Hox proteins are a deeply conserved group of transcription factors originally defined for their critical roles in governing segmental identity along the antero-posterior (AP) axis inDrosophila. Over the last 30 years, numerous data generated in evolutionarily diverse taxa have clearly shown that changes in the expression patterns of these genes are closely associated with the regionalization of the AP axis, suggesting thatHox genes have played a critical role in the evolution of novel body plans within Bilateria. Despite this deep functional conservation and the importance of these genes in AP patterning, key questions remain regarding many aspects ofHox biology. In this commentary, we highlight recent reports that have provided novel insight into the origins of the mammalianHox cluster, the role ofHox genes in the generation of a limbless body plan, and a novel putative mechanism in whichHox genes may encode specificity along the AP axis. Although the data discussed here offer a fresh perspective, it is clear that there is still much to learn aboutHox biology and the roles it has played in the evolution of the Bilaterian body plan. Hox genes belong to the ANTP class2. This class of genes also includes the closely related ParaHox genes, NK genes, and various others. It has been suggested that the evolution and expansion ofHox genes have played a key role in the rapid diversification of the body plans of all Bilaterians. Thus, this group of genes has fascinated evolutionary biologists for decades and continues to be studied by many research groups today.Hox proteins are a group of homeodomain-containing transcription factors that are renowned for their roles in patterning animal body plans and for their remarkably deep evolutionary conservation. Homeodomain proteins are defined by the presence of a highly conserved DNA-binding region known as the homeodomain and are encoded by Homeobox genes. In general, homeobox genes are a large family of similar genes and can be divided into 11 different gene classes in animals, and theHox genes were originally discovered inDrosophila and functional studies in the fly showed that these genes play a critical role in establishing segmental identity along the antero-posterior (AP) axis3. Subsequent analyses have shown that the role ofHox genes in establishing AP axis identity is conserved in vertebrates6. These data were very exciting and confirmed that their function was conserved in evolutionarily distant taxa. Since their original discovery in the fly over 30 years ago,Hox genes have now been cloned and analyzed in a wide array of animal groups ranging from hydra to humans. Collectively, these studies have provided key insights into the evolutionary origins ofHox genes and have reinforced the important role these genes have played in the evolution of Bilaterian body plans.Hox genes. The purpose of this review is not to provide a comprehensive detailed survey of the literature to date but rather to highlight recent data that have both challenged traditional views and enhanced our understanding ofHox genes and evolution.In this review, we provide a commentary on the recent advances on the origin, functional conservation, and regulative properties ofHox genes) is found outside of the metazoans2. During the evolution of metazoans, the sponges diverged first, followed by cnidarians , and both of these groups are more basal to the Bilaterians. Analysis of whole genome information from the demospongeAmphimedon queenslandica revealed the first conclusive evidence that sponges have several NK homeobox genes but do not have any definitiveHox or ParaHox genes7. In contrast, definitiveHox-like genes have been identified in the Cnidarians; however, the expression patterns of these genes do not follow a clear AP pattern or show any correlation with the BilaterianHox code in determining axis specification8. Phylogenetic analyses of ANTP class genes have shown that theHox and ParaHox genes are more closely related to each other than they are to the NK subclass7. Therefore, the current collection of genomic and phylogenetic data support the hypothesis that the NK,Hox, and ParaHox genes arose prior to the emergence of Bilaterian animals. Furthermore, it has been proposed that all three gene subclasses are derived from a hypothetical ancestral ANTP class gene that underwent extensive tandem gene duplications that ultimately created the three distinct gene clusters1. Interestingly, each of these three gene clusters has been conserved to different extents in various evolutionary lineages within Bilateria8. For example, vertebrates have tightly linkedHox and ParaHox clusters and disrupted NK clusters, whereas dipterans (includingDrosophila) exhibit a disruptedHox cluster but have retained a tight NK cluster1. Despite these differences, the birth and diversification of ANTP class genes have been instrumental in the evolution of the Bilaterian body plan and have contributed to the subsequent radiation of these animal taxa into nearly every ecological niche on earth.None of the ANTP class of homeobox genes  with its “deregionalized” axial skeleton29 has been an intriguing evolutionary feature that has received considerable attention over the last decade with regard toHox gene expression and function30. In limbed lizards, two distinct regional boundaries are observed in the axial skeleton: the cervical-thoracic and the thoracic-lumbar, both of which have been shown to correspond to sharp boundaries of differentialHox gene expression patterns28. In contrast, it has been reported that the snake-like body plan lacks clear boundaries, resulting in a “deregionalized” axial skeleton with an increased number of vertebra and ribs and a reduction or loss of limbs and sternum29. Previous studies in mice have shown that the inactivation of all three genes in theHox10 paralogous group  results in the transformation of the ribless lumbar vertebrae into a posterior extension of the thorax, as defined by the presence of ectopic ribs32. These and many other genetic studies demonstrate that the activity of the genes in theHox10 paralogous group controls key processes in somatic patterning that lead to the inhibition of rib development. However, expression analyses in snake embryos have shown that bothHoxa10 andHoxc10 are expressed in rib-bearing regions of the axial skeleton, suggesting the possibility that snakeHoxa10 andHoxc10 genes have lost the ability to suppress rib-bearing vertebrae30. Generation of transgenic mice that ectopically express snakeHoxa10 showed that this paralog is able to efficiently block rib formation in mice, indicating that rib-repressing properties are still present in the snake protein33. Instead, a polymorphism was identified in a Hox/Pax-responsive enhancer that is involved in Hox-mediated regulation of rib formation, which results in this enhancer being unable to respond to Hox10 proteins33. In addition, this polymorphism was also found in other animals with extended rib cages. These data indicate that the evolution of this Hox/Pax enhancer has played a critical role in the evolution of axial skeletons by modulating responses to either rib-suppressing or rib-promotingHox genes.There is an overwhelming amount of data that support that28. Using a statistical geometric morphometric analysis on the vertebral morphology, Head and Polly28 concluded that there was no consistent difference in the shape variance between limbed and snake-like squamates and that three to four distinct vertebral regions, including the cervical, thoracic, and lumbar regions, could be identified in all taxa irrespectively of the presence or absence of limbs. In other words, snake-like body plans do indeed have regionalized precloacal axial skeletons; the differences in the morphologies of the vertebrae are just more subtle as compared with limbed reptiles. In addition, the authors asserted that the newly identified morphological boundaries of the snake vertebral columns correspond to similar mapped expression boundaries ofHox paralogs in snakes, suggesting that the AP axis of these animals is governed by a normally functioningHox code.A recent report that more closely analyzed the morphological differences of snake vertebrae has challenged the traditional view that the anterior axial skeleton of snakes is, in fact, “deregionalized”28. Indeed, this hypothesis is supported by acquired fossil evidence from Paleozoic amniotes, including extinct stem members of Reptilia and Mammalia, that shows that these animals exhibited “deregionalized” axial skeletons with very subtle changes in their primaxial morphology28. These data support a model wherein regionalized vertebral columns (including the ones in snakes) are a derived feature that has arisen through modifications of a more “deregionalized” ancestral body plan. In this case, the evolution of the snake-like body plan is not an exception but rather just another example along the continuum ofHox function in sculpting derived body plans in the diverse Bilaterian taxa.From an evolutionary perspective, the “deregionalization” of the snake axial skeleton made the assumption that this body plan evolved from an ancestor that exhibited a regionalized AP vertebral axis. The new data reported in Head and Polly challenge this assumption and instead suggest that the regionalized axial skeletons of limbed reptiles and other derived vertebrate taxa are descended from an axial plan that displayed very little regionalization in the first placeHox genes have been co-opted for novel functions in the development of many organ systems. For example, previous studies have shown that the expression patterns of theHox geneUltrabithorax (Ubx) are associated with the differential enlargement of particular hind-limb segments in different insect species35. In a similar fashion, theHox geneAbdominal-B is required for the formation of the lantern organ on the posterior abdomen in the firefly36. Although studies in insects are informative, our most comprehensive understanding of co-optedHox gene functions comes from studies in mice. These studies have identified several important roles forHox genes in the development of organs that correspond to their expression along the AP axis. Some of the many examples include the following: theHox3 genes in the development of the thymus, thyroid, and parathyroid38;Hox5 genes in lung development40;Hox6 genes in pancreas development41;Hox9,Hox10, andHox11 genes in the reproductive tract46;Hox10 andHox11 genes in kidney development49; andHoxb13 gene for prostate development50. AlthoughHox genes have been shown to play important roles in many aspects of organogenesis, it has been difficult to place these highly conserved transcription factors into established regulatory networks. This represents an important gap in our understanding ofHox biology that needs to be addressed in much greater detail.In addition to their highly conserved roles in AP patterning, numerous studies have indicated thatHox genes, which in turn regulate different sets of target genes that govern the formation of anatomical regions that have specific features51. However, howHox genes encode this specificity has been a long-debated question. All Hox proteins have similar DNA-binding domains (the homeodomain) and they all bind similar DNA sequences with high affinity56. One well-established means by whichHox genes achieve specificityin vivo is to bind DNA co-operatively with other DNA-binding co-factors57. To date, the three amino acid loop extension (TALE)-homeodomain genes, which include the PBC/PBX and MEIS classes of homeodomain proteins, are the best described co-factors; however, it is clear that others exist61. The PBC/PBX class comprises fly Extradenticle (Exd) and vertebrate Pbx homeoproteins, whereas the MEIS class includes fly Homothorax (Hth) and vertebrate Meis and Prep homeoproteins57. In addition to the presence or absence of co-factors, a recent report has significantly contributed to additional understanding of howHox genes encode specificity inDrosophila54. Briefly, these researchers identified clusters of low-affinity binding sites in enhancers of theshavenbaby (svb) gene that specifically confer binding of an Ubx-Exd complex. Mutation of these sites into high-affinity sites enabled the enhancer to respond to otherHox genes (Scr), suggesting that the native low-affinity Ubx-Exd binding sites confer specificity for Ubx-Exd dimers over other Hox proteins and probably over other homeodomain proteins as well. Interestingly, although the individual Ubx binding sites were not conserved in another fly species (Drosophila virilis), clusters of other low-affinity binding sites were identified and found to be required for enhancer function, suggesting that this mechanism may be an evolutionarily conserved strategy used bysvb enhancers. Determining whether similar mechanisms conveyHox specificity in more derived Bilaterian species will be particularly informative and will provide insight into whether this mechanism is a highly conserved feature.It has been well established that the diversity along the AP axis of animals results from the differential expression ofHox gene organization and function and their profound impact on the evolution of metazoan body plans continue to fascinate evolutionary and developmental biologists today. As a result,Hox genes continue to be investigated by a large number of research groups. The focus of these studies encompasses many different aspects ofHox biology, includingHox gene regulation, identification of downstream targets, and uncovering novel functions for these proteins. In addition,Hox genes have been associated with a number of human diseases62 and this in turn supports an increased need to understand the potential role(s) of these genes in the onset and progression of disease. Finally, functional roles ofHox genes have also been identified during postnatal development65, and there is increasing interest in understanding the roles that these genes play in the formation of post-embryonically derived structures and the maintenance of organ systems. There remains much more to learn aboutHox gene biology and thus it is certain that these genes will continue to fascinate investigators for decades to come.The remarkably deep conservation of


Post-traumatic stress disorder (PTSD) has been associated with an inflammatory state. However, few studies have addressed the mechanisms underlying this immune imbalance that favors inflammation or how this imbalance contributes to PTSD. Whether the immune imbalance influences responsiveness or unresponsiveness of patients to PTSD treatments is currently not known. This review brings forward an immune emphasis to a mental health disorder that is unprecedented in its prevalence among combat Veterans of the ongoing conflicts in Iraq and Afghanistan and which also afflicts civilians who have undergone extreme traumatic experiences, such as following natural disasters, serious accidents, or assaults. Included is an overview of the correlative associations in human subjects between PTSD and inflammation and studies in animal models of PTSD, demonstrating causal contributions of inflammation and immune dysregulation to PTSD-like behavior following stress exposure. Over 2.5 million U.S. service members have been deployed at Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) arenas since 2001, with an unprecedented proportion 15.7%) of them developing post-traumatic stress disorder (PTSD) following combat exposure , 4. PTSD% of themIn the past two decades, psychological and pharmacological treatments have been developed for PTSD, but many patients do not respond to these treatments, placing them at risk for developing a chronic illness with poor long-term outcomes . PharmacIn the past decade, there has been an effort to identify the biological causes of PTSD. This effort has suggested that the biological dysfunction can result from immune alterations associated with PTSD , but relStudies involving human subjects with PTSD have indicated a linkage between immune alterations and PTSD following trauma exposure, though it is unlikely that the primary cause of PTSD is immune-mediated. Measurement of the various immune mediators including pro-inflammatory cytokines in PTSD subjects has been somewhat haphazard, but collectively, the results of these studies have suggested immune alterations toward increased levels of inflammatory cytokines , 24, 26.+ cells from PTSD patients are also reduced, further illustrating the immune skewing toward a dysregulated state (The imbalances in cytokines in subjects with PTSD are reflected not only by increased plasma levels of inflammatory cytokines but also by imbalances in immune cell compositions. This is seen by increases in peripheral blood levels of pro-inflammatory Th1 and Th17 cells and reduced numbers of anti-inflammatory cells, such as Treg , 22. Leved state .Consistent with the pro-inflammatory skewing seen in subjects with PTSD is an increased incidence of allergies in this population. For example, the incidence of adult-onset asthma was shown to be increased subsequent to PTSD-associated trauma . A compaBecause of the direct association between skewed immune reactivity toward increased levels of inflammatory cytokines and disease severity in combat-exposed Veterans with PTSD, it has been suggested that immune activation is a contributor to their clinical status . A prospAssessments of inflammatory cytokine levels in the cerebral spinal fluid of subjects with and without PTSD have not been extensively measured. However, the results of such studies are conflicting, with demonstrations of both increases and no difference in levels of IL-6 among subjects with and without PTSD , 34. In The plasticity of immune cells is driven by the cytokine milieu and raises the question of whether the inflammation-skewed immune reactivity of PTSD patients can undergo rebalancing. While studies have shown an imbalance toward inflammatory immune reactivity in PTSD patients, less clear is whether recovery from PTSD restores the immune balance. In fact, there are surprisingly few studies examining if clinical improvements of PTSD are accompanied by immune normalization. In one such study, women with PTSD had elevated levels of inflammatory cytokines, but those who recovered from PTSD had reduced levels of inflammatory cytokines that were similar to levels in healthy women who had not experienced trauma . Also suModulation of serotonin can directly impact immune activity –42, and Studies with animal models have clearly established that the immune–brain communications are intimately intertwined. For example, immune mediators, such as IL-1, IL-6, and TNF-α, are able to cross the blood–brain barrier, and this is one way in which peripheral immune reactivity can have CNS impacts . InductiWhile animal models for PTSD are imperfect and unable to fully mimic PTSD in human subjects, studies using such animal models have been more comprehensive and definitive than studies of PTSD in human subjects. Several animal models for PTSD have been established and well characterized . An overvia soluble inflammatory mediators. In mice that were exposed to repeated social defeat, subthreshold stress resulted in trafficking of primed monocytes from the spleen to the brain and re-establishment of anxiety behavior (Using predator exposure together with social stress of daily cage cohort change as a rat PTSD model, it has been shown that the dysregulation of cytokines that is seen peripherally in human subjects with PTSD is also seen in select brain regions where levels of the inflammatory cytokines are increased, while levels of the anti-inflammatory cytokines are reduced , 26, 53.behavior , 59. HowSimilar to the results of the few studies that have been conducted to assess the impact of SSRIs on inflammatory mediators in human subjects , 44, stuA significant challenge to studying the immune association with PTSD is the variability in the type and severity of trauma exposure that led to PTSD. More conclusive results could be attained with a tightly controlled and relatively homogeneous population of subjects, with some having PTSD and others not. One such population could be Veterans of the currently ongoing conflicts in Iraq and Afghanistan, who are likely to be otherwise relatively healthy. However, such highly focused and tightly controlled studies would have to lead to studies that would be applicable to a broader population with PTSD. In studies with either a tightly controlled homogeneous population or a broader population with PTSD, it would be critical to measure both pro-inflammatory and anti-inflammatory cytokines and immune inflammatory and anti-inflammatory cells since immune reactivity consists of a balance between pro-inflammatory and anti-inflammatory forces. While studies have measured select pro-inflammatory cytokines, very few have also examined the balance between pro-inflammatory and anti-inflammatory mediators in subjects with PTSD.Previously conducted studies that have suggested PTSD to be associated with an inflammatory state have traditionally measured levels of inflammatory cytokines in the blood plasma. However, analyses of cytokines in subjects undergoing other forms of stress exposure have shown more prominent immune alterations in saliva as opposed to plasma , 36. ColMore recent approaches to studying PTSD in humans have included advanced neuroimaging approaches and genetic approaches. For example, magnetic resonance images showed brain structural differences between subjects with and without PTSD, including differences in cortical thickness, volumes of caudate and right hippocampus, and total cerebral volume . DiffusiThe underwhelming level of responsiveness to treatments for PTSD urges the exploration of alternate treatment. If immune–brain communications are contributors to PTSD following the initial trauma, then this opens the possibility of immune intervention. However, immune modulatory treatment approaches need to be accompanied by mechanistic studies to define the relationships in PTSD between behavior and peripheral and CNS immune reactivities. A key question is whether treatment effectiveness with SSRIs is a consequence of immune modulation and whether immunological mechanisms bear responsibility when SSRI treatment is ineffective. Alternate treatments being tested include magnetic brain stimulation , but theThis manuscript was written by MY with close collaboration and contribution by ZW.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.


Correct protein folding and inhibition of protein aggregation is facilitated by a cellular “quality control system” that engages a network of protein interactions including molecular chaperones and the ubiquitin proteasome system. Key chaperones involved in these regulatory mechanisms are the protein disulfide isomerases (PDI) and their homologs, predominantly expressed in the endoplasmic reticulum of most tissues. Redox changes that disrupt ER homeostasis can lead to modification of these enzymes or chaperones with the loss of their proposed neuroprotective role resulting in an increase in protein misfolding. Misfolded protein aggregates have been observed in several disease states and are considered to play a pivotal role in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral sclerosis. This review will focus on the importance of the thioredoxin-like CGHC active site of PDI and how our understanding of this structural motif will play a key role in unraveling the pathogenic mechanisms that underpin these neurodegenerative conditions. Protein disulfide isomerases EC 5.3.4.1) are key metabolic proteins which primarily reside in the endoplasmic reticulum (ER) and operate in synergy with other chaperones, such as glucose-regulated protein (78 kDa) (GRP78) that controls the processing and correct folding of proteins ] have been resolved using NMR  , where two of these (a and a′) have a catalytic redox-active –CGHC- motif , followed by ER-associated degradation (ERAD), which specifically recognizes terminally misfolded proteins. Molecular chaperones such as the heat shock proteins  are ubiquitously expressed in all cells and in all subcellular compartments. They represent a diverse group of proteins and are characterized based on their dependence on ATP, Excess reactive oxygen and nitrogen species (ROS/RNS) generated through oxidative metabolism, or triggered from environmental toxins and also normal aging can cause an imbalance between the production of ROS/RNS and the cell's defense systems, including anti-oxidant enzymes (such as the glutaredoxin system), glutathione, and molecular chaperones  deposits, and neuritic changes such as neurofibrillary tangles (NFT) , was found to also co-localize with tau in NFTs  activation and superoxide production are elevated in microglia and may contribute to motorneuron death, through increased cellular S-nitrosylation (Wu et al., In vitro studies showed that PDI acts as an important regulator of NOX activation and subsequent ROS production in microglial cells, suggesting that an up-regulation of PDI may not just have a protective role in protein aggregation but also in regulating UPR-triggered NOX activation, in a cell-type specific manner (Jaronen et al., in vivo? Is it possible to generate a therapeutic translation to mimic increased PDI expression that is not subject to S-nitrosylation? Or will increased expression of PDI stimulate unfavorable metabolic reactions, attenuating its potential role as a target therapeutic.An increase in the generation of ROS/RNS through external and internal cellular mechanisms can overwhelm the anti-oxidant and chaperone systems contributing to an increase in cellular calcium, mitochondrial dysfunction, protein misfolding/aggregation leading to cell death. This pathogenic pathway shares common features across all neurodegenerative conditions despite clear genetic links that differentiate between them. A role for PDI in protein misfolding has emerged as a key link to understanding how these aggregates accumulate in the brain with similar patterns of colocalization of PDI with disease specific aggregates. Despite clear evidence that protein aggregation in central to the pathology of neurodegenerative conditions, many questions remain unanswered. How do these models of protein misfolding translate 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.


In general, autologous veins are the optimal replacement material for an infected vascular graft in terms of handling, durability and resistance to reinfection. In the absence of suitable autologous material, several options are available, each of which has specific advantages and drawbacks with regard to these characteristics.In recent years, xenogeneic materials  have been increasingly used as replacement material in the setting of infections. Bovine and equine pericardial patches are applied in particular as self-made tube grafts in the aortic region and also in infections of iliacofemoral prosthetic grafts and shunt infections.The results of small clinical series on durability and resistance to reinfection are promising.It is feasible to use biosynthetic materials to replace infected intracavitary and extracavitary vascular grafts with remarkably low reinfection rates; however, the unique mechanical properties of the grafts as well as the initially increased thrombogenicity, need to be taken into consideration. Xenogeneic materials are increasingly being applied in arterial reconstruction procedures in vascular surgical routine. Their availability, good handling and high resistance to infection have led to these grafts also being used for procedures in the septic surgery environment. Initial results from application studies are now available.Gewebegesetz) came into effect in 2009, the procurement, processing, storage and transplantation of human tissue are subject to strict requirements, significantly limiting the availability of these materials. Xenogeneic grafts now hold a firm place in elective vascular surgical practice. The term  refers to materials of non-human biological origin. Originally, the shortage of suitable human donor organs led to attempts to transplant non-human organs but acute rejection processes posed the greatest obstacle. These mechanisms can now be even further suppressed in pigs as donor animals for human heart transplants by breeding knockout lines for superficial antigens and the use of immunoadsorption techniques. Despite this progress, xenotransplantation of living tissue or functional organs has not yet reached the clinical routine. Denatured xenogeneic vessels are not suitable for vascular replacement due to their tendency to degenerate and high thrombogenicity. Human Allo-Grafts used in vascular surgery are rendered cell-free and hence epitope-free, by means of special processing. Thus, they induce no specific immune response. This article discusses the role that the various currently available grafts can play in the setting of infection.Due to its high resistance to infection and excellent long-term stability, autologous vascular grafts nowadays represent the best method in septic vascular surgery; however, should this option be unavailable, alloplastic materials lag far behind despite various modifications  to the vein in terms of the characteristics mentioned. Furthermore, the removal of (in particular deep) veins causes additional access morbidity and significantly prolongs procedural times. The use of biological graft materials was restricted for a long time due to the limited long-term function, degeneration and aneurysm formation, as well as high occlusion rates . In view of the age and comorbidity-related reduction in life expectancy among patients requiring vascular surgery due to underlying infectious diseases or septic complications, allografts have come to play an important role in clinical routine, particularly in the case of intracavitary infections; however, since the revised version of the German Tissue Act  was detected in as many as 22 % of the infections, 50 of the patches remained free of reinfection and did not require revision surgery over a mean follow-up of 2.1 years.The use of pericardial patches to replace the alloplastic patch infections seen relatively frequently in the inguinal region has already been described. McMillian et al. published a series of 51 patients in whom PTFE patches in the inguinal region were replaced with bovine pericardial patches [In the case of Szilagyi III inguinal infections repaired using bovine patches, the patch remains in place, unless bleeding is present (Zülke-Harnoss grade III) and treatment is carried out with debridement, sartorius myoplasty, negative pressure wound therapy (NPWT) and antibiotic therapy.Reconstruction using pericardial tubes has also been described in aortic graft infections and inflammatory changes in the native aorta. As early as 1997, the working group led by Pirelli  publisheWe also use the bovine pericardial patch as graft material for localized infection of plastic prostheses in shunt surgery Fig. . Here, iBiosynthetic grafts consist of a polyester mesh enclosed in ovine collagen according to the principle of a Sparks mandril graft. Once processed, involving in particular fixation with glutaraldehyde, a stable collagen matrix forms. Due to the low infection rates when used in shunt surgery and elective bypass surgery as well as the encouraging results with xenogeneic patches in the infected surgical setting, efforts have also been made in recent years to evaluate biosynthetic grafts as graft materials for infections. Initial results on infected infrainguinal prosthetic grafts were published by our working group in 2012 . These iIn December 2015 Krasznai et al. published a series of three patients with infected aortic grafts that could be reconstructed in situ using biosynthetic material . All infXenogeneic grafts have found broad application in vascular surgery in the form of pericardial patches. There is a growing body of clinical data to suggest a rationale for their use in the contaminated surgical field or even as replacement material for infected synthetic patches and grafts in certain situations. Biosynthetic vascular grafts are highly resistant to infection when used in the elective setting; however, their use as replacement material for infected infrainguinal vascular grafts is only justified if autologous venous material is absent or insufficient and if good results have been seen in small application studies. Their special mechanical properties require particular consideration, most notably in femorocrural applications. Initial experience with their use in intracavitary graft infections has been gained.With careful preoperative evaluation and patient selection, xenogeneic grafts represent a valuable treatment option in septic vascular surgery. The use of biosynthetic grafts in particular is technically challenging and follow-up requires experience and careful attention.


The rotation length is a key component of even-aged forest management systems. Using Fennoscandian forestry as a case, we review the socio-ecological implications of modifying rotation lengths relative to current practice by evaluating effects on a range of ecosystem services and on biodiversity conservation. The effects of shortening rotations on provisioning services are expected to be mostly negative to neutral , while those of extending rotations would be more varied. Shortening rotations may help limit damage by some of today’s major damaging agents , but may also increase other damage types (e.g. regeneration pests) and impede climate mitigation. Supporting  and cultural  ecosystem services would generally be affected negatively by shortened rotations and positively by extended rotations, as would most biodiversity indicators. Several effect modifiers, such as changes to thinning regimes, could alter these patterns. A major proportion of the world’s managed forests are subjected to even-aged management systems where stands are harvested through clearcutting. The stands are subsequently regenerated naturally or artificially, and allowed to grow (with or without thinning) until final felling. A key parameter describing even-aged forest management systems is rotation length, i.e. the time elapsed between two final fellings. The choice of a rotation length is an integral part of any forest management regime Curtis . It is dPinus radiata) plantations  forests of Central Europe -dominated forest  to decrease the risk of storm and root rot damage , rotation lengths are unlikely to remain constant in the future. Over recent decades, rotation lengths have been shortened in the coniferous forests of the northwestern USA Curtis , New ZeaMost past studies about rotation lengths have focused on economic aspects of wood production; very few have addressed the effects on several forest-based values simultaneously , regulating services , supporting services , cultural services  and biodiversity conservation. The latter is considered a foundation for all ecosystem services MEA . The stuTo evaluate the implications of modified rotation lengths, there is a need to define a benchmark for comparison. Here, we use the economically optimal rotation length for wood production based on a discounting rate of 2.5 % as a benchmark representing current practice in Fennoscandian forestry  and Norway spruce. To better isolate the effects of rotation lengths per se, we focused on stands which are dominated by these two native tree species during most of the rotation , assuming that changes to rotation lengths are not accompanied by changes in the identities of the species forming the main tree cohort. Hence, we did not evaluate the effects of shortened rotations stemming from the use of faster-growing non-native species or hybrids, neither does our evaluation encompass ‘short-rotation forestry’ systems for energy crops .Production forests in boreal Fennoscandia are dominated by the two native conifers Scots pine  rises after stand establishment, peaks when maximum leaf area is attained and then declines Assmann ; Fig. 1.However, forest management decisions are not only driven by wood volume considerations, but also by economy and other factors. Faustmann  proposedIn managed Fennoscandian forest stands, the LEV curve is typically asymmetrical around the apex Fig. , implyinLonger rotations generally imply a larger harvested volume per final felling and hence potentially more efficient logistics, an economic advantage typically not included in the LEV. At the same time, extending rotations may reduce wood supply to the industry during the period of transition to the new rotation length Curtis . MoreoveVaccinium myrtillus and cowberry V. vitis-idaea) and edible mushrooms have large economic  form an important food resource year round  can be four times as large during the earlier phases of the rotation compared to later phases  herding is practiced over most of northern Fennoscandia. During the winter, semi-domesticated reindeer graze mostly in forest  and arboreal lichens  constitute the main food source. Shortened rotations are expected to have predominantly negative impacts on reindeer husbandry , affecting both pine and spruce seedlings. Shorter rotations imply that a given site is more often in the regeneration stage, which may increase the importance of pine weevil damage, since the weevil depends on the availability of stump roots after final felling  and—to a lesser extent—the pine shoot beetle (Tomicus piniperda). Shortened rotations would most likely decrease, and extended rotations increase, damage by these species because the amount of suitable breeding material is expected to increase with tree age  and shoot dieback  can be expected to increase in importance under shortened rotations because they affect mostly young to middle-aged forest  the proportion of the landscape that is in a highly flammable condition. Also, forestry machinery is in itself a relatively frequent fire starter, especially in stony areas. Once stand closure is completed, further changes in flammability with age may be relatively small, but have not been assessed for Fennoscandia, except for post-fire succession . If final felling takes place before the culmination of the MAI (as is the case for rotations shorter than under our benchmark scenario), the average wood volume yield and hence the substitution effect will be reduced, with negative impact on climate mitigation. Changes to thinning regimes allowing higher stocking would be positive for carbon storage and may also increase the wood volume yield compared to more intensive thinning  or reduction (extended rotations) of those associated with conventional forest management Table . From a Tree harvesting will result in a reduction of the base cation pool in the soil  are protected by law. Yet, a significant number of remnants are damaged or destroyed during forestry operations. Due to more frequent soil scarification and machine driving, shorter rotations are expected to increase the risk of physical damage to such objects  and processes operating at a smaller grain , although the two strategies may yield diverging effects on harvesting logistics and the provision of specific wood products. The effects of shortening rotations on other provisioning services are expected to be negative to neutral in most cases , while the effects of extending rotations on these services would be mainly positive or uncertain.For regulating services, it is difficult to draw any general picture. Shortening rotations may help limit damage by some of today’s most important damaging agents , but may also increase other types of damages . As regards climate change mitigation, significantly shortening rotations would likely be detrimental to both carbon storage and fossil fuel substitution. Substitution is deemed most important as its benefits exceed those of carbon stock changes in the long term  may have different effects compared to planned continuous management for wood production involving additional thinning(s). In addition to thinning, several other effect modifiers were identified as particularly important: tree retention at harvesting, salvage logging, tree species and snow cover. Although the expected modifying effects of some of these factors were clear, our analysis also suggested that there are significant gaps in knowledge as to how these and other ecological and silvicultural factors may modulate the effects of changed rotation lengths on ecosystem services. For example, the effects of changed rotations on the capacity to control ungulate browsing damage are subject to much uncertainty due to complex relationships between forage availability and the distribution of the ungulates in the landscape, both of which, in turn, depend on specific ecological settings and silviculture Månsson .All things considered, our evaluation based on Fennoscandian conditions illustrates that the expected benefits of shortening or extending rotations for specific ecosystem services will necessarily be accompanied by varied and often contrasting effects on other services. This stresses the need for improved communication and structured dialogue among stakeholders to develop and implement landscape-scale rotation-length strategies which maximize possible synergies and minimize conflicts related to the provision of different ecosystem services.Several authors have proposed implementing a variety of rotation lengths within forest landscapes  to gain quantitative knowledge about the effects of rotation modifications of given magnitudes, and (2) to refine knowledge about the effects of changed rotations under the range of ecological and silvicultural conditions characterizing current and future forests. Our evaluation allowed identifying the general directions of changes to forest values that may be expected from shortening or extending rotations. However, it did not provide answers regarding, for example, the quantitative effects of extending rotations by one decade vs. half a century. This is currently hampered by a paucity of empirical studies directly evaluating the effect of specific rotation lengths on biodiversity or ecosystem services other than wood production. Such studies would require large-scale experimental systems including forest stands which belong to different age classes (including post-mature stages) and share a similar origin. In the case of biodiversity conservation, most past studies have compared biodiversity in intensively managed younger forest originating from clearcutting with near-natural, post-mature forest stands that have never been clearcut (see however Martikainen et al.


Although there is evidence that significant sleep problems are common in children with autism spectrum disorder (ASD) and that poor sleep exacerbates problematic daytime behavior, such relationships have received very little attention in both research and clinical practice. Treatment guidelines to help manage challenging behaviors in ASD fail to mention sleep at all, or they present a very limited account. Moreover, limited attention is given to children with low-functioning autism, those individuals who often experience the most severe sleep disruption and behavioral problems. This paper describes the nature of sleep difficulties in ASD and highlights the complexities of sleep disruption in individuals with low-functioning autism. It is proposed that profiling ASD children based on the nature of their sleep disruption might help to understand symptom and behavioral profiles (or vice versa) and therefore lead to better-targeted interventions. This paper concludes with a discussion of the limitations of current knowledge and proposes areas that are important for future research. Treating disordered sleep in ASD has great potential to improve daytime behavior and family functioning in this vulnerable population. Autism spectrum disorder (ASD) is a developmental disorder characterized by deficits in social communication and repetitive and stereotyped interests and behaviors . Autism Currently, one of the most burdensome complaints among parents of children with autism is disrupted sleep, with more than 40–80% of children experiencing sleep problems, compared with 25–40% in typically developing children (TYP) . Given tASD is characterized by notable phenotypic heterogeneity, which is often viewed as an obstacle to the study of etiology, diagnosis, treatment, and prognosis . The degASD is frequently accompanied by co-morbid disorders and associated problems, one of which is sleep disruption , 15. OneSince ASD is considered to be a multifaceted disorder reflected in different symptom profiles across individuals, it is not surprising that a multitude of sleep problems are prevalent in this population. Moreover, the variability of sleep profiles in ASD is suggestive of the mixed phenotypic profiles of ASD samples. Among children with ASD, the most common sleep issues are prolonged sleep latency, decreased sleep efficiency, reduced total sleep time, increased waking after sleep-onset, bedtime resistance, and daytime sleepiness; see  for a reAlthough highly prevalent and persistent, the etiology of sleep problems in children with ASD remains uncertain . SeveralOther theories have been put forward to suggest that sleep disruption may be a secondary condition influenced by other co-occurring medical and psychiatric conditions that are present in ASD. Gastrointestinal disorders (GI) are common in ASD children with more than 50% of children experiencing constipation or diarrhea, often resulting in induced toilet awakenings throughout the night . SeizureThere is increasing evidence of severe sleep problems in children with autism, although little research exists for evidence-based sleep treatments within this population . Sleep dIn typical development, sleep disruption is associated with emotional and behavioral problems such as internalizing and externalizing symptoms . MoreoveThe current research highlights clear uni-directional relationships between sleep and behavior in individuals with an ASD. It is well researched that sleep problems worsen ASD symptomatology across most core domains, as well as exacerbate pre-existing behavioral problems. These relationships have been fairly well investigated in cross-sectional studies using objective measures with individuals with mixed groups of ASD samples and individuals with high-functioning autism. Objective tools such as polysomnography  and wrist actigraphy (a tool that uses an accelerometer to detect and record muscle activity) have been used successfully to validate relationships between poor sleep and daytime behaviors in a mixed sample of ASD children , 65, 71.Although previous studies have identified clear relationships between poor sleep and challenging behaviors in ASD, as reviewed above, it is still unclear what specific sleep problems and symptom relationships are unique to individuals with low-functioning autism. As mentioned, current research has primarily focused on individuals on the higher functioning end of the autism spectrum, and individuals with low-functioning autism who potentially have the most severe sleep and behavioral deficits have been relatively ignored in the literature. Studying sleep in children with low-functioning autism presents with unique methodological challenges, namely subjective parent reports confer reporting bias and negative halo effects  and indiAnother key limitation of the research to date is that very few studies examine behavioral problems and sleep disturbances in ASD longitudinally, with most studies being cross-sectional. Cross-sectional studies only capture an ASD profile at one specific age presentation, and most studies have combined both children and adolescents in their samples. Little is known about how sleep changes over time in ASD and what factors might be associated with this change, for example, age and stages of development. In ASD, one study found no relation between sleep difficulties and developmental stage  , whereasLastly, treatment guidelines to help manage challenging behaviors in individuals with low-functioning autism often fail to mention sleep at all, or they present a very limited account. Identifying and providing treatment for sleep problems in ASD is imperative for improving sleep, as well as for encouraging more positive prognoses by improving daytime behavior and family functioning in this population. One specific proposal is for researchers to identify factors that result in an ASD phenotype and then design targeted therapeutic interventions to reverse or ameliorate specific deficits. For example, exposure to highly arousing stimuli before bed may increase pre-sleep arousal and sleep-onset latency and result in an increase in self regulatory behaviors (such as self-injurious behaviors) the following day in children with low-functioning autism. Heightened light sensitivity from exposure to blue-enriched light from computer and/or tablet screens might also be linked to circadian timing and melatonin issues, increasing sleep-wake circadian rhythm abnormalities in this population. Sound sensitivity inherent within ASD may be linked to lower waking thresholds, sleep fragmentation, and so on. In this paper, it is proposed that profiling ASD children based on the nature of their sleep disruption might help understand symptom and behavioral profiles (or vice versa) and therefore lead to better-targeted interventions.Although there is reason to believe that serious sleep problems are common in children with ASD and that poor sleep exacerbates problematic daytime behavior, these conclusions are still premature and require further investigation. Gaining more specific insight into the individual nature of sleep difficulties in ASD opens up a novel avenue for designing interventions, as sleep is an area with a potential for remediation. Since sleep is a central mechanism for adaptive functioning , it is highly plausible that sleep deficits play a leading role in the symptoms seen in ASD including the exacerbation of challenging behaviors. To date, however, studies have failed to provide conclusive evidence about the relationship between sleep and behaviors seen in low-functioning individuals  with autism. This review highlights the value of defining sleep profiles for children with ASD and integrating different aspects of their symptom profile to their sleep deficits (and vice versa). In turn, this knowledge will result in novel therapeutic targets and interventions that will hopefully improve long-term outcomes of nearly 1 in 68 individuals affected by this pervasive, developmental disorder.


Autism is a pervasive developmental disorder characterized by profound social and verbal communication deficits, stereotypical motor behaviors, restricted interests, and cognitive abnormalities. Autism affects approximately 1% of children in developing countries. Given this prevalence, identifying risk factors and therapeutic interventions are pressing objectives—objectives that rest on neurobiologically grounded and psychologically informed theories about the underlying pathophysiology. In this article, we review the evidence that autism could result from a dysfunctional oxytocin system early in life. As a mediator of successful procreation, not only in the reproductive system, but also in the brain, oxytocin plays a crucial role in sculpting socio-sexual behavior. Formulated within a (Bayesian) predictive coding framework, we propose that oxytocin encodes the saliency or precision of interoceptive signals and enables the neuronal plasticity necessary for acquiring a generative model of the emotional and social ‘self.’ An aberrant oxytocin system in infancy could therefore help explain the marked deficits in language and social communication – as well as the sensory, autonomic, motor, behavioral, and cognitive abnormalities – seen in autism. Using recent advances in our understanding of learning and inference, we consider how this single but pervasive deficit could result in the autistic phenotype.Although structural brain abnormalities , soft neRecently, a Bayesian model for autism has been advanced, suggesting that “people with autism see the world more accurately – as it really is – as a consequence of being less biased by prior experiences.” . This foIn this paper, we extend the Bayesian model to incorporate neurodevelopment and its physiologic substrates by proposing that a dysfunction in the oxytocin system, early in life, could account for the development of autism. As a key mediator of birth , lactatiIn brief, we suppose that an early pathophysiology in the oxytocin system could disrupt the assimilation of interoceptive signals and exteroceptive cues within generative models of the ‘self’. These primary deficits would impair the child's ability to assign salience to socially relevant signals in the environment and disrupt the sensory attenuation necessary for proper homeostatic regulation, coordinated movement, and an outward focus during social encounters—thus undermining the imitation-based observational learning that normal children enjoy. Without a predilection for social stimuli and imitative responses, the behavioral repertoires or routines that eventually progress – through hierarchical assimilation into social interactions, language, biological movement, Theory of Mind and empathic responses – would fail to develop.We start with a brief overview of the Bayesian brain and how oxytocin might implement the neuromodulation necessary for successful (interoceptive) inference and learning. With this theoretical perspective in place, we then consider the known neuromodulatory function of oxytocin and how aberrant neuromodulation might give rise to the autistic phenotype. Finally, we review the empirical evidence supporting this theory—evidence that speaks to abnormal interoceptive processing and subsequent failures of socio-emotional learning in autism and suggest how this theory might inform our approach to therapeutic treatment.22.1prediction error. In predictive coding schemes, prediction errors are transmitted from sensory cortex up hierarchical processing pathways to update representations in higher cortical levels. These representations correspond to probabilistic expectations  about the causes of sensory input and adjust top-down predictions to reduce prediction errors at lower levels. The implicit comparison of descending (top-down) predictions and ascending (bottom-up) evidence selects the relevant information (prediction errors) that violate top down predictions. These violations inform higher cortical levels—serving to recursively update the predictions such that optimal representations emerge at each level of the cortical hierarchy, thereby furnishing an explanation of the sensory world at multiple levels of description  nondiscriminatory touch, itch, tickle, temperature, hunger, nausea, thirst, sleepiness, and sexual desire. These sensations are used to maintain homeostasis, to infer emotional states, to elicit behaviors, and ultimately to provide a sense of the embodied self . PredictOxytocin influences the transmission of interoceptive signals, providing information about the internal milieu pertinent to homeostasis and reproduction. The participation of oxytocin in interoceptive signal transmission has been associated with almost every modality, including: olfaction, for review see ; taste ; light ; sensatiOxytocin receptor distribution in the brain supports a role for oxytocin in the transmission and modulation of interoceptive signals (prediction errors) in neuronal circuits. Oxytocin receptors are found in key hubs of the autonomic nervous system (the solitary nucleus of the brainstem (NTS) and the hypothalamus), they populate limbic areas , and inhabit the major source of acetylcholine in the brain  . Althoug2.3The physiology of predictive coding requires flexible neuronal communication on a short time scale  for perceptual inference and the more enduring changes in synaptic plasticity that ensue as the learning of generative models develop. The neural mechanisms subserving gain or precision control  have not been conclusively determined, but several mechanisms hold explanatory promise. Among these, communication through changes in synchronous activity (coherence) has the adaptive power to account for many of these operations on a time scale relevant to perceptual inference . These m2.4Neuromodulatory effects of the sort associated with oxytocin (described below) play an important and ubiquitous role in predictive coding. The relative precision of prediction errors at different levels of the hierarchy, or in different sensory modalities, has a profound effect on the recurrent hierarchical message passing that underlies predictive coding: the potency of ascending prediction errors on subsequent hierarchical processing depends upon their precision . ComputaIn the setting of interoceptive inference, precision adjusts the gain of signals conveying homoeostatic and reproductive  relevant information. Early in development, interoceptive precision will allow salient interoceptive information, such as satiety, temperature, thirst, pain, tickle, smell and taste signals to be transmitted up hierarchical (interoceptive) pathways to progressively more multimodal areas to allow for accurate inferences. Learning, in the form of strengthened synapses or a more defined network in higher cortical areas, depends upon these ascending (precision weighted) prediction errors. Later, prediction errors that have successfully been assimilated into the higher level generative models through learning will influence the predicted precision of signals coming from specific interoceptive channels lower in the hierarchy. Crucially, this scheme implies a circular causality among inference, learning (or memory) and attention (or sensory attenuation). This means that inference, learning and precision depend upon each other in a way that is mandated by the reciprocal message passing of approximate Bayesian inference—of which predictive coding is a key, neuronally plausible, example  cues such as eye gaze, a mother's face, tone of voice and biological movement may act as contextual modifiers to increase interoceptive signal precision and thereby promote emotional inferences early in development. Later, as the social brain emerges through developmental learning, these same cues will take on a salience that will capture attention. The neuromodulation underlying this vitally important control, first of interoceptive precision for accurate inference, then for the synaptic plasticity underlying learning of the generative model, and ultimately for appropriate context dependent top-down modulation that mediates attention and sensory attenuation we propose, depends upon oxytocin.2.5As discussed in previous papers on active inference, traditional neurotransmitters , glutamate, norepinephrine, and acetylcholine) can all modulate precision or the prediction error gain to promote the accurate inferences crucial to learning appropriate generative models . The oxyN-methyl-d-aspartate (NMDA) type glutamate receptors are thought to mediate top-down neuromodulation  . Prior tDuring the embryonic and prenatal stages of development, the NKCC1 transporter dominates, and more chloride ions are transferred into the cell than out of the cell. The KCC2 transporter does not become active until later in development, thus during embryonic stages, the sole activity of the NKCC1 creates a chloride gradient that allows GABA transmission to excite cells instead of inhibit them. Oxytocin dramatically changes the activity of GABA neurons with the onset of labor by inactivating the NKCC1 transporter. In rats, during parturition – and for a few postnatal days – GABA neurons become inhibitory. As oxytocin levels remit, GABA transmission transiently becomes excitatory again, until post-natal expression of the KKC2 transporter begins to exert its opposing effects on the chloride gradient, once more allowing GABA to assume it mature role in the brain as an inhibitory neurotransmitter . The perThis remarkable effect of oxytocin on GABAergic transmission has not been studied in the human brain, but several physiologic findings suggest that a similar mechanism takes place in the human newborn. For example, infants exposed to higher levels of oxytocin through vaginal deliveries resist pain and can withstand hypoxia more effectively . In addi4.3A potential paradox exists when applying predictive coding to the reflexive suppression of proprioceptive or interoceptive prediction errors. This paradox results from the fact that the simplest way to resolve sensory prediction errors would be to change top-down predictions. However, this would preclude any remedial movement or autonomic response. It is therefore necessary to attenuate the precision of ascending sensory prediction errors to enable descending predictions to be fulfilled by peripheral reflexes. This permissive suspension of sensory precision takes the form of sensory attenuation . Sensory4.4We have seen that the attenuation of interoceptive precision may be necessary for self-generated action or behavior that relates to interoception and the maintenance of homeostasis, an interoceptive form of action. The role of precision and attenuation of interoceptive prediction errors may therefore be fundamental in the organization and selection of autonomic reflexes. In other words, homoeostatic regulation may require the temporary suspension of interoceptive precision—attending away from the current interoceptive state of the body, such that top-down predictions can elicit peripheral sympathetic and parasympathetic reflexes. That homeostatic regulation depends upon a sense of bodily ownership supports the notion that homeostatic action is an integral part of active (embodied) inference.The finding that the rubber hand illusion can affect autonomic thermoregulatory control over the limb that has been transiently forsaken, suggests that a sense of bodily ownership, or a well-informed top down prediction, facilitates interoceptive control , yet seeEvidence for oxytocin's ability to attenuate interoceptive precision in the context of self-generated action – and thereby facilitate autonomic responses – exists in both the animal and clinical literature. In rodents, oxytocin promotes GABA mediated inhibitory activity in the central nucleus of the amygdala, the main projection from the amygdala to brain stem nuclei and the hypothalamus in the fear circuit  in prepa4.5Sensory attenuation may be fundamental to social interactions as well as homeostatic regulation. Oxytocin could exert multiple influences on prosocial and affiliative action or behavior through sensory attenuation. An ability to act, whether through movement or behavior, often requires sensory attenuation. In this context, interoceptive sensory attenuation pertains to shifting attention outward, away from the self. By reducing anxiety and self-absorption, oxytocin dependent sensory attenuation would promote approach behaviors , althougIn addition to initiating social interactions, oxytocin may enable social success once engaged, through interoceptive sensory attenuation. As with action observation, social interactions require the balanced attention to exteroceptive cues and attenuation of internal cues, in order to make inferences about others. Besides an attentional focus on salient biologic details, inference about the visceral or emotional state of the ‘other’ requires a careful sensory attenuation of our own interoceptive signals—in order to infer the emotional or autonomic state of others without interference from our own interoceptive cues. A successful social interaction therefore requires both the attribution of salience to exteroceptive cues, such as eye gaze and tone of voice in the ‘other’ and the ability to suppress inappropriate interoceptive cues. These abilities have to be learned as part of the generative model: the neuromodulation that attributes precision to prosocial cues must rely on prior expectations about facial expressions, tone of voice, and bodily stance that have been accrued through experience, and successful sensory attenuation of our own interoceptive signals depends on learning fine grained generative models of the self-learning that we suggest depends on oxytocin-dependent modulation of interoceptive cues.4.6Interoceptive sensory attenuation may also scaffold the processing imperative for the emergence of cognitive empathy and compassionate behavior. In the hierarchy of emotional reactions to another, emotional contagion represents the most primitive form of empathy and entails experiencing their emotional state. The transformation of affective contagion into cognitive empathy (Theory of Mind) requires successful attenuation of one's own emotional (autonomic) reaction and, implicitly, maintaining the boundaries of the self. Thus, cognitive empathy that does not automatically elicit an autonomic echopraxia or emotional contagion requires a well-developed sense of self . ExogenoIn rodents, oxytocin selectively facilitates GABA transmission in a subpopulation of amygdala cells, decreasing the freezing response, while maintaining the visceral appreciation of fear . One can4.7In the proposed model, differences in context can explain some of the apparently contradictory effects of oxytocin. Although over-simplified, the dichotomy between perception and action dictates whether oxytocin behaves to either attenuate or enhance interoceptive signals. Oxytocin participates in interoceptive sensory attenuation in the context of self-generated action with interoceptive consequences, which, in our minds, refers to homeostatic regulation, allostatic behaviors to fulfill drives, and social interactions. To accomplish these goals, oxytocin dependent sensory attenuation generally increases the precision of higher level predictions, based on learned generative models of the self, to dampen unhelpful interoceptive prediction error signals that would otherwise preclude action by causing a revision of the prediction, or by promoting echopraxia. Thus, in the context of self-generated action, one would expect oxytocin to dampen interoceptive signals. The evidence from Viviani's experiment, described above – where oxytocin mediated a switch from a freezing response to promoting action in rats – supports this prediction . In cont4.8•A primary disruption of the oxytocin system interferes with accurate interoceptive inference early in development.•A developmental neuromodulatory deficit in oxytocin impairs the modulation of interoceptive signals and prevents their contextualization. This contextualization is necessary to learn associations between interoceptive cues and their exteroceptive, kinesthetic and proprioceptive precedents.•A failure to learn context-sensitive associations between interoceptive and exteroceptive cues , precludes context sensitive attributions of salience to socially and emotionally relevant stimuli.•Impaired integration of interoceptive signals with salient information from other sensory domains prevents the infant from acquiring a higher level representation of ‘self,’ embellished with an emotional dimension that is distinct from ‘other’.•An impoverished sense of ‘self’ compromises interoceptive sensory attenuation. Impaired interoceptive sensory attenuation undermines self-generated action and behavior in the interoceptive domain, including: homeostatic regulation, self-stimulation, coordinated biological movements, and imitation based behaviors, eventually leading to difficulties with theory of mind and cognitive empathy.In summary, without adequate attenuation of interoceptive precision, internal prediction errors cannot be used to inform multimodal representations of emotional states that distinguish self from non-self, nor would the normal associations between emotional states and exteroceptive cues be learned. This would result in confusing the interoceptive state of self from others , diminished emotional affordance of exteroceptive cues , and poorly formed representations of the ‘self’ (poor ego boundaries). This means that a dysfunctional oxytocin system could prevent the sensory attenuation necessary to develop a mindfulness of others, to engage in social interactions and to learn complex behavioral repertoire is based on social imitation. We therefore suggest that autism is a result of the following etiological sequence:In the final section, we turn to the evidence for the deficits predicted by these theoretical considerations. We first consider the evidence for the primary pathophysiology, which we suppose is a failure to prescribe appropriate precision to interoceptive signals due to abnormal oxytocin-dependent neuromodulation and the ensuing diminished emotional affordance of social and emotional cues in the environment and impoverished generative models of the self. We then look at the evidence for the secondary consequences of this failure; namely, poor interoceptive sensory attenuation and the resulting impairments associated with this dysfunction.55.1Given the etiological sequence described above, a (primary) failure to modulate interoceptive precision would disrupt the context-sensitive assimilation of prediction error signals necessary to acquire generative models for inference about the emotional state of self and others. Impaired interoceptive inference would therefore give rise to alexithymia, or an inability to recognize and define one's own emotions. Several studies confirm that individuals with autism have difficulty understanding their interior landscape and cannot identify or name their own emotions with appropriate nuances, independent of their language capabilities , often t5.2Deficits in emotional affordance have been documented in autism since 5.3In the visual domain, autistic individuals maintain less eye contact over the course of their development; first with their mothers or primary care givers, and then with their peers , for rev5.4Besides eye contact and facial emotional processing, human interactions rely heavily on communication through the auditory domain as well. Vocal communication includes not just language, but the prosody embedded in speech . The perThese findings, in both the visual and auditory domains, suggest that autistic individuals do not acquire the predictive and attentional predilection for biological and social stimuli. This is consistent with a selective failure to learn associations – in hierarchical models – that jointly predict exteroceptive and interoceptive consequences of social encounters. Endogenously controlled shifts in attention enhance the perception of external stimuli and increase the efficiency of sensory processing . One wouThe literature confirms that attentional deficits result in learning delays and disabilities . Observa5.5An inability to incorporate specific interoceptive signals into complex generative models of the world should also result in an impoverished sense of self; a self not embellished with a recognized emotional dimension. In other words, if the interoceptive signals modulated by oxytocin are not contextualized, they will prevent the development of high level representations or generative models of the interoceptive and emotional self—especially a sense of self that is distinct from the ‘other’. The concept of an underdeveloped sense of self appears in several theories of autism including early psychoanalytic theories , Theory During self-evaluation, autistic individuals activate the ventromedial prefrontal cortex and the mid cingulate differently than neurotypical controls  and a reA failure to elaborate deep generative models of the embodied and socio-emotional self could also explain the coordination difficulties associated with autism , in the 5.6A failure to attenuate interoceptive signals immediately suggests an autonomic hypersensitivity and consequent difficulties in interoceptive and emotional regulation . Numerous disturbances in autonomic regulation have been documented in autistic children. Autistic individuals exhibit many symptoms of heightened baseline sympathetic activity and poor autonomic regulation, resulting in less parasympathetic tone , as demo5.7Repetitive self-stimulation behaviors such as scratching, head banging, twirling, and rocking – often labeled as stereotypies – commonly occur in autism  and may 5.8Compromised interoceptive control and reduced interoceptive attenuation could translate into an emotional state resembling anxiety. Autistic individuals report many anxiety symptoms, especially as they mature into adulthood. A recent meta-analysis of comorbidity in the adolescent and young adult population with autism spectrum disorder found that almost 40% suffered from a clinically significant anxiety disorder . Paulus 5.9By its very name, autism connotes self-absorption, and apparent deficits in empathy towards others have long been a presumed hallmark of the disorder . In a pr6Inspired by the social neuroscience findings on oxytocin and behavior, the search for a link between the oxytocin system and autism has gained traction over the past decade. Oxytocin peptide and plasma level abnormalities , recepto7By casting the oxytocin-dependent failure of interoceptive attenuation in a developmental context, a circular dependency emerges between a primary deficit in interoceptive processing and the learning of interpersonal and emotional generative models. The experience-dependent plasticity inherent in this learning will necessarily entail the contextualization of interoceptive and exteroceptive cues that underwrite attention, affordance, and sensory attenuation. A failure to learn this model renders the autistic child insensitive to the contingencies that would normally equip them with descending neuromodulatory control over their sensory signals. One can imagine that the ensuing vicious cycle gives rise to the devastating consequences observed in autism. This circular dependency has implications for therapeutic interventions: exogenous oxytocin in this population alone may not ameliorate symptoms. Instead, administration of oxytocin may need to be combined with behavioral (learning) paradigms to leverage the plasticity unleashed by this neuropeptide.The current evidence for oxytocin as a therapeutic intervention in autism supports a more nuanced approach. Small clinical studies have suggested that intranasal administration of oxytocin improves social cognition individuals with ASD, both acutely , and ove8Although this paper reviews the evidence for a dysfunction in oxytocin mediated interoceptive signal modulation; as it relates to homeostatic regulation, the development of generative models of the self, and sensory attenuation in autism, we have neither attempted to detail how a primary dysfunction in the oxytocin system occurs nor to incorporate the numerous genetic and neurochemical abnormalities associated with autism into this hypothesis. Many abnormalities or associations intersect with the oxytocin system at some level and provide support for our hypothesis. Among the neurotransmitters implicated in autism, anomalies in the serotonin system have been the most closely examined. Demonstrations of abnormal platelet serotonin levels in the autistic population occurred early in the field  and seroThe GABA neurotransmitter system has also been implicated in the pathogenesis of autism, through both genetic linkages with regions coding for GABA-A receptor subunits in families with autism  and as aVariants in the vasopressin receptor have also emerged as candidate targets to explain autism . BecauseOther models of autism, such as the extreme male brain , suggestWe have not discussed possible etiological reasons for a disrupted oxytocin system nor have we addressed why some individuals with autism may experience certain symptom clusters to a greater extent than others. Many different physiological and genetic insults could potentially disrupt the oxytocin system and some of the heterogeneity of phenotypic expression could result from these differences. Polymorphisms in the oxytocin receptor gene , epigeneThe reliability of oxytocin assays has been questioned  and cont9so, as regulation is the one function that counts biologically, we can expect that natural selection will have made the brain as determinate as possible”. This simple observation lays the foundation for how a single neuropeptide system could have such specific, yet widespread and devastating effects, especially when considered in a developmental framework.Our Bayesian account of neurodevelopment in autism rests on the role of oxytocin in modulating the precision of interoceptive signals. The implicit contextualization of interoceptive cues underwrites the experience-dependent plasticity necessary to acquire generative models of the emotional self (and others). In this framework, a (primary) developmental pathophysiology in the oxytocin system – and the (secondary) failure to elaborate generative models of the interpersonal world – prevents autistic infants from recognizing and selectively attending to emotionally salient cues. As a result of this oxytocin dependent failure to prescribe appropriate salience to exteroceptive cues and to facilitate interoceptive attenuation, an onslaught of unfiltered sensory information overwhelms the child, promoting protective behaviors and derailing the observational learning so important in early development. Thus, impaired interoceptive inference initiates a cascade of difficulties culminating in a – now all too common – autistic phenotype. As the British scientist Ross Ashby in 1962, stated: “


Alpha-1-antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease and is a prototype of liver diseases caused by the pathologic accumulation of aggregated mutant alpha-1-antitrypsin Z (ATZ) within liver cells. In the case of ATD-associated liver disease, the resulting “gain-of-function” toxicity can lead to serious clinical manifestations, including cirrhosis and hepatocellular carcinoma. Currently, the only definitive therapy for ATD-associated liver disease is liver transplantation, but recent efforts have demonstrated the exciting potential for novel therapies that target disposal of the mutant protein aggregates by harnessing a cellular homeostasis mechanism called autophagy. In this review, we will summarize research advances on autophagy and genetic liver diseases. We will discuss autophagy enhancer strategies for liver disease due to ATD and another genetic liver disease, inherited hypofibrinogenemia, caused by the proteotoxic effects of a misfolded protein. On the basis of recent evidence that autophagy plays a role in cellular lipid degradation, we also speculate about autophagy enhancer strategies for treatment of hepatic lipid storage diseases such as cholesterol ester storage disease. Therapeutic strategies that enhance autophagy, using either drugs or gene transfer with a transcriptional activator of autophagy, have recently been shown to reverse hepatic accumulation of misfolded protein and hepatic fibrosis in a mouse model of ATD. In this review we will discuss autophagy enhancer strategies for liver disease due to ATD and another genetic liver disease, inherited hypofibrinogenemia, caused by the proteotoxic effects of a misfolded protein. On the basis of recent evidence that autophagy plays a role in cellular lipid degradation, we also speculate about autophagy enhancer strategies for treatment of hepatic lipid storage diseases such as cholesterol ester storage disease.Alpha-1-antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease. It is characterized by accumulation of a misfolded secretory protein in the endoplasmic reticulum of liver cells. In some affected homozygotes this “proteotoxic” state leads to hepatic fibrosis/cirrhosis and hepatocellular carcinoma. Investigations in a variety of model systems have shown that macroautophagy is activated when the mutant α1-Antitrypsin (AT) is an abundant serum glycoprotein predominantly synthesized by liver parenchymal cells. It is a prototype member of the serine protease inhibitor family, known as serpins, with a particular strong profile for inhibiting neutrophil elastase, cathepsin G, and proteinase 3. The classical form of ATD (referred to as PIZZ) results from a point mutation in the AT gene that leads to a lysine to glutamate substitution at residue 342 of the protein that renders the mutant AT protein (termed ATZ) prone to misfolding. A number of studies have shown that ATZ is also prone to polymerization and aggregation, and it is likely that this aggregation-prone tendency plays a distinct role in the nature of the pathology of the disease [ disease , 6.The clinical presentation of ATD-associated liver disease is highly variable and may become apparent in distinct forms during infancy, childhood years, adolescence, or at 50–65 years of age . PatientIn adults, ATD-associated liver disease may be recognized either because of portal hypertension or because of the detection of hepatocellular carcinoma (HCC). HCC is an important manifestation that is likely caused by chronic proteotoxicity that drives liver fibrosis and hyperproliferation of hepatocytes. Support for this hypothesis comes from experimental studies that have found that ATZ accumulation in hepatocytes is associated with impaired cell proliferation and chronic regenerative signaling . A SwediTo understand the mechanism of the liver disease associated with ATD, our laboratory focused initially on mechanisms by which mutant ATZ is degraded when it accumulates within cells. Early studies using yeast and mammalian cell lines showed that the proteasomal pathway participated in intracellular degradation of mutant ATZ –13. IndeAutophagy was firstly implicated in ATD when increased autophagosomes were observed in human fibroblast cell lines engineered for expression of ATZ . Increas C. elegans model of ATD [Another series of studies using a completely different system for modeling ATD, yeast expressing human ATZ, also showed the importance of autophagy . These sl of ATD .In addition to the proteasomal and autophagic pathways for disposal of ATZ, a recent study showed that a pathway from Golgi complex to lysosome that involves the endosomal protein sorting receptor sortilin plays a role in degrading intracellular ATZ . We suspκB and TGF-β signaling pathways are part of the distinct gene expression profile associated with intracellular accumulation of ATZ, and these pathways are likely central to the hyperproliferation and fibrosis, respectively, which characterizes the hepatic pathology of ATD [To understand the molecular mechanism by which the cells mitigate the proteotoxicity of intracellular ATZ accumulation and presumably protect ATD hosts from liver disease, we also focused on the signaling pathways that modulate proteostasis. Using mammalian cell line and mouse models with inducible expression of ATZ and genomic analysis, we found that the NF-y of ATD , 20. Geny of ATD .Because autophagy is activated when mutant ATZ accumulates in cells and participates in intracellular disposal of ATZ, we reasoned that it was a potentially attractive target for drug therapy to mitigate the proteotoxicity that causes liver damage in ATD. From a list of drugs that have been purported to have autophagy enhancer properties, we investigated the effect of carbamazepine (CBZ) in cell line and mouse models of ATD. We selected CBZ because it is approved by the US Food and Drug Administration (FDA) with an extensive safety profile from its use as anticonvulsant and mood stabilizer. We found that CBZ enhanced autophagy and mediated a marked increase on the degradation of mutant ATZ in cell line models . More im C. elegans model of ATD [ in vivo and mediated a decrease in hepatic fibrosis [ huntingtin in different models of Huntington's disease. Furthermore, several compounds identified in these screenings are in the phenothiazine family, for example, fluphenazine, pimozide, and fluspirilene [The concept that autophagy enhancer drugs counteract the accumulation and proteotoxicity of misfolded proteins has been further substantiated by the results from an automated high-content screening using a novell of ATD . The inil of ATD . In nanofibrosis . As Flu fibrosis , 24. Thepirilene , 23, 24.2+ and preventing calpain-1-mediated cleavage of autophagy gene ATG5 [The specific molecular target of CBZ and the phenothiazine drugs that leads to enhanced autophagy of ATZ remains largely unknown. Because the classical mTOR antagonist rapamycin had minimal effects on ATZ disposal in cell line models and did not alter hepatic ATZ levels in the PiZ mouse model in our studies , we haveene ATG5 . NeverthSeveral other drugs have recently been shown to induce autophagy. Glucosamine and N-acetylglucosamine increased autophagy in mammalian cell lines . AlthougStudies by Shoji-Kawata et al. have identified a potent autophagy-inducing peptide which could potentially be utilized for drug development. Building on prior observations that the HIV protein Nef inhibits autophagy by directly interacting with the autophagy regulatory factor beclin 1 , 31, the in vivo [A recent study showed that activation of autophagy using gene transfer of the transcription factor TFEB can ameliorate the proteotoxicity of ATZ. TFEB is a master gene that regulates autophagy and lysosomal gene expression . It appe in vivo . These rATD serves as a paradigm for gain-of-toxic function liver disease resulting from the pathologic intracellular accumulation of misfolded proteins. Similar phenomena occur in two other rare liver diseases—fibrinogen storage disease and cholesterol ester storage disease. The defects in each of these conditions lead to abnormal intracellular accumulation of substrates that are hepatotoxic and can result in significant clinical liver disease. These disorders illustrate the essential role of autophagy in liver disease and provide insights into the potential efficacy of therapeutic strategies designed to enhance autophagic function.Fibrinogen Storage Disease. Fibrinogen is a 340 kD dimeric plasma protein produced by hepatocytes that is a central component of the coagulation cascade. Each half of the dimer is composed of three polypeptide chains  that are assembled in the ER. Several mutations in the fibrinogen gamma chain have been reported  that are associated with fibrinogen storage disease, an autosomal-dominant disorder that is characterized by low circulating plasma fibrinogen levels and abnormal accumulation of fibrinogen components within the hepatocyte ER [ocyte ER . ReminisγD chain was expressed in yeast, initial clearance of the protein from the ER was performed by ERAD. However, once ERAD was saturated, γD aggregates accumulated within the ER, and clearance of these aggregates was dependent on autophagy. These results suggest that the mutant fibrinogen Aguadilla behaves similarly to mutant ATZ in the fact that it accumulates within the secretory pathway, has a tendency to polymerize/aggregate, and is degraded by proteasomal and autophagic mechanisms. Based on these findings as well as work by the Perlmutter group that demonstrated amelioration of experimental ATD-associated liver disease by the autophagy-enhancing drug carbamazepine, Puls et al. recently conducted a small study of two patients with fibrinogen storage disease in which they found that administration of carbamazepine at antiepileptic doses was associated with normalization of alanine-aminotransferase and reduction of markers of apoptosis and necrosis [Experimental studies in yeast models of Aguadilla-variant fibrinogen storage disease by Kruse et al. demonstrated that disposal of mutant fibrinogen from the ER is mediated by two proteostasis mechanisms: endoplasmic reticulum-associated degradation (ERAD) and autophagy . When thnecrosis .Cholesterol Ester Storage Disease. Cholesterol ester storage disease (CESD) is an autosomal recessive condition that results from mutations in the LIPA gene, which encodes lysosomal acid lipase (LAL). LAL is a critical component of the low-density lipoprotein (LDL) receptor pathway that is responsible for hydrolyzing cholesterol esters that have been taken up into lysosomes. LIPA mutations associated with deficient LAL activity lead to intracellular accumulation of cholesterol esters and triglycerides [ LIPA mutations that cause nearly complete absence of LAL activity and presents during infancy with hepatosplenomegaly, cholestasis, intestinal malabsorption, adrenal calcifications, and diffuse xanthomatosis [ycerides . The mosomatosis , 38. Lesomatosis . C. elegans system, the lysosomal lipases lipl-1 and lipl-3 (worm homologues of human LAL) are important to the mobilization of cytosolic fat through a specific autophagic process termed as lipophagy. Larvae that were double mutants for lipl-1 and lipl-3 accumulated three times the cytosolic fat as wild-type larvae, an observation that is reminiscent of cholesterol ester accumulation seen in CESD [3H-labeled cholesterol [Lysosomal function is critical for efficient autophagic degradation of substrates, and recent experimental studies have provided evidence for the key role of autophagy in lipid metabolism. In a in CESD . Anotherlesterol .Severe CESD disease may lead to the need for liver transplantation, underscoring the need for novel therapies that can ameliorate the natural course of this condition. Lipid-lowering therapies including statins and cholestyramine have not been shown to reverse liver disease. More recently, efforts have focused on enzyme replacement therapy using recombinant human LAL , which in experimental mouse studies appeared to reduce hepatic cholesterol ester load and reduced the presence of foamy macrophages in the liver, spleen, and intestines of these mice. This agent is currently in clinical trials , 39. DueBecause autophagy mediates turnover of damaged organelles and degradation of denatured and misfolded proteins and also mediates disposal of stored lipids, it represents a critical cytoprotective mechanism in homeostasis and during stress states. It appears to be particularly important in diseases caused by misfolded proteins and this may be because it is specialized for degradation of insoluble and soluble proteins. Recent studies have shown that strategies which enhance autophagy can reverse the consequences of proteotoxicity in the liver. These strategies include drugs and viral-mediated gene transfer approaches using the transcriptional activator of the autophagolysosomal system, TFEB. Because some of the drugs are FDA-approved and have been extensively used in clinical medicine, we should see results from clinical trials in the next several years.