin; Bdnf: Brain derived neurotrophic factor; BNSTp: Principal nucleus of the Bed Nucleus of the Stria Terminalis; CORT: Corticosterone; CpG: Cytosine- Phosphate- Guanine; CRF: Corticotrophin-Releasing Factor; DNA: Deoxyribonucleic acid; Dnmt: DNA methyltransferases; ER∝: Estrogen Receptor Alpha; FST: Forced swim test; GR: Glucocorticoid receptor; H3K9: Histone 3 Lysine 9; HDAC: Histone deacetylase complex; IVF: In vitro fertilization; MBD proteins: Methyl-CpG binding domain proteins; MeCP2-Methyl: CpG binding protein 2; NAc: Nucleus Accumbens; NRSF: Neuron-restrictive silencing element; PND: Post Natal Day; POA: Pre Optic Area; PVN: Paraventricular Nucleus; SCVS: Sub Chronic Variable Stress; SiRNA: Short Interfering Ribonucleic Acid; TST: Tail suspension test.The author has no competing or financial interests to disclose.GEH wrote and edited the manuscript.