Despite its evident universality and high social value, the ultimate biological role of music and its connection to brain disorders remain poorly understood. Recent findings from basic neuroscience have shed fresh light on these old problems. New insights provided by clinical neuroscience concerning the effects of brain disorders promise to be particularly valuable in uncovering the underlying cognitive and neural architecture of music and for assessing candidate accounts of the biological role of music. Here we advance a new model of the biological role of music in human evolution and the link to brain disorders, drawing on diverse lines of evidence derived from comparative ethology, cognitive neuropsychology and neuroimaging studies in the normal and the disordered brain. We propose that music evolved from the call signals of our hominid ancestors as a means mentally to rehearse and predict potentially costly, affectively laden social routines in surrogate, coded, low-cost form: essentially, a mechanism for transforming emotional mental states efficiently and adaptively into social signals. This biological role of music has its legacy today in the disordered processing of music and mental states that characterizes certain developmental and acquired clinical syndromes of brain network disintegration. Music is universal and generally highly valued in human societies. These attributes are biologically grounded in the phylogenetically ancient neural machinery of emotion, reward and memory . Young cRecent findings from cognitive neuroscience have shed new light on this old problem. Potential precursors to speech have been identified in geladas  and hintA further complementary approach to understanding the neurobiology of complex cognitive phenomena such as music is to assess neuropsychological effects of brain damage on those phenomena. This clinically focussed approach is neurobiologically compelling for two key reasons. First, in contrast to studies in the healthy brain, clinical studies  identify neural substrates that are critical for function rather than merely epiphenomenal and delineate the relations between cognitive subprocesses . Second, the window opened by brain disorders on underlying cognitive architecture is particularly germane to the case of music, for which original biological functions have been largely obscured by the now dominant effects of cultural evolution. While we cannot rerun hominid evolution, the effects of brain damage can, in part, recapitulate the original evolutionary pathway. A substantial body of clinical data has now been amassed regarding the effects on music structural and emotion processing in developmental and acquired brain disorders, including autism .Here we propose a new evolutionary model of music as a biologically sanctioned mechanism for transforming private, emotional mental states efficiently into public social signals. The model is outlined in Call sounds are widely used by primates to convey emotionally laden conspecific information, particularly over long distances where visual cues are reduced ; this inIn line with previous suggestions , we specThis evolution of proto-musical vocal signalling may have been driven, in part, by an increasingly complex and flexible interaction between essentially ‘public’ (dyadic or group) and ‘private’  communicative functions. As elementary call sounds with conspecifically sanctioned, ‘public’ semantic value became linked into sequences modulated by caller emotional state in the context of primitive ‘conversations’, this would have promoted increasingly complex ‘off-line’ processing by the listener in preparing responses that were, in turn, modulated by the listener’s own emotional state. This off-line processing would, in turn, have set the stage for elaboration of fully autonomous privately rehearsed signals. While this public–private interaction of communication codes would have operated for proto-linguistic as well as proto-musical signals, it was proto-music (we argue) that, by virtue of its acoustic properties, governed coding of emotional states.Facility in transitioning between public and private proto-musical signalling would have been socially and biologically advantageous both at an individual and group level because it would tend (for example) to promote empathy, pair bonding and social cohesion. This role of early musical signalling could, therefore, plausibly have been subject to evolutionary selection pressures. One might go further and propose certain ‘design features’ that these musical precursor codes were required to possess to be selected; these features would include not only repeatability and modularity , but also more contentiously, sufficient ‘encryption’ to prevent uncontrolled access by all listeners  to the caller’s internal emotional states and potential vulnerabilities . The proIncreasingly sophisticated combinatorial use of call sounds by early hominids would have facilitated transmission of signals coding ambiguous states, whether instantiated in the world at large (proto-language) or in private emotional experience (proto-music). Successful resolution of such ambiguities would facilitate appropriate behavioural responses. We argue that the development of proto-linguistic and proto-musical ‘meta-signalling’ capacities provided a medium for representing and adaptively resolving apparent ambiguities and inconsistencies in the arena of the physical environment and social interactions, respectively. The scope of such meta-signalling would have extended to complex affective mental states accompanying social scenarios without immediate survival value; for example, those accompanying grief and mourning, social dominance or submission. Indeed, social situations routinely require abstraction of their inter-personal meaning and resolution of ambiguity if they are to be managed successfully; a prime instance of which is sarcasm  has been advanced as an argument against a biological role of music  with no obvious biological purpose. We do not of course wish to imply here that music is now solely a diversion or a means of generating pleasure. In most societies, (including the developed West) music continues to play a pervasive role in rituals, social cohesion and cooperative action among members of groups sharing a common musical culture . Rather,vs other complex cognitive phenomena (notably language) and among musical functions, observed in association both with focal brain lesions and neurodegenerative diseases , brain disorders allow us to assess the extent to which music can model generic cognitive processes such as theory of mind. Frontotemporal dementia is the paradigmatic acquired disorder of human social behaviour . In addiOur model of music biology foregrounds predictive and adaptive decoding of patterned vocal signals and is, therefore, most closely aligned with previous accounts emphasizing a problem-solving or pattern-decoding function of music see . HoweverOur model suggests several avenues for future experimental evaluation. The vocalizations of other primate species could be compared quantitatively with human singing . The lim


Puccinia graminis f. sp. tritici (Pgt) poses a threat to food security. These concerns have catalyzed an extensive global effort toward controlling this disease. Substantial research and breeding programs target the identification and introduction of new stem rust resistance (Sr) genes in cultivars for genetic protection against the disease. Such resistance genes typically encode immune receptor proteins that recognize specific components of the pathogen, known as avirulence (Avr) proteins. A significant drawback to deploying cultivars with single Sr genes is that they are often overcome by evolution of the pathogen to escape recognition through alterations in Avr genes. Thus, a key element in achieving durable rust control is the deployment of multiple effective Sr genes in combination, either through conventional breeding or transgenic approaches, to minimize the risk of resistance breakdown. In this situation, evolution of pathogen virulence would require changes in multiple Avr genes in order to bypass recognition. However, choosing the optimal Sr gene combinations to deploy is a challenge that requires detailed knowledge of the pathogen Avr genes with which they interact and the virulence phenotypes of Pgt existing in nature. Identifying specific Avr genes from Pgt will provide screening tools to enhance pathogen virulence monitoring, assess heterozygosity and propensity for mutation in pathogen populations, and confirm individual Sr gene functions in crop varieties carrying multiple effective resistance genes. Toward this goal, much progress has been made in assembling a high quality reference genome sequence for Pgt, as well as a Pan-genome encompassing variation between multiple field isolates with diverse virulence spectra. In turn this has allowed prediction of Pgt effector gene candidates based on known features of Avr genes in other plant pathogens, including the related flax rust fungus. Upregulation of gene expression in haustoria and evidence for diversifying selection are two useful parameters to identify candidate Avr genes. Recently, we have also applied machine learning approaches to agnostically predict candidate effectors. Here, we review progress in stem rust pathogenomics and approaches currently underway to identify Avr genes recognized by wheat Sr genes.The recent resurgence of wheat stem rust caused by new virulent races of  Puccinia graminis f. sp. tritici (Pgt) causes stem rust or black rust, one of the most devastating diseases affecting common and durum wheat, barley, and triticale , was detected in Uganda  which defeated the resistance gene SrTmp in the widely cultivated wheat variety “Digalu,” introduced to provide protection against the Ug99 race group  genes with complementary race specificity, in combination with non-specific partial resistance genes  genes  reproduction on a cereal host (Poaceae), such as wheat, and sexual recombination on an alternate host , with each cell containing two haploid nuclei dikaryotic genetics. However, toward the end of the growing season, as the cereal host starts to senesce, the fungus may initiate the sexual stage through formation of diploid (2n) teliospores. These thick-walled, two-celled spores can remain dormant until the spring and then complete meiosis to generate haploid basidiospores that can infect the alternate host Berberis (barberry) or Mahonia  genes, often known as “major” or “seedling” resistance genes in the wheat and barley context, are one of the fundamental resources utilized in disease resistance breeding programs. These R genes generally conform to the “gene-for-gene” model, and confer resistance to pathogen races carrying a corresponding Avr gene  class  and pathogen (Melampsora lini), respectively, many of which are now cloned  genes described in wheat and its close relatives  and in this case virulence arose from a transposable element insertion in the promoter of the gene  confers resistance against stem, leaf and stripe, rust fungi as well as barley yellow dwarf virus and powdery mildew and encodes a putative adenosine triphosphate-binding cassette (ABC) transporter protein  also confers multi-pathogen resistance and encodes a hexose transporter  induced in a standard set of differential lines containing known Sr genes , Gabo (Sr11), Spica (Sr17), and Festival (Sr9b) soon after their release was considered to be the result of mutation  or two mutations (in a homozygote) are required. This may explain some of the observed differences in the durability of Sr genes in particular environments with varying pathogen populations. Alternatively, some virulence mutations may impose fitness costs.Similarly, Australia has also struggled with the economic losses caused by 21 Park, . Becauseme Park, . The prePuccinia triticina, can undergo anastomosis and nuclear migration .Clearly, identifying Pgt isolate, CDL 75-36-700-3, was assembled based on Sanger sequencing of plasmid and fosmid clones  between the two haploid genomes in this isolate. Subsequent analysis of global isolates has led to the development of a high throughput SNP genotyping array. The PgtSNP 1.5 k chip has been used to genotype Pgt isolates from Northeast Africa to examine the genetic relationship between races of Pgt . Comparison of these genome sequences with the original 21-0 progenitor pathotype identified a total of 25 effector candidates containing sequence changes that could be responsible for conferring these virulence phenotypes.The Australian a et al.  initiateSr genes that have been used historically and subsequently overcome. Identifying Avr genes corresponding to important new Sr genes will require a different approach. A promising strategy at this time is to use a mutagenesis approach to generate genetic diversity that can then be associated with sequence and virulence changes. The feasibility of this approach was demonstrated in early mutagenesis experiments  will affect the ease of identifying virulence mutations. Indeed, spontaneous virulence mutants provided a valuable resource in cloning Avr genes from M. lini, but were only detected for heterozygous Avr loci (Dodds et al., Pgt isolates in mutagenesis experiments is advantageous because the mutability of different races is likely to differ on specific Sr genes. Recently, a spontaneous mutant of Pgt virulent to the broadly effective and now cloned Sr50 was identified (Mago et al., Pgt mutants against a range of Sr genes to identify new Avr gene candidates.Both of these resources are however limited by the genetic variation that occurs within a single segregating family or collection of field isolates, which mostly represents ts Luig, . BecauseAvr genes will require demonstration of activity through functional assays. In many disease systems, this can be achieved by either transformation of a virulent pathogen to test for an avirulent phenotype, or by transient expression of the candidate effector in a resistant host to test for defense induction. Although transformation of flax rust is possible, it relies on silencing a previously identified Avr gene for selection (Lawrence et al., Pgt or other rust fungi. Likewise Agrobacterium-mediated transient protein expression is not available for wheat. Other potential assays include bacterial systems developed in Pseudomonas and Xanthomonas species that can deliver effector candidates via Type 3 Secretion (Sohn et al., Avr candidates and crossing these to the Sr resistant line to test for cell death defense induction and transient expression by biolistic transformation (Jones et al., Sr genes have been cloned, these may be co-expressed with the Avr candidates in a heterologous system, such as Nicotiana benthamiana. This approach was used recently to confirm the identity of AvrPm3f from wheat powdery mildew as it triggered cell death when recognized by the corresponding wheat Pm3f resistance gene (Bourras et al., Lastly, confirmation of the identity of genetically defined Sr genes to be deployed in new wheat cultivars, informed by knowledge of the corresponding Avr genes and their population genetics. In light of this, the identification of effectors in Pgt and understanding the underlying mechanisms that generate genetic variability in Pgt are two research priorities. The coordinated international surveillance efforts led by the Borlaug Global Rust Initiative and the Durable Rust Resistance in Wheat Project during the last 8 years have created a platform to enable pathogenomics studies in recently emerged virulent isolates from multiple points of origin. In combination with historical collections of Pgt isolates these resources provide a valuable experimental system to address these research priorities. Recent breakthroughs in cloning Sr genes from wheat have provided tools such as perfect molecular markers to facilitate the production of gene pyramids or stacks. In parallel, these advances also provide materials for generating transgenic events with multiple Sr genes at a single location which will greatly simplify the breeding constraints of multiple unlinked genes. Cloned Avr genes will provide a means to verify the function of individual Sr genes in such combinations. The ability to rotate between stacks with different R gene components would also contribute to resistance durability (McDonald, Brachypodium distachyon may provide novel sources of resistance genes from outside the wheat and barley gene pool (Ayliffe et al., Pgt (Zambino et al., B. distachyon (The International Brachypodium Initiative, Keeping stem rust at bay has not been an easy task; however, for over 80 years breeding for disease resistance and the deployment of resistant cultivars has been a powerful strategy to lessen the frequency of stem rust disease outbreaks (Leonard and Szabo, All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There is growing interest in the role of bone in knee osteoarthritis. Bone is a dynamic organ, tightly regulated by a multitude of homeostatic controls, including genetic and environmental factors. One such key environmental regulator of periarticular bone is mechanical stimulation, which, according to Wolff’s law, is a key determinant of bone properties. Wolff’s law theorizes that repetitive loading of bone will cause adaptive responses enabling the bone to better cope with these loads. Despite being an adaptive response of bone, the remodeling process may inadvertently trigger maladaptive responses in other articular structures. Accumulating evidence at the knee suggests that expanding articular bone surface area is driven by mechanical stimulation and is a strong predictor of articular cartilage loss. Similarly, fractal analysis of bone architecture provides further clues that bone adaptation may have untoward consequences for joint health. This review hypothesizes that adaptations of periarticular bone in response to mechanical stimulation cause maladaptive responses in other articular structures that mediate the development of knee osteoarthritis. A potential disease paradigm to account for such a hypothesis is also proposed, and novel therapeutic targets that may have a bone-modifying effect, and therefore potentially a disease-modifying effect, are also explored. Historically, osteoarthritis (OA) had been considered a disease predominantly affecting articular cartilage. More recently, it has been appreciated that OA affects the entire joint and all of its constituent tissues and that a spectrum of structural changes ranges from early asymptomatic disease detected on magnetic resonance imaging (MRI) to painful end-stage radiographic disease requiring joint replacement surgery.There is growing recognition for the role of bone in both early- and late-stage knee OA. Indeed, radiographic criteria for the diagnosis of OA developed in the 1950s included subchondral sclerosis and osteophytes as hallmarks of disease [Bone is a dynamic tissue that is tightly regulated by a multitude of homeostatic controls. One key environmental regulator of periarticular bone is mechanical stimulation. Wolff’s law relates to the response of bone to mechanical stimulation and states that bony adaptation will occur in response to a repeated load . It is iWhen periarticular bone is subjected to increased loading, a number of bone properties change. These include, but are not limited to, an expanding subchondral bone cross-sectional area, changes in bone mass, and remodeling of the trabeculae network. Although these changes likely represent appropriate homeostatic responses of bone to increased loading, they also appear to inadvertently predate maladaptive responses in other articular structures, most notably cartilage. For instance, animal studies have demonstrated that surgical damage to subchondral bone leads to degradation in the overlying articular cartilage in dogs  but thatThis review hypothesizes that adaptations of periarticular bone in response to mechanical stimulation cause maladaptive responses in other articular structures that mediate the development of knee OA. Furthermore, this review explores one potential mechanism hypothesizing how bony adaptation to increased mechanical load may inadvertently predate early knee OA. Novel therapeutic agents that may have a bone-modifying effect, and therefore potentially a disease-modifying effect, are also explored.Julius Wolff 1836–1902), a German anatomist and surgeon, theorized that bone will adapt to the repeated loads under which it is placed [, a GermaIt is now recognised that remodeling of bone in response to a load occurs via sophisticated mechanotransduction mechanisms. These are processes whereby mechanical signals are converted via cellular signaling to biochemical responses . The keySome of the most convincing evidence to substantiate the role of Wolff’s law at the knee has been derived from animal models. Mice with varying loads applied to the tibial diaphysis demonstrated that knee loading was an effective means of enhancing bone formation in a loading frequency-dependent manner . LikewisP < 0.005) [Among humans, some of the earliest work linking knee joint loads and bone adaptation in vivo was born from gait analyses. Gait analyses enable biomechanical variables that estimate knee joint loads to be examined from force platforms. For instance, the external knee adduction moment is a dynamic measure that occurs during the stance phase of human ambulation. It acts to disproportionately distribute joint loads to the medial tibiofemoral compartment  and is a< 0.005) . Since t< 0.005) , 13. Mec2 kg per m2, P = 0.001) and, to a lesser extent, the lateral  tibial bone area [2) also had greater medial tibial bone area compared with normal weight subjects [Obesity is another factor that can increase knee joint loading. Indeed, the unequivocal link between obesity and knee OA , 15 may one area . Those wsubjects . This meBone adaptation also occurs when a joint cannot adequately distribute external loads secondary to derangements in articular structures. The primary role of the meniscii at the knee is to cushion and redistribute joint loads. Therefore, when the function of a meniscus is impaired by an anatomical tear or extrusion, or menisectomy, joint load would be expected to increase, with potential ramifications to subchondral bone. It has been shown that meniscal surface area strongly reflects the ipsilateral proximal tibial plateau area , and menBone mass and density at the knee can be studied by measuring local periarticular bone mineral density (BMD) with dual-energy x-ray absorptiometry and by using fractal analysis to produce a description of trabecular bone microarchitecture based on the cross-linkage, number, and size of trabeculae , 24. TheHowever, the inconsistencies in the response of bone architecture to mechanical load are likely attributable to whether or not significant time has elapsed to enable bony remodeling. For instance, in animal models of induced knee OA, the acute and rapid resorption of periarticular bone , 29 may Knee alignment is an important determinant of periarticular BMD. Whereas varus deformity is associated with greater medial rather than lateral tibial BMD, valgus deformity is associated with greater lateral tibial BMD , 26. In There is a paucity of animal and human studies examining the association between obesity and periarticular BMD at the knee. Indeed, few data are available examining the association between obesity and BMD at varied anatomical sites, and despite the popular belief that obesity may be protective against osteoporosis, this is contentious –32.Akin to the increases in articular bone area expansion that occurs when menisci are damaged, it has been shown that meniscal damage is also associated with higher regional periarticular tibial BMD in the same compartment . HoweverDespite the proposition that, in skeletal biology, trabeculae align with the orientation of dominant compressive loads, this has not been widely tested and evidence supporting this hypothesis is derived from animal studies. A study of birds has shown that fine trabecular bone in the distal femur has a high degree of correspondence between changes in joint angle and trabecular orientation, supporting the prediction that trabecular bone adapts dynamically to the orientation of the peak compressive force . LikewisFew studies have examined the association between obesity and trabecular structure at the knee  in either humans or animals. In a study of adolescent black females, it was found that obese people had a lower trabecular compartment area at the distal tibia than their non-obese counterparts . In a stTrabeculae are also affected by joint damage, and it has been shown that there is lower apparent trabecular number with greater apparent residual trabecular thickness and separation in people with meniscal tears . In a moBone and cartilage are intimately related since the avascular hyaline cartilage is reliant in part on the vascularized subchondral bone to remain viable. Technetium scintigraphy work has demonstrated that increased bone metabolism is related to OA severity . HoweverSeveral in vivo human studies have examined the association between tibial plateau size and changes in cartilage volume. In a population study of 324 adults, larger baseline proximal tibial bone area was associated with increased cartilage volume loss over the course of 2 years at both the medial and lateral tibial sites . NeverthSeveral studies have shown a positive association between BMD at a number of sites, including total body, femur, and spine, and knee cartilage volume –45. HoweIn people with established knee OA, it has been shown that the medial-to-lateral tibial BMD ratio was positively associated with medial joint space narrowing . LikewisThe trabecular structure of bone also appears to be a determinant of cartilage changes at the knee. In an induced model of knee OA in guinea pigs, trabeculae were thicker and further apart and topographically mirrored untoward histomorphometric changes in cartilage . In women = 1,754) demonstrated that high systemic BMD increased the risk for incident knee OA, as measured by the onset of joint space narrowing [Cartilage response to systemic bone mineral density may vary according to disease status. There is conjecture as to whether a higher systemic BMD is to the benefit or detriment of cartilage. This may differ on the disease state . A large radiographic study . Both animal and human studies have shown promising data supporting calcitonin in mitigating the symptoms and structural changes of OA. A recent animal study examined the efficacy of calcitonin on the progression of early-stage OA in a surgically induced model of OA among rabbits . IntramuAmong human studies, post-menopausal women with moderate to severe painful radiographic knee OA treated with intranasal calcitonin demonstrated improved pain, stiffness, and function after 3 months of treatment and these improvements remained consistent for 1 year . MoreovePTH has been shown to act via the type 1 PTH receptor to induce matrix synthesis and suppress maturation of chondrocytes . It was As theorized by Wolff’s law, when knee bone is subject to increasing loads, it responds with compensatory geometrical changes, most notably an expansion in subchondral bone cross-sectional area. Paralleling these geometric changes is the remodeling of bone architecture with a long-term increase in periarticular BMD and remodeling of the trabeculae network. Although these adaptive bone changes help bone to better cope with increased joint loads, they also appear to inadvertently predate maladaptive responses in other joint structures, most notably hyaline articular cartilage.A potential mechanism for DMOADs may be at the level of various methods of inhibiting bone resorption. After acute injury, such as ACL rupture, animal models of OA have consistently demonstrated a rapid increase in localized periarticular bone resorption. We have speculated that this acute period likely represents an overburdening of bone by a sudden increase in mechanical load. However, as bone adapts, compensatory mechanisms, such as an increase in periarticular BMD, secondary to microfractures may enable the bone to withstand increased bony loads. It is speculated that anti-resoprtive therapies such as bisphosphonates and strontium ranelate may have a DMOAD effect by inhibiting this initial resorptive phase of overburdened periarticular bone. Alternatively, other bone-modifying agents such as calcitonin and PTH analogues are attracting increasing attention as potential DMOADs. Further work is required to examine novel therapeutic agents that may have a bone-modifying effect, and therefore a disease-modifying effect, in knee OA.


Globally, there were estimated to be around 7.3 million people in 2009 with trachomatous trichiasis (TT).Deploying community-based screening and counselling using dedicated mobile surgical teams in high-burden districts, integrating with other eye care services and leveraging political support at all administrative levels are among potential solutions to improve trichiasis surgical uptake.In the Amhara Region of Ethiopia it was recognised that many trichiasis patients were not accepting offers of surgery through local, freely provided outreach services. This was explored in focus group discussions, which identified a variety of concerns. First, most trichiasis patients mistakenly believed that the surgical wound needs up to 2 months to heal, during which time they should avoid sunlight exposure, involvement in productive activities and getting near to fire or smoke, or else TT would recur. Patients also believed that the operation was very painful and were unaware that it is conducted under local anaesthesia. They were very concerned about the quality of surgery. Consequently, patients either tended to decline surgery  or chose surgical services provided by external surgical teams over the locally available surgical services. Despite these concerns, and apparently incomplete patient knowledge, surgical programmes tended to focus their ‘patient mobilisation’ efforts (efforts to improve the uptake of services) on simply creating awareness of surgical services; they did not engage sufficiently with communities to address their concerns.It is essential to address the concerns of trichiasis patients and their relatives through discussion and counselling. In Amhara, community-based screeners (eye ambassadors) have been trained to identify, counsel and refer patients. They visit all households in their target villages and examine everyone aged 15 years and older using a torch. If people are identified as having TT, eye ambassadors talk with them and their relatives to address their concerns and correct misunderstandings. The patient is then referred to the nearest health facility for examination and further counselling (by trichiasis surgeons).There is some evidence that this discussion-based approach is working. In a cluster of six large villages where 43 eye ambassadors identified and counselled patients, 240 operations were performed within the following two weeks. In an adjacent cluster of villages, five outreach visits were organised at the same time using the usual mobilisation methods ; this resulted in just one patient undergoing an operation. In a third cluster, an outreach visit organised using just public announcements in the market led to no patients coming for surgery. However, when the eye ambassador approach was used in the same cluster a short while later, 114 patients underwent surgery in less than a week.Different service delivery models can be adapted based on local needs and the availability of resources. In many trachoma endemic countries, there are insufficient trichiasis surgeons to clear the current trichiasis backlog using traditional static and outreach models. To achieve GET 2020, particularly in high-burden areas, more productive approaches are needed. One approach is to deploy a dedicated mobile team of trichiasis surgeons and ancillary staff to travel to districts of high trichiasis burden. With good coordination and communication with communities in need, hundreds of operations can be conducted by a single team within a few weeks. In Amhara, our mobile team performed more than 1,378 trichiasis operations within three months. In addition, the quality of surgery is likely to be higher due to the high volume and the increased opportunities for supportive supervision. Community-based trichiasis screeners and counsellors can help to provide pre- and post-operative support and services.Gaining political support at all administrative levels is needed. At the GET 2020 meeting held in Addis Ababa in 2014, the Ethiopian Health Minister made it a personal mission to clear Ethiopia's trichiasis backlog within 18 months. He announced a fast-track initiative and provided additional funding for surgeons.One of the biggest challenges in clearing the trichiasis backlog is convincing trichiasis patients to accept surgery. Investing in developing surgical teams without ensuring patient uptake of surgery would be wasteful. Training and deploying community-based screeners appears to be a very effective method.


Neuropathic pain (NP) is a highly invalidating disease resulting as consequence of a lesion or disease affecting the somatosensory system. All the pharmacological treatments today in use give a long lasting pain relief only in a limited percentage of patients before pain reappears making NP an incurable disease. New approaches are therefore needed and research is testing stem cell usage. Several papers have been written on experimental neuropathic pain treatment using stem cells of different origin and species to treat experimental NP. The original idea was based on the capacity of stem cell to offer a totipotent cellular source for replacing injured neural cells and for delivering trophic factors to lesion site; soon the researchers agreed that the capacity of stem cells to contrast NP was not dependent upon their regenerative effect but was mostly linked to a bidirectional interaction between the stem cell and damaged microenvironment resident cells. In this paper we review the preclinical studies produced in the last years assessing the effects induced by several stem cells in different models of neuropathic pain. The overall positive results obtained on pain remission by using stem cells that are safe, of easy isolation, and which may allow an autologous transplant in patients may be encouraging for moving from bench to bedside, although there are several issues that still need to be solved. Regardlisorders . It has isorders –7. One oisorders , 9. It iIn the last years many researchers, including us, have tried to relieve neuropathic pain by using stem cells of different origin. The first moving idea was based on the capacity of stem cell to offer a multipotent cellular source for replacing injured or lost neural cells and for delivering trophic factors to lesion site; in this way, stem cells can represent not only a pain treatment but a way for repairing the damaged nervous system at the basis of NP development. Soon we and others realized that the capacity of stem cells to contrast experimental neuropathic pain was not completely dependent upon their regenerative effect; in fact many research papers described an antinociceptive effect of the stem cell achieved before the appearance of regenerative effect . In thisConsidering the nature of the lesion at the basis of NP development that takes place in PNS or CNS, neural stem cells (NSCs) seem to be the most appropriate type of cells to prompt a physiological repair of the lesion, due to their capacity to differentiate into neurons, astrocytes, and oligodendrocytes, even though it was suggested that also mesenchymal stem cells, under particular conditions, can originate cells of the neural lineage –13. NeurOur group  describeRegarding their effects on pain relief, NSC, injected when the pathology was already established, induced a significant reduction in allodynia and hyperalgesia already 3 days after administration, demonstrating a therapeutic effect that lasted for at least 28 days. Responses changed with the number of administered NSCs and the effect on hyperalgesia could be boosted by a new NSC administration. Treatment induced changes in cytokine profile at lesion site, decreasing significantly the proinflammatory cytokine Interleukin-1 both as mRNA and protein, while cells were unable to normalize the levels of the anti-inflammatory cytokine IL-10 decreased by CCI. The effect on pain relief was also demonstrated by a reduction of spinal cord Fos expression in laminae I–VI. Moreover we observed a reparative process and an improvement of nerve morphology, due to NSC treatment, which was present at a later time, when pain was already controlled by NSC treatment. Since NSC effect on pain symptoms preceded nerve repair and was maintained after cell disappearance from the lesion site, we believe that the regenerative, behavioral, and immune NSC effects are largely due to microenvironmental changes that they might induce in the lesion. Our results support the idea of a general bystander effect exerted by transplanted NSC . These pAll the papers mentioned above described the use of neural precursors/stem cells isolated from rodents; in literature, to our knowledge, there is only one paper which showed the results of using human neural stem cells in experimental animal models of NP. In this paper human neural stem cells are shown to be capable of surviving and differentiating in a traumatically injured environment improving the locomotor recovery . HoweverMSC are a heterogeneous subset of stromal stem cells which can be isolated from different sources: bone marrow , umbilicA basic description of bone marrow may help clarify the origin of bone marrow derived mesenchymal stem cells. Bone marrow consists of a hematopoietic component (parenchyma) and a vascular component (stroma). The parenchyma includes hematopoietic stem cells and hematopoietic progenitor cells while bone marrow stroma contains multipotent nonhematopoietic progenitor cells, bone marrow stromal cells (MSC) that are known as multipotent cells capable of differentiating under specific experimental conditions into several types of cells, for example, osteoblasts, chondrocytes, adipocytes, and myocytes . MoreoveOne of the first groups to assess the effect of rat bone marrow stromal cells in an experimental rat model of peripheral neuropathy was the group of Musolino . They de6) were therapeutically injected into the hind limb muscle 8 weeks after diabetes induction. The authors described an increase in VEGF and bFGF mRNA expression in MSC-injected diabetic rats and colocalized VEGF and bFGF in MSC in the transplanted site thus suggesting that MSC are responsible for growth factors secretion at the injected site. MSC were able to ameliorate all the alterations induced by diabetes such as hypoalgesia, delayed nerve conduction velocity, and decreased sciatic nerve blood flow. Moreover, MSC transplantation was able to normalize sural nerve morphometry restoring the axonal circularity, decreased in diabetic rats. The same positive effect on nerve conduction velocity amelioration was also reported by Kim and Jin [Rat bone marrow MSC has also been used in another type of neuropathic pain treatment, not derived from a direct nerve lesion, but consequence of the metabolic dysfunction present in diabetes which is one of the main causes of painful neuropathy in human. Shibata and colleagues tried in fact to improve diabetic polyneuropathy induced in rat by using Streptozotocin (STZ) . MSC  model in mice and administer hBMSC therapeutically, that is, 4 days after the surgery, injecting them either in the mouse lateral cerebral ventricle  or systeThe group of Waterman  develope6 hASCs was able to completely abolish thermal hyperalgesia starting one day after the injection [The great advantage of these cells, over the other kinds of MSC, is given by the possibility of isolating them by using low invasive procedures. These cells are in fact located in mature subcutaneous adipose tissue and can be obtained as litter of the fatty tissue after liposuction; the use of this tissue allows to obtain a large amount of MSC thus reducing, in some cases, the need of ex vivo culturing, leading eventually to lower the risk of developing chromosomal abnormalities due to the culture itself. Moreover, these cells are characterized by low immunogenicity and by high immunomodulatory properties which make them suitable for treating diseases in which the neuroinflammatory component plays a crucial role, such as NP. Not least these cells might be easily used for autologous transplant. Despite the high potential of these cells, their use for experimental neuropathic pain treatment is still limited. Our paper, recently published , was thenjection . The effnjection . In factnjection . The dosnjection . We assuThese same cells and hATSCs, human adipose tissue-derived stem cells treated in vitro with ZnO shell nanoparticles in order to improve stem cell function, were recently used by In Choi et al. ; these cHuman umbilical cord (UC) is a promising source of mesenchymal stem cells (MSC) and is nowadays under researchers' investigation. UC contains two umbilical arteries (UCAs) and one umbilical vein (UCV), both embedded within a specific mucous connective tissue, known as Wharton's jelly (WJ), which is covered by amniotic epithelium. MSC can be isolated from all these compartments by using different techniques; today it is still unclear which one is the best compartment in UC for clinical use. UC-MSC possess a gene expression profile similar to that of embryonic stem cells, but their collection procedure is considered ethically correct, and they are characterized by a faster self-renewal rate than MSC isolated, for example, from bone marrow. Moreover they have other attractive advantages which are summarized here: (1) a noninvasive collection procedure for autologous or allogeneic use; (2) a lower risk of infection; (3) a low risk of developing teratoma; (4) multipotency, and (5) low immunogenicity with a good immunosuppressive ability . Roh and7, i.v.) of rat marrow mononuclear cells, containing mixed stem cell populations, 10 days after rat CCI, was able to induce neuropathic pain recovery . The authors did not investigate into the mechanisms involved in such modulations. Freshly isolated rat bone marrow-derived mononuclear cells (BM-MNCs) were also used for contrasting diabetes neuropathy induced in rats by STZ [An improvement in experimental neuropathic pain treatment was also obtained using other types of cells isolated from bone marrow and in particular by using bone marrow derived mononuclear cells. A paper of Klass et al.  describes by STZ . Cells iIn recent years, the possibility to apply stem cells for the treatment of neuropathic pain has attracted much attention, as demonstrated by the increasing number of preclinical studies in the literature .In whole the preclinical data here reported suggest positive effects of stem cells for relieving experimental neuropathic pain. An interesting point that emerges from the detailed analysis of the preclinical data is that peripheral neuropathic pain seems to be more responsive to stem cell treatment than pain arising from central lesion such as spinal cord injury. Moreover in SCI, stem cell treatment is not always able to positively and contemporarily affect both pain symptoms and motor recovery, indicating that different mechanisms can underlie the different effects.6 cells/mice and we did not register any macroscopic adverse effect: no animal died or changed its habits/behaviour and no side effects have been observed. The safety of a similar dose of hASC intravenously infused in animals and humans was also described by Ra and colleagues [It is important to underline that one of the main aspects concerning stem cells usage is both their fast onset and long lasting effect on pain relief; a single administration of cells is in fact able to induce an antiallodynic and antihyperalgesic effect which persists for long time, as it is still present up to 90 days after injection . Generallleagues ; the autlleagues  describelleagues  describelleagues  that replleagues . Finallylleagues  and immulleagues  effects lleagues . On the


Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is increasingly used in research and clinical settings to enhance the effects of cognitive training. In our present review, we will first summarize studies using tDCS alone and in combination with cognitive training in older adults and patients with Alzheimer’s dementia (AD). We will also review one study  that sho Due to the constant growth of the elderly population worldwide, Alzheimer’s dementia (AD) and other neurodegenerative disorders are rising exponentially . Even duTranscranial direct current stimulation is a non-invasive brain stimulation technique that is increasingly used in research as well as in clinical settings to probe and modulate cortical plasticity. tDCS involves the application of at least two electrodes on the scalp of the participant. One electrode serves as the anode and the other one as the cathode. A continuous week current (0.5–2.0 mA) is applied between the two electrodes and flows from the anode to the cathode. To minimize chemical reactions at the electrode-skin interface, tDCS should be performed with non-metallic, conductive rubber electrodes, covered by saline soaked sponges or rubber electrodes used with conductive gel. As the current flows between the electrodes, it passes through the brain and modulates neural activity underneath the electrodes dependent on the direction, intensity, and duration of the current : at currSince tDCS always involves the application of an anode and a cathode, terms such as “anodal tDCS” (atDCS) and “cathodal tDCS” (ctDCS) are inaccurate. However, authors use this terminology to indicate that they specifically refer to the effects caused under anode or cathode. When authors use the term “atDCS over the dorsolateral prefrontal cortex (DLPFC),” for instance, they refer in particular to the excitability enhancing effect of tDCS on the DLPFC where the anode has been placed. Likewise, the terminology “ctDCS over the DLPFC” indicates that authors refer in particular to the excitability decreasing effect of tDCS under the cathode. Since in most studies using a cephalic electrode montage one smaller electrode  is placed over the target brain region, whereas the other electrode is placed over contralateral frontopolar cortex and enlarged  to render stimulation over this cortex functionally inefficient , the latN-methyl-D-aspartate (NMDA) receptor-dependent processes; In contrast to TMS, tDCS does not directly elicit action potentials  but renders neuronal populations more or less ready to fire in response to additional input. In other words, tDCS changes the likelihood that an incoming action potential will result in post-synaptic firing both immediately during stimulation and a short period of time after stimulation (“after-effects”). Thus, the primary mechanism involved in tDCS is a subthreshold alteration of the resting membrane potential involving ionic concentration shifts within the extracellular fluid, whereas the after-effects of tDCS on cortical excitability involve synaptic plasticity of glutamatergic connections  can be distinguished. The first strategy aims to increase cortical excitability or training-induced LTP-like mechanisms in a specific brain area of interest . Since the DLPFC has been found to be involved in working memory e.g., , increasA potential limitation of tDCS is its limited spatial accuracy. As the current passes through the brain from anode to cathode and modulates neural activity simultaneously underneath anode and cathode, it can be difficult to relate the effects of tDCS to a specific brain region. It should also be noted that tDCS not only affects the brain regions directly under the electrodes but may also modulate functional connectivity between remote but functionally associated brain areas  or influWhen following established protocols, tDCS is considered safe and does not cause side effects other than discomfort including itching sensations underneath the electrodes or mild headache . Since tAll aging individuals will develop some degree of decline in cognitive capacities as time progresses. Aging impacts the human brain and all processes that underlie the ability to think and reason  ranging from a loss of neurons  and cortical thinning, impaired neurotransmitter-receptor binding and signaling, an accumulation of neurofibrillary tangles and amyloid plaques, or altered concentrations of various brain metabolites  is known to decline with advancing age and early in the course of dementia. In a recent study , we focuSince impaired semantic word retrieval is also an early marker of age-related cognitive decline , we alsoIt has to be noted that different studies in older subjects used very different stimulation protocols. Most studies used unilateral atDCS with a “reference” electrode placed over the frontopolar cortex. Some authors also applied bilateral anodal stimulation with an extracephalic reference electrode montage. Using a bilateral stimulation protocol with an extracephalic reference, however, might lead to a significantly different current flow compared to the majority of tDCS studies that used a cephalic reference electrode montage  is a progressive neurodegenerative disorder that most often starts with decline in learning and memory formation, but eventually affects attention, executive control functions, reasoning, and language as well . Most prSince tDCS modulates cortical excitability and induces effects that resemble synaptic plasticity of glutamatergic connections , which can outlast the duration of stimulation for some hours , atDCS mn = 10 patients, no control group) was rather small. Nevertheless, these initial results are very promising. Since effects could already be demonstrated after a single tDCS session, repeated or daily applications over a longer intervention period  might induce even greater improvements. This latter issue was addressed in a study by per se, or consolidation, learning strategies, encoding, or retrieval processes had been enhanced.All three studies , 2012 shAs we already discussed for tDCS studies in healthy older subjects, studies in patients with AD used different stimulation protocols as well. While some authors used unilateral atDCS with the reference electrode  over the contralateral frontopolar cortex e.g., , others B-receptor activity  in other brain regions.On the other hand, even though previous modeling studies have shown that atDCS results in modulation of large cortical areas e.g., , this doTables 1 and 2). The latter protocol might avoid some of the shortcomings caused by a cephalic reference montage such as unwanted reversed effects of tDCS under the reference electrode which might be of special importance in clinical settings when a homogeneous shift of cortical excitability is needed  over a specific target area  and the cathode over a “reference” region , studies that place both anode and cathode over the target area bilaterally, and paradigms that use an extracephalic reference electrode montage  might induce greater improvements. As has been shown in healthy young subjects, repeated stimulation after a short interval of 20 min  results in initially reduced yet ongoing excitability enhancement (LTP-like plasticity) while temporally contiguous stimulation and repeated stimulation after a prolonged time interval  might also result in a reversal of neuroplasticity . Also, iD-Cycloserine, a partial NMDA agonist, can be used to consolidate neuronal excitability enhancements induced by atDCS. In addition, it has also been found that dopamine (or the dopamine precursor L-dopa) significantly prolongs the after effects of tDCS . Hence, there has not been a systematic investigation into the effects of tDCS on specific cognitive functions and brain regions yet. For instance, in the studies reported, the temporal cortex, the temporoparietal cortex, the DLPFC, inferior frontal cortex, or motor cortex was targeted. This suggests that some of the areas seem to be more inclined to tDCS enhancement than others. As stated in a review by As one can see from the review of reports in older subjects and patients with AD and MCI, there is a variety of studies targeting different brain regions and functions. Functions of interest are motor learning, working memory, memory formation , declarative memory retrieval, decision making, and error awareness , the effects of serotonergic agents are of particular interest. A study published by Table 1) and found that tDCS was only beneficial in older adults with higher education. In the less educated group, tDCS provided no benefit to verbal or visual working memory performance. The authors interpret these findings as evidence for differential frontal recruitment in both groups as a function of strategy. In a related study, the authors investigated the influence of strategy use and motivation on working memory enhancement. This study also revealed that the use of specific working memory strategies in combination with prefrontal tDCS enhanced working memory performance in individuals with higher working memory capacity. Financial motivation further amplified the working memory enhancing effect of tDCS in both low and high capacity groups (Third, it has to be noted that cognitive decline during healthy and pathological aging does not affect all individuals equally. Clear associations exist between the rate and severity of cognitive decline and a variety of individual factors. These factors include, among others, the level of oxidative stress and free radical damage, chronic inflammation processes, imbalanced and declining hormone levels, as well as other medical conditions. The influence of overweight and diabetes, suboptimal nutrition, physical activity, social support, and lifelong cognitive stimulation on aging and cognitive decline has also been reported (for a review, see y groups . These sWith the present review article, we aimed to summarize the existing and ongoing work investigating effects of tDCS in healthy and pathological aging. As we demonstrated in this review, little work has been done so far in MCI patients and only one tDCS study with MCI patients has been published . This isThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The tumor microenvironment presents significant barriers to the infiltration of anti-tumor immune effector cells as well as to the delivery of cancer therapeutics. In part, physical parameters such as high interstitial pressure, defective vascular elements and abnormally dense stromal elements contribute significantly to poor uptake of immune cells. However, growing evidence also shows that tumor-cells can produce inflammatory cytokines as well as express certain surface receptors that drive both the accumulation of immunosuppressive cells as well as block the activation of antigen-specific immune effector cells, such as CD8+ T cells, which are able to traverse the physical barriers to the interior of tumors.In a brief introduction to this session, I will highlight some exciting new advances in tumor immunology/immunotherapy as well as outline several properties of focused ultrasound (FUS) that could make it a very attractive immune adjuvant that can non-invasively manipulate the tumor microenvironment for enhanced anti-tumor immunity. I will also highlight several recent publications which strongly support the ability of FUS to stimulate endogenous anti-tumor immunity and support its combination with immunotherapy.


Protein localization and dynamics can now be visualized in living cells using the fluorescent protein fusion technique, but it is still difficult to selectively detect molecules with a specific function. As a posttranslational protein modification is often associated with a specific function, marking specifically modified protein molecules in living cells is a way to track an important fraction of protein. In the nucleus, histones are subjected to a variety of modifications such as acetylation and methylation that are associated with epigenetic gene regulation. RNA polymerase II, an enzyme that transcribes genes, is also differentially phosphorylated during the initiation and elongation of transcription. To understand the mechanism of gene regulation in vivo, we have developed methods to track histone and RNA polymerase II modifications using probes derived from modification-specific monoclonal antibodies. In Fab-based live endogenous modification labeling (FabLEM), fluorescently labeled antigen-binding fragments (Fabs) are loaded into cells. Fabs bind to target modifications in the nucleus with a binding time of a second to tens of seconds, and so the modification can be tracked without disturbing cell function. For tracking over longer periods of time or in living animals, we have also developed a genetically encoded system to express a modification-specific intracellular antibody (mintbody). Transgenic fruit fly and zebrafish that express histone H3 Lys9 acetylation-specific mintbody developed normally and remain fertile, suggesting that visualizing histone modifications in any tissue in live animals has become possible. These live cell modification tracking techniques will facilitate future studies on epigenetic regulation related to development, differentiation, and disease. Moreover, these techniques can be applied to any other protein modification, opening up new avenues in broad areas in biology and medicine. Thanks to the discovery of fluorescent proteins and development of live cell microscopy technologies, any protein can now be visualized in living cells and in organisms   is specifically enriched in transcription start sites and enhancers of active or potentially active genes Fig. . Others,Histone modifications change locally and globally during development and differentiation and in response to external stimuli. As dysregulation of histone modifications is often associated with diseases such as cancer (Portela and Esteller RNA polymerase II (RNAP2) is a multi-subunit DNA-dependent RNA polymerase that transcribes most genes and some small noncoding RNA. The catalytic, largest, subunit of RNA polymerase II Rpb1) harbors heptapeptide (YSTPSPS) repeats at the C-terminal domain (CTD)  with a fluorescent dye and loaded it into cells. However, this initial attempt using the whole IgG did not work well; cytoplasmically loaded IgG did not enter the nucleus because it is bigger than the nuclear pore  were suitable for detecting the endogenous histone modifications  will be valuable tools for understanding the dynamics of histone modifications and transcription in both cell cultures and in vivo. In particular, developing a panel of mintbody probes specific to various modifications should be encouraged, as the genetically encoded system is versatile and convenient to use. In addition, cells expressing mintbodies will be useful for screening and evaluating potential diagnostic inhibitors that affect epigenetic modifications. While other techniques such as FRET-based sensors can also monitor epigenetic regulation in living cells, in particular the balance between the modifying and demodifying enzymes, they cannot quantify the endogenous modifications themselves even though they seem to be suitable for assaying the effects of inhibitors (Sasaki et al.


The methods of cognitive neuroscience are beginning to be applied to the study of political behavior. The neural substrates of value-based decision-making have been extensively examined in economic contexts; this might provide a powerful starting point for understanding political decision-making. Here, we asked to what extent the neuropolitics literature to date has used conceptual frameworks and experimental designs that make contact with the reward-related approaches that have dominated decision neuroscience. We then asked whether the studies of political behavior that can be considered in this light implicate the brain regions that have been associated with subjective value related to “economic” reward. We performed a systematic literature review to identify papers addressing the neural substrates of political behavior and extracted the fMRI studies reporting behavioral measures of subjective value as defined in decision neuroscience studies of reward. A minority of neuropolitics studies met these criteria and relatively few brain activation foci from these studies overlapped with regions where activity has been related to subjective value. These findings show modest influence of reward-focused decision neuroscience on neuropolitics research to date. Whether the neural substrates of subjective value identified in economic choice paradigms generalize to political choice thus remains an open question. We argue that systematically addressing the commonalities and differences in these two classes of value-based choice will be important in developing a more comprehensive model of the brain basis of human decision-making. There is converging evidence that the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), and associated ventral striatum carry information related to the subjective value of choice alternatives. Functional neuroimaging studies in humans have shown value-related signals in vmPFC and ventral striatum in a wide range of paradigms, involving many types of reward, such as food, money, and social reward such as attractive faces , allowing the results to be summarized quantitatively in relation to regions commonly associated with subjective value signaling in economic or other reward-related decision paradigms. We compared the results of these studies to the findings from a recent meta-analysis of fMRI studies of value-based choice, mainly assessed with economic paradigms, to assess whether there are common regional activation patterns related to subjective value across these two literatures.A systematic literature search was conducted in May 2014 to identify papers discussing the neural basis of political behavior in humans. The search terms “politics,” “political,” “Democrat,” “Republican,” “brain” and “neuroscience” were used on Google Scholar and Web of Knowledge. The database searches were supplemented by manual review of the citations in these papers. Papers were included in the first stage of the literature review if their central focus was the link between political behavior and the brain, whether review articles or experimental studies. This yielded 27 papers investigating topics such as face judgment in political contexts, partisanship, motivated reasoning, political interest, political attitudes and automatic processing of political preference.a priori as being higher for larger amounts of money. None of the neuropolitics papers identified in the present search were captured by that meta-analysis.In a second step, we applied the inclusion and exclusion criteria that were used in a recent meta-analysis of over 200 fMRI studies investigating value-based choice  to this The same criteria applied to our sample of neuropolitics literature yielded English-language papers in which BOLD signal was measured with fMRI, as a function of positive and/or negative subjective value. As in http://www.loni.usc.edu/ICBM/Downloads/Downloads_ICBMprobabilistic.shtml), as in For the studies meeting these criteria, Talairach coordinates were converted to MNI space and activation foci were coded according to whether they corresponded to positive or negative subjective value. The list of coordinates so identified are those voxels that showed significantly increased BOLD signal in relation to a behavioral measure of either higher or lower subjective value in a political task. Although the sample size was insufficient to provide a full formal test of whether there were consistent patterns across the political studies, we nonetheless followed the same methodology to provide at least a qualitative sense of common patterns of activation. First, we looked for common patterns of activation related to positive or negative subjective value across the neuropolitics studies, tested against the null hypothesis that foci were distributed randomly, taking into account the probability of gray matter in each voxel  that corresponded to our search terms and inclusion criteria. Of these, 10 were review papers, and 17 reported primary data. In the latter set, six focused on political attitudes and emotion, three on party identification, two on political interest, and nine on specific processes carried out in political judgment contexts . Clearly, neuropolitics is still an emerging field with relatively few original research reports to date . The 10 studies reporting primary data that did not meet inclusion criteria examined neurobiological correlates of individual differences in political traits  rather than studying evaluative behaviors or choices that could yield a contrast related to subjective value. Thus, just under half of the existing neuropolitics studies (7/17) provided primary data relating subjective value in political contexts to the brain.Seven of these 17 original studies met the inclusion and exclusion criteria applied in the Table 2).The seven studies that met inclusion criteria reported data from a total of 187 subjects. Three of these seven studies investigated face judgment in political contexts, while the remaining four studied motivated reasoning, political interest, attitude change in response to advertising and automatic processing of political preference. Across these 7 fMRI studies, reporting either a binary contrast or a continuous parametric analysis in a total of 13 tasks, four studies reported activations linked to behavioral measures of positive subjective value  and four reported activations related to behavioral measures of negative subjective value   was 75%  for contrasts related to positive subjective value and 50%  for contrasts related to negative subjective value. With this sample size, foci would need to overlap in all four studies to be distinguishable from chance. Figure 1), i.e., fell within the brain regions consistently related to subjective value in reward-based decision making paradigms, a number not different from chance in this small sample. An additional two foci associated with negative subjective value were identified when the analysis was repeated, collapsed across hemispheres (Table 2).Perhaps the most important finding of this systematic review is that only a handful of fMRI studies of neuropolitics met criteria for inclusion, whereas the same criteria yielded 206 studies reporting on subjective value in other  decision neuroscience paradigms. Few foci related to subjective value in the politics studies fell within areas that the prior meta-analysis identified as commonly carrying signals related to either positive or negative subjective value in economic or other reward contexts. Of all the foci reported in the political studies , only five passed the masking stage of our ROI analysis  may be particularly effective at eliciting automatic value-related brain activity  or secondary  rewards in the experiment, or are cued by stimuli that have such associations in real life. This coincidence of choices and reward is known to drive the release of dopamine in both the basal ganglia and frontal lobes, neural events that underpin value-driven learning . On thisactivity  similar The two political studies that reported activation foci for negative subjective value that corresponded to the regions associated with negative subjective value in economic paradigms also used face stimuli. Overall, this systematic review highlights both points of contact and points of departure between existing research on decision-making grounded in studies of economic value and reward and the emerging literature examining the brain bases of political behavior. On the one hand, identifying the conditions under which brain circuits associated with value defined in economic choice are also engaged in political choice will be informative for neuropolitics and decision neuroscience more generally. On the other, the field of neuroeconomics would benefit from broadening its scope to address aspects of decision-making that have not been a major emphasis to date, but are clearly important in political behavior, such as heuristics and how person-specific characteristics influence decision-making. Finally, given the complexity of political behavior, we can expect that understanding its brain basis will need more than insights from decision neuroscience. Social neuroscience in particular has obvious relevance to many aspects of politics considered beyond the narrow perspective of choice that was the organizing principle of this systematic review.SK carried out the literature review and data synthesis, and drafted the manuscript. DM, DS and EG contributed to the conception of the review, interpretation of the findings, and writing of the manuscript. JM and JK contributed to the quantitative meta-analysis and revised the manuscript. LF conceived of the review, coordinated interactions with co-authors, contributed to synthesis of the findings, and revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A major theme in thermoelectric research is based on controlling the formation of nanostructures that occur naturally in bulk intermetallic alloys through various types of thermodynamic phase transformation processes  in Figure Eutectic solidification seems more promising because the solidification process involves three-phase equilibrium, therefore it is easier to form a homogeneously distributed nanostructure over a large volume of material at appropriate solidification rates. However, at any temperature where diffusion is active, the lamellae will coarsen to remove interfaces and lower the total energy. Similarly, an ordering reaction like the one depicted in Figure 2 (Burmeister and Stevenson, 2 (Ma et al., Experimentally, each one of the situations depicted in Figure Given the challenges with controlling the nanostructure in multi-component thermoelectric compounds, it is unlikely that thermodynamic-driven processes implemented with simple heat treatments will be effective in producing reliable, nanostructured bulk materials. The value for zT is highly temperature dependent in any given material. If diffusion is active near the temperatures at which zT is large, precipitate coarsening will quickly eliminate any improvement in device efficiency. A strategy for fixing shape and size of precipitates over time at elevated temperatures is needed to make use of a high zT in this case.2Te3. For higher temperature operation, approaches that pin interfacial motion with impurities or that produce special interfaces with decreased mobilities might be possible with more exotic processing techniques. To draw more analogies with metallurgical processing, structural metals are not normally used with an as-cast microstructure. In addition to heat treatments, forging, working, and hot/cold rolling of metals must be used to achieve a microstructure more suitable for structural applications. Similarly, other post-processing steps can be implemented in bulk thermoelectric materials to produce low mobility interfaces that can retain nanostructures at elevated temperatures.An analogy can be found in precipitation hardened Al alloys, which are operated at low temperatures where diffusion is slow in order to retain their precipitate distribution and structure. At elevated temperatures, such alloys lose the mechanical properties for which they are designed. For thermoelectrics, such a strategy would only work for materials with an optimal zT at low temperatures, such as materials based on alloys of Bi or BiMany studies of high zT materials often use advanced sintering techniques, such as field assisted sintering or hot pressing (Biswas et al., 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.


Mandibular premolars are known to have numerous anatomic variations of their roots and root canals, which are a challenge to treat endodontically. The paper reviews literature to detail the various clinically relevant anatomic considerations with detailed techniques and methods to successfully manage these anomalies. An emphasis and detailed description of every step of treatment including preoperative diagnosis, intraoperative identification and management, and surgical endodontic considerations for the successful management of these complex cases have been included. Endodontics is the branch of dentistry which is concerned with the morphology, physiology, and pathology of the human dental pulp and periradicular tissues. Its study and practice encompass the basic and clinical sciences including biology of the normal pulp and the etiology, diagnosis, prevention, and treatment of diseases and injuries of the pulp and associated periradicular conditions . EndodonClinically, how does the endodontist utilize this information regarding tooth anatomy to enhance efficacy in root canal treatment? Awareness of the probable variations in root and root canal anatomy reduces the possibility of missed canals during treatment. Also, it inculcates an outlook, wherein the tooth in question is approached with a view that an anomalous root or root canal is a certainty rather than a rarity. However, this is just the first step towards reliable endodontics. Once the anomaly has been identified preoperatively, it is an added challenge to negotiate the variations by identifying them intra-operatively, followed by cleaning, shaping and obturating the same.Mandibular premolars have on multiple occasions been stated to be the most challenging teeth to be treated endodontically, especially when they present with multiple roots or canals , 4. Theiidentification,endodontic management,surgical management.An exhaustive search was undertaken to identify associated literature of mandibular premolars through MEDLINE/PubMed database using keywords “root canal anatomy,” “root canal morphology,” “mandibular premolars,” “mandibular first premolar,” and “mandibular second premolar,” alone or in combination. Documented case reports of variations in mandibular premolar anatomy were identified and a systematic review of the relevant articles was performed for articles dated May 2013 and before. Different clinical techniques applied to manage the endodontic variations of mandibular premolars were summarized under the following headings:A recently published systematic literature review by Kottoor et al.  summarizThorough preoperative clinical assessment is the first step in trying to unfold any external or internal radicular aberrations. Meticulous observation of the coronal and radicular anatomy and landmarks are prerequisites for the detection of variable anatomy . AtypicaRadiographs provide much needed information about root canal morphology. Accurate multiple preoperative radiographs, straight and angled, using the paralleling technique are essential to provide evidences about the number of roots. A second radiograph 15 to 20 degrees mesial or distal to the horizontal long axis of the root, is useful to accurately diagnose the number of roots and canals in premolar teeth . A suddeIn mandibular premolars with three canals, the cervical half of the root is generally wider than usual, with little or no taper . Two perAdditional developmental anatomic variations of mandibular premolars include fusion or gemination , fusion CBCT is also a useful tool for the preoperative diagnosis of complex root canal anatomy . The sag(i) Access Cavity. Detection and management of the entire root canal system in mandibular premolars are extremely challenging, and optimum access cavity preparation is an absolute necessity. In single-canalled lower premolars, the access can be somewhat more circular in nature. However, if a second canal (or bifurcation) is suspected, a buccolingually directed oval access cavity is more appropriate  Root Canal Exploration. Means of magnification (ocular loops) and additional lighting (fibre optic illumination) are recommended. Additionally, examination of the pulp chamber floor with a sharp explorer (DG-16/CK-17), troughing of grooves with ultrasonic tips, staining the chamber floor with 1% methylene blue dye or ophthalmic dyes, performing the sodium hypochlorite “champagne bubble” test, and visualizing bleeding points are important aids in locating root canal orifices [lorer DG-/CK-17, tThe distance between two root canal orifices of mandibular first premolars with two root canals is mostly within 1–3 mm; that is, when 1 root canal orifice has been probed, another root canal orifice can be probed within 1–3 mm. However, wider distances (up to 5 mm) have also been noted between canal orifices .The root canal system of premolars with two roots and three root canals is usually characterized by one large lingual canal and two smaller mesiobuccal and distobuccal canals in the buccal root. A third canal should be suspected clinically when the pulp chamber does not appear to be aligned in its expected buccal-lingual relationship . AccordiThe role of microscopy in endodontics should not be understated. The dental operating microscope should be used to facilitate the observation of anatomical landmarks in the pulp chamber floor that may help to identify supplementary root canals or root canal aberrations . FurtherTactile examination of all the walls of the major canal with the tip of a small, precurved scouting K-file is recommended, in order to probe for a catch, which may indicate the orifice of an additional canal. The presence of an additional canal should be suspected whenever an instrument demonstrates an eccentric direction on deeper penetration into the canal, termed directional control, as reported by Green . Under tRadiographic interpretation of some accessory roots and their root apices may be difficult due to their close proximity to each other, and also there exists a possibility of superimposition by other roots. An apex locator is very useful in such cases and can be used to estimate the root canal lengths prior to a confirmatory working length radiograph . If a woYang et al.  reportedAn important aspect that needs to be considered during instrumentation of multiple canals in mandibular premolars is the presence of a sharp curve especially in the bifurcation or trifurcation area . CautionPrior to commencing the mechanical instrumentation of accessory roots and root canals, it is mandatory to identify and evaluate the morphological features including the thickness of the root dentine. Sandhya et al.  reportedIn addition to the multiplicity of canals, the pulpal space of mandibular premolars also commonly contains isthmuses, lateral canals, apical ramifications, and other irregularities . The useOne aspect that should not be overlooked in such cases is the best possible removal of calcium hydroxide intracanal medicament. Any calcium hydroxide remnants may interact with the sealer and result in an inferior seal . RemovalRoot/root canal bifurcation or trifurcation can occur at the cervical, middle, or apical thirds of mandibular premolars. Obturation of these complex root canals may require technique modifications. (i) Cervical Third Bi- or Trifurcation. Most of the cases can be managed using warm vertical compaction with small sized heat carriers, pluggers, and narrow back filling needles. However, if the root canals are very thin, lateral compaction with thin spreaders or single cone obturation with 6% taper cones is recommended [ommended . (ii) Middle Third Bi- or Trifurcation. Enhanced magnification and illumination along with adequate coronal canal flaring to access the bifurcated canal orifices are recommended for this technique. When the coronal space is insufficient to accommodate multiple master cones at once, the larger master cone can be cut extraorally, at the level of the bifurcation or orifice. This shortened master cone can then be speared at the blunt, cut end with a spreader or a file in a clockwise rotation (rotation . The gut(iii) Apical Third Bi- or Trifurcation. Obturating such root canal systems requires good clinical skill along with a dental operating microscope with higher depth of focus. One technique proposed by Hermann and Hülsmann is called the “Squirt technique” [chnique” , 36. In Maintaining patency of the off-shoot canal is of prime importance. For this purpose, a file could be placed in one of the canals to prevent its blockage while the other is obturated up to the level of the bi-or tri-furcation by warm vertical compaction . The addSurgical endodontics of anomalous mandibular premolars could be performed in conjunction with orthograde root canal treatment, especially for complex apical trifurcations or C-shaped canals. Careful examination of the resected root-end for circumferential openings, using the dental operating microscope, is critical. This allows for identification of any apical third variations and their subsequent retrograde management. A higher incidence of apical ramifications in the apical 3–6 mm of C-shaped Mongoloid mandibular premolars was reported by Lu et al. . In suchMandibular premolars, because of their complex canal systems, are often considered the most difficult of all teeth on which to perform successful endodontic treatment , 4. AccoClinicians undertaking treatment of such complex anatomy cases need to be extremely patient as prolonged and multiple appointments are very much a certainty. The time involved in treating such complex cases of variable tooth anatomy is mainly dependent on the clinical skill, expertise, and proficiency of the endodontist and the armamentarium available to achieve optimum clinical outcome.Practitioners who regularly treat different population origins should be aware of racial differences and their influence on pulp space anatomy. The risk of missing anatomy during root canal treatments is high due to the complexity of the root canal system in mandibular premolars. Hence, a thorough understanding of normal anatomy and common variations, careful interpretation of angled radiographs, use of three-dimensional imaging, proper access cavity preparation, and a detailed exploration of the interior of the tooth, ideally under magnification, followed by adequate cleaning, shaping, and obturation could collectively play a vital role to ensure endodontic success.


A report on the Epigenetic Engineering Meeting hosted by the Barts Institute of Cancer, held in London, UK, May 7, 2014 This short and focused meeting was set up to bring the audience up to date with a specific set of techniques broadly categorized as epigenetic engineering (or epigenetic editing). The speakers reminded us of very important questions that still linger, like Damocles’ sword, over the field of epigenetics: what is the real role of epigenetics during gene transcription and development? Are epigenetic modifications the cause or consequence of these processes? While the jury is still out, this meeting reminded us that the tools needed to answer these philosophical questions are finally available and improving by the hour. Moreover, there was also a general consensus that epigenetic editing might provide the next big advance in cancer treatment. Epigenetic-editing treatments might finally allow targeted modulation of gene expression and could bypass the side effects of current epigenetic drugs.Epigenetics has been defined in several ways, but none of these definitions includes an answer to the recurrent question: what are the actual roles of epigenetic modifications? With the explosion of ChIP-seq-based studies, we have now gathered epigenetic information (DNA methylation and histone modification maps) for hundreds of cell lines. We know that there is a strong correlation between certain epigenetic marks and the transcriptional status of nearby genes. We also understand that epigenetic information represents a sort of cellular barcode that is constantly modified during differentiation, and probably throughout cancer initiation and progression. Nevertheless, these ChIP-seq studies are frequently labeled as descriptive and correlative, and as not offering any answers to the consequentiality or temporal hierarchy between epigenetic and transcriptional reprogramming.de novo DNA methyl-tranferases (DNMT3) to small zinc-finger effectors, Jurkowski and colleagues were able to target EPCAM and VEGFA, two key genes involved in cancer development. More importantly, they demonstrated that adding the DNMT3 co-activator could accelerate the reaction leading to a stronger repression. Interestingly, DNA methylation was found to be highly directional and to reflect the topology of DNA-zinc finger interactions. It was also noted that the number of methylated nucleotides was consistently higher than expected. This phenomenon is attributed to the cooperative binding of individual zinc finger-DNMT3 fusion proteins and can be exploited to increase the desired silencing effect.Tomasz Jurkowski  presented compelling evidence to show that we can now begin to address this causality dilemma. He outlined how his laboratory, like many others, is exploiting DNA-targeting molecular machines, such as zinc fingers, TALEN and Crispr-Cas9, fused with epigenetic modifiers . The goal is to change the epigenetic information at specific regulatory loci, such as enhancers and promoters, in order to shut down or activate single genes. By fusing Caenorhabditis elegans, an organism that lacks DNA methylation altogether, Miska’s group demonstrated how trans-generational gene silencing is mediated by a non-coding RNA mechanism (piwi-RNA). Miska suggested that piwi-RNAs might be seen as the ‘guardian of the epigenome’, with an involvement in maintaining retro-transposon silencing. Use of a different worm that has DNA methylation abilities  hinted at the possibility of RNA-directed DNA methylation, a fascinating hypothesis for mammalian genomics enthusiasts. Finally, Donna Bond  presented exciting data from the plant kingdom. Using modified viruses, Bond and colleagues were able to silence (via DNA methylation) single genes epigenetically. The virus itself was not transmitted across generations, but its silencing effects were carried out in the pollen of infected plants and passed on to the new generation.DNA de-methylation was also the weapon of choice for James Angstman . In Angstman’s work, the aim was to test how many CpG sites must be de-methylated in order to re-activate gene expression. The data derived from studying the β-globin promoter suggested that not all CpG sites are equivalent and introduced the idea of insulator CpGs, as opposed to regulatory CpGs. Eric Miska  reminded the audience that the border between epigenetics and genetics is far more labile than expected. Using These results are impressive and demonstrate how epigenetic editing can be effectively used to regulate the expression of single genes reversibly. A problem that has not yet been overcome involves specificity: the zinc finger and CrispR-Cas9 strategies have not yet reached single locus specificity, but they still offer a major advancement compared with the use of genome-wide epigenetic drugs such as 5-azacytidine.in vivo usage. They also present several advantages as tools for epigenetic editing when compared to small interfering RNA (siRNA), cDNA or artificial transcription factors. For example, epigenetic editing using zinc fingers offers sustained and inheritable gene suppression without the integration of foreign DNA or siRNA. On the other hand, gene activation is regulated by the endogenous environment and automatically induces the correct gene isoform rather than leading to the non-physiological expression of a pre-determined isoform.The other face of epigenetic editing deals with another crucial component of epigenetic information: histone modification. Since the seminal work of Allis and colleagues that formalized the theory of the histone code, various laboratories have tried to draw a direct link between covalent tail modifications and transcription. David Cano Rodriguez  gave the audience two clear examples of how we might use histone modifications to ‘wake the sleeping beauties’ (tumor suppressors) and ‘silence the screaming’ (oncogenes). Zinc fingers are extremely promising for this purpose as their chemistry is compatible with de novo deposition of some histone marks, H3K9me3 induction was linked to a strong reduction of H3 acetylation and H3 lysine 4 tri-methylation. These data once again highlight the complex relationship between epigenetic information and transcription and recommend caution when discussing the role of epigenetic modifications in isolation.Using zinc fingers fused with the catalytic subunit of the PRC2 repressor complex, Rodriguez and colleagues were able to methylate histone 3 specifically at the Neu/Her2 gene. Her2 expression directly leads to drug resistance in breast cancer and can only be targeted using expensive monoclonal antibodies. The suppression of the Her2 gene was functional and led to a significant reduction in cell proliferation. The transcriptional status of Her2 was also manipulated in the opposite direction, using a transcriptional activator to demonstrate the specificity of zinc-finger targeting. Importantly, whereas activation resulted in A common thread among all of the work described at this meeting was that all of the epigenetic editing was conducted at promoter elements. This approach was adopted to simplify interpretation of the results and to draw a straight line between regulatory regions and the regulated genes. This use of strategy, however, may also explain why the observed changes in transcription were often very subdued but very significant. It was proposed that simultaneous targeting of promoters and associated distal elements, such as enhancers, could dramatically improve our ability to reprogram the epigenetic barcode of cells. In the future, such strategies could lead to efficient differentiation protocols for induced stem cells. Equally important, we can envision a future in which gene manipulation will not necessarily include only genetically engineered intervention but could include a ‘softer’ and more versatile toolkit.Clinical trials using zinc-finger epigenetic editing are now in phase II for HIV/AIDS and Alzheimer's disease. Studies such as those presented at this meeting let us hope that more and more oncogenes or tumor suppressors will be targeted effectively in the near future of epigenomic medicine.The author declares that he have no competing interests.


The increase of human tissue clinical use has lately generated a relevant donors demand, which in terms of tissue donation is not limited to brain dead donors, but generalized to cardiac arrest donors (multi-tissue donor) and alive donors.No time urgency.Storage.Tissue extraction can be adjusted to clinical demands and tissue bank availabilities.Donated organs and tissues both come from an alive or dead donor, which implies similarities in terms of ethical requirements. However, there are several aspects that differentiate both protocols and make a difference in the approach.These distinguishing factors previously mentioned make tissue donation after cardiac arrest possible.The tissue donor after death has as origin a patient who dies from cardiac arrest. In this scenario, tissue donation inclusion in end life care pathway is essential in order to enhance the tissue donor pool after death.During the period 2004-2014, an awareness raising initiative in tissue donation process and the multi-tissue donor was carried out, that consisted on:Daily routine visit to Observation and Intensive Care departments by the transplant coordinator and/or intensivist on call, in order to evaluate patients who had been admitted in these areas, their pathology and potential inauspicious prognosis.Mortality review within the past 24 hoursOminous prognosis admissions review within the past 24 hoursTraining programmes and awareness raising initiatives in donation process for hospital health professionals, focusing on Emergency Medicine and Critical Care departments. Solid organ and tissue donation training programmes, Reference Guide to consent for donation, Hospital sessions, donation and transplant activity registers sessions per department each 3 months.During the previously mentioned period of time in which this new proactive attitude towards donation has been carried out, donation activity has constantly increased, going from no multi-tissue donors before 2004 and 2 in 2006 to 26 in 2014; in fact, 6% of the total number of deaths occurred in 2014 in the emergency department and intensive care unit led to multi-tissue donation (2 or more tissues donated per donor), and health professionals established the exitus -donation link.In the last years we have witnessed a spectacular progress in the clinical use of human tissue in different areas which has generated a considerate tissue donor demand. Tissue donors generated by patients who die of cardiac arrest and are not candidates for solid organ donation (the majority of them) suppose a relevant source of tissue donors that should always be considered.We would like to thank donor relatives for their priceless contribution and understanding. Thanks to them thousands of people are born again.