Endocannabinoids (eCBs) are bioactive lipids which primarily influence synaptic communication in the nervous system. They are synthesized by neurons but also by microglia, especially under inflammation. To exert their function, eCBs travel across the intercellular space. However, how eCBs move extracellularly remains obscure. Our recent evidence indicates that reactive microglia release extracellular vesicles (EVs), which may represent an ideal vehicle for the transport of hydrophobic eCBs. Hence, in this study we investigated whether microglial EVs carry eCBs and may influence neurotransmission. First we analyzed the eCB content of EVs and found a clear enrichment of anandamide (AEA) in EVs relative to parental microglia. This analysis revealed higher AEA levels in EVs shed from the plasma membrane (microvesicles), compared to those which originate from the endocytic compartment (exosomes). To bioassay the activity of vesicular AEA, we used patch clamp analysis of miniature inhibitory post-synaptic currents (mIPSC) on hippocampal neurons in vitro. Exposure of neurons to microvesicles (MVs) induced a significant decrease in mIPSC frequency, mimicking the action of CB1R agonists. The involvement of vesicular AEA in this phenomenon was inferred from the ability of the CB1R antagonist SR141716A to block the reduction of mIPSC frequency evoked by MVs. Western blot analysis showed that MVs induces an increase in ERK phosphorylation, which was completely inhibited by SR141716A. This indicate that CB1R activation by AEA-storing MVs translates into downstream signaling. Finally, consistent with a surface localization of AEA, MVs membranes maintained their capability to decrease mIPSC frequency. Overall, this study shows that microglial MVs carry AEA on their surface to stimulate CB1R on target GABAergic neurons thus playing a crucial role in the modulation of inhibitory transmission.


Trichomes are differentiated epidermal cells on above ground organs of nearly all land plants. They play important protective roles as structural defenses upon biotic attacks such as herbivory, oviposition and fungal infections, and against abiotic stressors such as drought, heat, freezing, excess of light, and UV radiation. The pattern and density of trichomes is highly variable within natural population suggesting tradeoffs between traits positively affecting fitness such as resistance and the costs of trichome production. The spatial distribution of trichomes is regulated through a combination of endogenous developmental programs and external signals. This review summarizes the current understanding on the molecular basis of the natural variation and the role of phytohormones and environmental stimuli on trichome patterning. Plants have evolved sophisticated morphological and chemical systems to cope with biotic and abiotic challenges. Differentiated epidermal cells such as leave hairs or trichomes represent one of these systems. Trichomes develop on above ground organs including seeds and fruits and occur in a large variety of morphologies. They can be single-celled or multicellular, branched or unbranched, and glandular or non-glandular, characteristics often used for species identification , 2008. TIn adverse environments, trichomes are beneficial because they influence the water balance, protect photosynthesis and reduce photoinhibition. Their density is negatively correlated with the rate of transpiration  and thatSolanum lycopersicum) with its parasite Cuscuta pentagona  on grapevine buds (Botrytis cinerea on harvested tomato (Phoma clematidina on clematis (Beauveria bassiana on poppy (Solanum berthaultii) and its resistance to Phytophthora infestans (Cicer arietinum) with Ascochyta rabiei the concentration of a highly acidic trichome exudate is crucial. At low concentrations the exudate promotes germination of Ascochyta rabiei conidia while at high concentrations germination is inhibited (Nicotiana tabacum) produce a potent inhibitor, T-phylloplanin, which inhibits germination of the oomycete Peronospora tabacina  and negative regulators . GL2 encodes a homeodomain protein required for subsequent phases of trichome morphogenesis such as endoreduplication, branching, and maturation of the cell wall. The negative regulators are seven partially redundant single-repeat MYBs such as CAPRICE (CPC), TRIPTYCHON (TRY), ENHANCER OF TRY AND CPC 1, 2, 3 , and TRICHOMELESS1 and 2  promote trichome initiation and morphogenesis  by inducn leaves  and appln leaves . For then leaves .Arabidopsis (As mentioned above trichomes can be induced by wounding and insect attack  and the bidopsis  and thatbidopsis .CONSTITUTIVE EXPRESSION OF PR GENE (cpr) mutants  lines  mapping. The first QTL analysis discovered a major locus, named REDUCED TRICHOME NUMBER (RTN) in Arabidopsis thaliana and used recombinant inbred lines (RIL) derived from a cross between the low trichome density Ler and the medium density Col-accessions . With the availability of the 1001 Arabidopsis genomes association studies of the remaining candidate genes are now straight forward  lines . Larkin cessions . This locessions  and evencessions  as majorT2 SAD2; , TTG2, C density . While t forward .Arabidopsis they are still not sufficient to explain all the naturally occurring variations in this plants species. Great potential for the identification of still missing regulators will come from next generation sequencing possibilities in combination with classical genetic, population genetic and comparative approaches using different plant species. There are already several examples where trichome patterning regulators from wild relatives or even crops and distantly related species such as cotton, tomato and hop have been successfully and functionally studied in the model plant Arabidopsis (Although the major players of trichome density regulation have been identified in the model plant bidopsis . HoweverThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Abdominal stab injury is potential life-threatening injuries. Operation should be considered if wound violate the peritoneal layer and/or complicated with hemodynamic compromise, peritonitis, impalement, or evisceration. It is well known there are several diagnostic tools to evaluate the necessity of operation for a patient with abdominal stab injury. Despite numerous diagnostic tools, including local wound exploration, CT, diagnostic peritoneal lavage, or FAST, were currently performed in emergent department neither of them has satisfying sensitivity and specificity. Abdominal wall ultrasonography has been used many abdominal wall disease, like hernia, abdominal wall hematoma. We used abdominal wall ultrasonography for diagnosis of abdominal wall stabbing injuryFeasibility of abdominal wall ultrasonography for diagnosis of abdominal wall stabbing injuryA 76-year-old man visited our emergent department due to multiple anterior abdominal stab wounds for suicide. His initially vital signs were relatively stable. Physical examination revealed multiple stabbing wound with bleeding, local tender over wound without rebounding tenderness. Laboratory finding is nothing particular. Patient received local wound exploration by senior surgical resident but inconclusive. Focused Assessment of Sonography for Trauma also showed negative result. Therefore, we perform the abdominal wall ulrasonography and revealed an apparent penetrating tract through the abdominal wall and disruption of peritoneal layer.(figure 2 and video 1) We use Toshiba Nemio in sterile method from start to finish. Computed tomography also revealed penetrating injury of abdominal wall and no obvious free air.(figure 3) Finally, the patient underwent the laparoscopic surgery and revealed four abdominal wall stab wounds at the mild abdomen near the umbilicus and the epigastric area(fiugre 4), perforation of transverse colon. Then he received laparoscopic repair of abdominal wall injury and colostomy. Patient was discharged smoothly after surgery.We performed the abdominal wall ultrasonography to evaluate the stab wound and successfully diagnosed the wound penetrating peritoneal layering. Moreover, in comparison with other diagnostic tools, abdominal wall ultrasonography can provide additional advantages, such as rapid, painless, non-invasion, non-radiation and more detail of wound tract structure. By using the ultrasonography, which could follow the tract of abdominal stab injury (the direct sign) and hematoma beneath the stab wound(the indirect sign) in another case(figure 5), or positive of FAST. Abdominal wall ultrasonagraphy can help clinicians to make the decision easier in further management of abdominal stab injury.The abdominal wall ultrasonography could demonstrate the tract of stab wound, and provide more detail of wound, and help the decision making, especially in hemodynamic stable patient. Further prospective study is need for evaluating the abdominal wall ultrasonograpy in stabbing wound.


We built a network of curated interactions between human proteins involved with centrioles, centrosomes, basal bodies and cilia to provide a global functional characterization of the Cilia/Centrosome Complex interactome (CCCI).http://string-db.org). Network analyses were performed using Cytoscape and communities were extracted using the MCODE algorithm. The gene-wise network was explored by Gene Ontology (GO) analysis. The transcription factor (TF) analysis was performed using information obtained from "ConsSites" and "tfbsConsFactors" track of the UCSC Genome Browser.Human ciliary genes were collected from available databases and interactions among genes were obtained from the STRING database  and in ciliopathy genes. We found 11 communities enriched in 30 TFs. The identified TFs are involved in developmental processes, cell cycle control, in the immune response and in muscle differentiation.CCCI is a publically available tool, which will allow to clarify the roles of previously unknown ciliary functions and to elucidate the molecular mechanisms underlying ciliary-associated phenotypes.


Recent advances in biomaterial science and tissue engineering technology have greatly spurred the development of regenerative endodontics. This has led to a paradigm shift in endodontic treatment from simply filling the root canal systems with biologically inert materials to restoring the infected dental pulp with functional replacement tissues. Currently, cell transplantation has gained increasing attention as a scientifically valid method for dentin-pulp complex regeneration. This multidisciplinary approach which involves the interplay of three key elements of tissue engineering—stem cells, scaffolds, and signaling molecules—has produced an impressive number of favorable outcomes in preclinical animal studies. Nevertheless, many practical hurdles need to be overcome prior to its application in clinical settings. Apart from the potential health risks of immunological rejection and pathogenic transmission, the lack of a well-established banking system for the isolation and storage of dental-derived stem cells is the most pressing issue that awaits resolution and the properties of supportive scaffold materials vary across different studies and remain inconsistent. This review critically examines the classic triad of tissue engineering utilized in current regenerative endodontics and summarizes the possible techniques developed for dentin/pulp regeneration. A routine clinical treatment for infected or necrotic pulp tissue is root canal therapy (RCT) which involves the extirpation of injured pulp and the filling of root canal systems with bioinert synthetic materials. In spite of its satisfactory clinical efficacy in infection control and pain elimination, classical treatment modalities like RCT only seek to seal the space of root canal system without restoring its original function. Therefore, various complications such as tooth fractures and reinfection occur more often in teeth that have undergone RCT due to their loss of sensory function and consequent lack of natural defense mechanisms . The hisstitutes . in vitro cultured cells and scaffolds into target anatomic location [Tissue engineering, an emerging popular domain of bioscience, is a multidisciplinary research area with the ultimate aim of restoring, maintaining, and regenerating damaged/lost tissue with biologically engineered replacements through combining the principles of biology, medicine, and engineering . The advlocation . This re in vitro colony formation, and trilineage mesenchymal differentiation potential [Stem cells are commonly defined as clonogenic cells that exhibit remarkable long-term self-renewal and multilineage differentiation capacity. Based on their distinction in plasticity , stem cells can be further subdivided into embryonic stem cells (ESCs) and postnatal stem cells . Althougotential . Numerou in vitro [Gronthos et al. were the pioneers that identified and characterized a stem cell population within adult human dental pulp tissue , 10. Isoin vitro –13. Whenin vitro , 14. In in vitro , 14, 15. in vitro osteogenic/odontogenic, adipogenic, and neurogenic differentiation capacity when induced by respective stimuli. In vivo studies employing animal models also demonstrated the odontogenic capacity of SCAP [SCAP were initially isolated and characterized by Sonoyama et al. from the apical papilla, an embryonic-like soft tissue located at the apex of incompletely developed human permanent teeth . Similar of SCAP , 17. Typ of SCAP . Conside of SCAP . in vitro differentiation potential towards the osteogenic and adipogenic lineages compared to DPSCs [ In vivo transplantation of SHED loaded on scaffolds/tooth slices into immunocompromised mice has resulted in the formation of tissue that closely resembles physiological dental pulp in cellular morphology and histological architecture [SHED were first isolated by Miura et al. from vital pulp remnants of exfoliated deciduous teeth . Althougto DPSCs . In vivoitecture , 22. An itecture .−/CD146− side population (SP) cells with type I and III collagen led to the formation of pulp-like tissues with capillaries and neuronal processes by day 14 [−/CD146− SP cells and CD 105+ cells with stromal cell-derived factor-1 (SDF-1) successfully induced complete regeneration of pulp-like tissue with vasculogenesis and neurogenesis within 14 days. This was followed by further formation of a continuous dentin-like structure along the dentinal wall of root canals [Positive or negative isolation strategy is normally adopted for the selection of a specific, more homogeneous subpopulation of MSCs with optimal phenotypes. Recently, these techniques have also been reported in the fractionation of dental pulp stem cells, designed to isolate subpopulations that possess higher angiogenic and neurogenic potentials, both of which contribute to pulp homeostasis . In a cay day 14 . In a cat canals , 27. In − SP cells with SDF-1 yielded tissues that were morphologically identical to that derived by transplanted pulp CD31− SP cells and all three regenerated tissues possess functional properties similar to normal pulp [Given that the availability and quality of dental pulp tissue sharply decline with age, nonodontogenic stem cells have been investigated as alternative sources among which stem cells harvested from bone marrow and adipose tissue showed greatest promise owing to their advantageous biological properties and partially shared gene expression profile of various growth factors, extracellular matrix (ECM) proteins, and transcriptional regulators , 29. Ishmal pulp . Consistmal pulp . Further in vitro [ in vivo study demonstrated the formation of dentin-like and dental pulp-like structures upon transplantation of the reconstructed tooth germs derived from miPSCs together with epithelium and mesenchyme into mouse subrenal capsule [The generating of induced pluripotent stem cells (iPSCs) is a groundbreaking work that revolutionizes the present scenario of regenerative medicine. This can be realized through reprograming adult somatic cells or terminally differentiated cells back to a pluripotent state via overexpression of four defined transcription factors –34. Analin vitro . These N capsule . DespiteWhen cell-based therapy is adopted for dentin/pulp tissue regeneration, the procuring of a readily available stem cell source is of the highest priority. While the favorable properties of low immunogenicity and immunosuppression exhibited by oral-derived adult stem cells offer much possibility for allogeneic cell transplantation, these adult stem cells will likely express histocompatibility antigens upon differentiation and will thus not be able to sustain the immunosuppressed state –41. HencConventionally, infected or inflamed pulp tissue will be completely removed by pulpectomy in order to create a sterile environment for the subsequent restorative treatment. However, a considerable portion of healthy and vital pulp tissue might also be discarded as medical waste together with the necrotic dental pulp. Recently various studies have reported successful isolation of viable stem cells from inflamed dental pulp, but with conflicting regenerative effects on dentin/pulp tissue. Yazid et al. showed that MSCs obtained from primary inflamed pulp exhibited highly dysfunctional MSCs stemness and minimal immunoregulatory capacity . By contThe right time for banking cells is a thought-provoking question. There seems to be a noticeable progressive age-associated reduction in regenerative capacity of MSCs present in multiple adult organs including teeth . MoleculIn addition to the physical state of dental tissue, other general health-associated parameters like smoking and nutrition are possible factors that can influence the physiological activity of dental pulp cells (DPCs) and overall biological properties of dental pulp tissue, although the evidence is weak , 54.A scaffold is one of the three essential components of classic tissue engineering strategy. Functionally, scaffolds provide a three-dimensional (3D) temporary structural framework for cell seeding, adhesion, proliferation, and spatial distribution until their complete replacement by the newly synthesized matrix of endogenous host cells , 56. Cur in vitro and also facilitating pulpal tissue regeneration in a full-length root canal in vivo [Collagen, a major macromolecular constituent of dentin ECM with excellent biocompatibility, is the most extensively studied naturally occurring material for dental tissue engineering. Comparison of different natural polymers including collagen type I, collagen type III, chitosan, and gelatin suggests that hDPCs plated on collagens, particularly type I collagen, perform best in terms of proliferation and mineralization capacity . Combine in vivo . When cu in vivo . de novo regeneration of vascularized pulp-like tissue in an empty root canal space accompanied by deposition of dentin-like tissues along dentinal walls formed by newly derived odontoblast-like cells [Synthetic materials such as polylactic acid (PLA), polyglycolic acid (PGA), and their copolymer poly lactic-glycolic acid (PLGA) have attained approval from the United States Food and Drug Administration (FDA) for wide application due to their nontoxic properties. An earlier study demonstrated that PGA accelerated collagen deposition and appeared to be more conducive to DPCs proliferation compared to alginate or collagen scaffolds . A highlke cells .β1 (TGF-b β1), and TGF-b β2, when platelets are activated [Platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) are other potential materials easily obtained from autologous blood and thus can minimize the risk of adverse immunological response. These can release many vasculogenesis-associated factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-b ctivated , 64. Recctivated , 65.In a nutshell, although both natural polymers and synthetic materials have demonstrated promising therapeutic effects on dentin/pulp regeneration, neither of them embraces all the favorable properties that can recapitulate the cellular physiological microenvironment. Natural polymers are usually afflicted with issues of purity and antigenicity. Synthetic polymers, albeit circumventing the potential risks of immunoreactivity and being more readily amenable to clinical applications with tailor-made physiochemical properties, still lack bioactive molecules present in native ECM that are necessary for cellular recognition and interaction, in addition to various technical challenges in regulating pore sizes and achieving high porosity structures .Recently, nanofibrous polymer scaffolds have been synthesized to biomimic ECM in structure and function. They appear superior to other scaffold materials at microstructural level or other morphological arrangements owing to their interconnected porous networks and advantages in high surface area to volume ratio . Most st in vivo. Comparisons of data extracted from different studies suggest that the fate of implanted stem/progenitor cells may be site-associated rather than being influenced by their origin, with a tendency to differentiate into the odontoblast phenotype when transplanted into the pulp chamber but into other cell lineages when transplanted into other target locations [ in situ dentin/pulp regeneration, may be lost during the transplantation process. It cannot be ruled out that the quiescent host stem cells residing in the niche of the transplantation site may be stimulated and recruited into the regenerated construct together with pulp-derived stem cells and thus pulp cell may lose its predominant effect on tissue mineralization [ in situ pulp regeneration is often disadvantaged by ischemic conditions due to the constricted opening at the root apex allowing for blood microcirculation while root fragments or tooth slices rarely face this problem. Despite the deficiency of ectopic models in mimicking the in situ tooth microenvironment in clinical practice, the implementation of orthotropic model encounters formidable challenges. After transplantation into the pulpectomized teeth, the fabricated tissue replacement has a tendency to adhere to the coronal portion of root canals, leaving the middle and apical parts incompletely filled [Several preclinical animal models based either on ectopic or on orthotropic transplantation approach have been developed to translate cell-based therapy into clinical reality. Although a substantial body of evidence has confirmed the regeneration of mineralized tissue, some studies still failed to detect the presence of dentin-like tissue but instead found tissues with bone-like morphology . This isocations . SCAP, alization . Additioy filled . This isy filled . In addiy filled , 82.The critical requirements for successful dentin/pulp regeneration are not confined to the morphogenesis of dentin/pulp-like tissue but should also be accompanied with angiogenesis and neurogenesis. It must be noted that the deposited dentin-like tissues on existing dentin structure are produced by the newly differentiated odontoblasts from the dentinal wall within the root canal space. Currently, potential strategies dedicated to optimizing stem cell-mediated dentin/pulp regeneration are directed towards two main objectives: firstly angiogenesis induction and, secondly, the promotion of tissue mineralization.The long-term survival of tissue-engineered implants largely depends on rapid establishment of adequate blood supply at the graft sites which functions as a conduit for nutrient transportation, oxygen delivery, and metabolic waste excretion. This principle is particularly relevant to dentin/pulp regeneration given that the opening at root apex is too constricted to allow for intracanal blood infusion . Due to  ex vivo pulp cell culture and expansion are normally conducted. For these reasons, some investigators have tried to simulate the conditions of pulp hypoxia and explore how DPCs respond to low oxygen levels. Amemiya et al. demonstrated that canine DPCs under hypooxygenation conditions exhibited higher formazan production and growth rate compared to pulp cells incubated under normoxic conditions [ in vitro than those incubated under normoxic conditions [ in vitro and in vivo [α, ephrinB2, and VEGF [Hypoxia is a common phenomenon encountered by dental pulp tissue under both pathological and nonpathological conditions. Due to their unique anatomical structure that is surrounded by hard dentin with only a narrow opening at root apices, DPCs are typically susceptible to ischemia during traumatic injuries when surrounding vascular bundles are severely ruptured or during restorative treatment whereby local anesthetics containing vasoconstrictors slow down the velocity of blood microcirculation. Exposure to ischemia blocks the oxygen influx transported by the blood stream and thus disrupts the oxygen homeostasis of dental pulp . In addinditions . Subsequnditions , 86. Lid in vivo . Consistand VEGF . Collectα-smooth muscle actin and several mesenchymal and endothelial cell markers by perivascular cells [ in vitro and found that HUVECs dramatically facilitated the osteogenic/odontogenic differentiation of cocultured DPSCs compared with either DPSC-alone or HUVEC-alone cultures. In turn, DPSCs stabilized and increased the longevity of the preexisting HUVEC-formed vasculature [ ex vivo tubular-like networks than coculture of ECs with bone marrow mesenchymal stem cells (BMMSCs). Interestingly, this study not only proved the pericyte-like topography and potential function of DPSCs but also identified that the mechanism of DPSCs in angiogenic induction was VEGFR-2 dependent [ in vitro study demonstrated that coculture of SCAP and HUVEC under hypoxia enhanced the formation of vessel-like structure with increased tubular length and branching points and that the secretion of VEGF by SCAP might be utilized by HUVECs [ in vivo study implied that contribution of DPSCs to vascular morphogenesis when coimplanted with HUVECs not only was confined to the paracrine effects of secreted proangiogenic factors like VEGF, but also involved cell migratory mechanisms and corresponding scaffold disruption [In recent years, many research groups have succeeded in vascularizing artificial tissue constructs via codelivery of ECs with MSCs of various types. The significance of coculture system is based on the speculation that intricate signaling cross talk may be established among heterogenous cell populations, possibly regulated by direct cellular interaction or paracrine signaling . This hyar cells . Dissanaculature . DPSCs hculature , 94. Conependent . Anothery HUVECs . Furthersruption . While p in vitro culture system specifically for DPCs [Conventionally, stem cells are combined with exogenous scaffold materials to form a 3D engineered structure before transplanting into target sites. However, in addition to those biomaterial-associated problems, this well-recognized technique has long been questioned due to the inadequate cell migration and cell retention within the supporting scaffolds. Above all, the aforementioned biomaterials are far from being able to replicate the natural ECM or the surface of implantable device. A decade ago, Iohara et al. pioneered a 3Dfor DPCs . Unlike for DPCs . Considefor DPCs . in situ evaluation of scaffoldless delivery system is required in large animal models.Recently, a similar but different innovative “scaffold-free” approach developed for regenerative medicine, designated as “cell sheet technology” (CST), has become a popular topic of active research in the field of periodontal tissue engineering –100. SupThe introduction of preengineered 3D tissue constructs into transplantation sites requires a viable and effective delivery system. In general, scaffold adopted for bone or another body tissue regeneration is often fabricated with a rigid structure in order to provide sufficient physical support. Proof-of-principle transplantation experiments have provided valuable mechanistic information for dentin/pulp regeneration when using relatively rigid scaffolds like PLLA casts with tooth slices or fragments to deliver pulp stem cells . However in vitro and locally delivered into engineered tissue.The lineage commitment and differentiation of dental stem cells during dentin/pulp tissue repair and regeneration markedly differ depending on multiple factors. Apart from their intrinsic gene expression and epigenetic profiles, the cellular fate of dental pulp-derived stem cells seems more likely to be determined by the bioactive signaling molecules within the local microenvironment , 108. Cu in vitro and in vivo [ in vitro study in which SCAP were cocultured with HUVECs, VEGF secreted by SCAP were metabolized by HUVECs to facilitate the formation of new vasculatures and the maturation of sprouted capillary networks [ in vivo study demonstrated that bFGF increased the survivability of DPSCs seeded on silk fibroin scaffold and resulted in the formation of pulp-like tissue replete with vasculature formation and calcium mineral deposition along the radicular dentinal wall after transplantation into SCIDM [Nakashima demonstrated recombinant human BMP2 and BMP4  induced tubular dentin and osteodentin formation on canine amputated tooth pulp when capped with inactivated dentin matrix , 111. St in vivo . In an inetworks . bFGF hanetworks , 117. Itnetworks . Notablynetworks . Recentlto SCIDM . However in vivo study further confirmed the efficacy of BMP-2 transfection therapy in potentiating tissue mineralization within the regenerated construct in favor of bone-like structure rather than dentin-like morphology [Loading scaffolds with bioactive drugs or protein molecules intended for promoting dental tissue regeneration has achieved favorable results . Neverthrphology . Howeverrphology . Additio de novo pulp regeneration in the full-length root. In addition, cells trapped within fibrin clots during revitalization/revascularization have neither a definite origin nor a predictable quantity and thus the phenotype of regenerated replacements filling in root canals cannot be well characterized, leading to variations in overall therapeutic efficacy. In comparison, cell transplantation based on the utilization of the meticulous triad of classic tissue engineering including stem cells, scaffolds, and signaling molecules has achieved promising outcomes. This cell-based method is capable of repairing tissue defects with an extensive size [ ex vivo cell manipulation, and ultimate shipping back to practitioners is a rather time-consuming process and the cost involved may be too excessive over relatively mature alternative therapies like dental implants or RCT. During the expansion period, cell senescence, loss of stemness, and microbial contamination are likely to occur, leading to biological deterioration and even cellular apoptosis. Worse still, MSCs are prone to experience malignant genetic transformation and thus arouse safety concern of tumorigenesis [Owing to the recent advances in the field of biomedicine, tissue engineering, and material science, great progress has been achieved in the development of regenerative endodontics. We are now at a stage of paradigm shift in endodontic treatment from traditional restoration to complete replacement of the compromised dental pulp tissues which can be realized by two scientifically meritorious approaches, cell transplantation and cell mobilization, including revitalization/revascularization procedure. While simple to operate, the cell mobilization approach may not be suitable to tissues with large size defects, especially in the circumstance ofive size , 122. Deigenesis . If thesTo date, no randomized clinical controlled trials have been conducted to compare the efficacy of cell mobilization or cell transplantation therapy and traditional endodontic treatment. Superior to tooth restoration, regenerative therapy is considered as a potential solution to address the deficiencies in tooth homeostasis, immune defense system, blood supply, and functional dentin-pulp complex formation. Moreover, it prolongs the life of natural dentition, defers the extraction fate of teeth with partially necrotic pulp, and thus ultimately improves the overall oral health-related quality of life. Collectively, additional studies in these fields should continue in order to work out a clinically translatable platform on dentin/pulp regeneration. Future research prospects in regenerative endodontics rely on the multidisciplinary collaboration of clinicians, biomaterial scientists, and engineers with expertise in their own fields and their joint contributions to the development of dentin/pulp regeneration therapy.


Existing literature suggests that organizational readiness for change (ORC) can influence implementing and sustaining an intervention program. Individual attitude toward innovation is one of the important components of ORC. There is a growing research effort to identify facilitators and barriers regarding positive attitudes toward innovation in clinical settings. The current study aims to explore how occupational stress and social support for work may affect attitudes toward innovation among health care providers in HIV clinics in China.323 health care providers were recruited from 42 HIV clinics across 12 cities/counties in Guangxi, China to participate in a self-administered survey including measures on demographics, work-related characteristics , occupational stress, social support for work (from the family and colleagues), and attitudes toward innovation. We conducted mediation analysis and Sobel testing to examine the relationship among variables of interest.After controlling for demographics  and work-related characteristics , occupational stress was negatively associated with positive attitudes toward innovation  while higher levels of social support from the family was associated with more positive attitudes toward innovation . Social support from the family significantly mediated the impact of occupational stress on attitudes toward innovation . However, no significant association was detected between social support from colleagues and attitudes toward innovation (p = 0.600).Social support for work from the family not only promotes attitudes favoring innovation, but also buffers the negative impact of occupational stress on attitudes toward innovation among health care providers in HIV clinics. Our findings suggest integrating both individual and family level factors into the strategies of improving ORC in HIV clinical settings.


The transdiagnostic theory of eating disorders proposes that clinical perfectionism, core low self-esteem, interpersonal problems and mood intolerance can maintain eating disorder psychopathology in some individuals. The current study aimed to explore eating disorder symptom severity as a function of these maintaining mechanisms in a community sample. Participants completed questionnaires online and were classified according to whether they met criteria for zero, one, or two or more mechanisms. A greater number of maintaining mechanisms was found to be significantly associated with higher global eating disorder examination questionnaire (EDE-Q) scores, and a higher prevalence of binge eating, purging and driven exercise. Moreover, participants with 2 or more maintaining mechanisms had more severe eating disorder symptoms than participants with 1, who in turn had more severe symptoms than participants with no maintaining mechanisms. Regression models evaluated the role of each maintaining mechanism in predicting different aspects of eating disorder pathology. Self-esteem, perfectionism and mood intolerance all predicted unique variance in global EDE-Q scores. There were differences in the maintaining mechanisms that predicted binge eating, purging and driven exercise. These results provide support for the transdiagnostic model of eating disorders and have implications for detecting and treating eating disorders in community samples.Peter Beumont Young Investigator award finalist stream of the 2014 ANZAED Conference.This abstract was presented in the


Surgical resection of colorectal liver metastases is not achievable in more than 70% of the cases. Although the liver directed therapies have become a part of the stand of care, lack of a preclinical model impedes the assessment of toxicity and therapeutic benefits attributed several candidate drugs or treatment regimens that can be designed. In the present study we aim develop and characterize a rat colorectal liver metastasis model.Growth characteristics of CC-531 cells were determined in vitro followed by subcapsular liver implantation in syngeneic WAG/Rij rats. Tumor growth progression was followed over 3 weeks by ultrasound (US) and magnetic resonance imaging (MRI). Growth characteristics were also assessed by histopathology and immunohistochemistry in harvested tumor tissues.The doubling time of CC-531 cells was found be under 24hrs and all the implanted rats grew tumors. US imaging showed hypoechoic masses and MRI showed contrast enhancement representing complex tumor microenvironments. Hematoxylin and Eosin staining confirmed tumor growth and uniform CD31 staining in tumor confirmed even vessel density.CC-531 can be used as a metastatic rat tumor colorectal liver metastases model with well-defined characteristics that can be readily followed by imaging whilst having a therapeutic window for interventions. In interventional oncology, many animal models of disease have been utilized to understand ablative and trans-catheter intra-arterial therapies. To date, there are many models of orthotopic hepatocellular carcinoma in a rat model, including the Morris (McA-RH7777),  NovikoffDeveloping this type of preclinical animal model of colorectal liver metastases can be challenging. One approach to achieving liver metastases is to implant colon cancer cells directly into the liver.  This modThe current study focused on validating this model of colorectal liver metastases, which can be used rapidly and reliably in a preclinical setting. By using a subcapsular injection of metastatic cells, distinct tumors develop and progress in situ. Changes in their microenvironment can be monitored non invasively and continuously early after implantation . Though In conclusion, CC-531 is an immunocompetent and orthotopic translational rodent model of colorectal liver metastases mimicking tumor microenvironment with liver metastases easily established, tracked and characterized by US and MR imaging.


Apical HCM tends to have a favorable outcome compared to other types. The presence and extent of late gadolinium enhancement (LGE), reflecting myocardial fibrosis, is closely correlated with increased cardiac mortality and strongly associated with surrogates of arrhythmia and subsequent sudden cardiac death. This study sough to investigate the difference in cardiac magnetic resonance (CMR) and echocardiographic and clinical manifestations between apical hypertrophic cardiomyopathy (HCM) and non-apical HCM.A total of 350 consecutive patients diagnosed with HCM  underwent CMR and echocardiography. Clinical characteristics including risk factors for sudden cardiac death were collected. Eighty-five patients were classified as apical type. On CMR, left ventricle (LV) volumetric parameters were measured, and the amount of LGE was calculated with gray-scale thresholds of 6 SD above the mean signal intensity for normal remote myocardium and also expressed as a ratio against total LV volume. Echocardiographic evaluations included left atrial volume index (LAVI), mitral inflow pattern, tissue Doppler of mitral annulus and LV dimension.Patients with apical HCM were less likely to present with history of syncope  and have family history of sudden cardiac death than those with non-apical HCM . Functional class was also more favorable in apical HCM . CMR volumetric parameters were not different between the two groups except LV mass index . LGE was less frequently detected , and the amount of LGE was significantly smaller in apical HCM . The E/e level and LAVI were also lower in apical HCM patients .Apical hypertrophy shows relatively small burden of myocardial fibrosis and less severe diastolic dysfunction, and subsequently more favorable clinical manifestations in comparison with other HCMs. This may be one explanation of why most patients with apical HCM show a benign course of disease compared to non-apical HCM.None.


Differential accessibility of DNA to nuclear proteins underlies the regulation of numerous cellular processes. Although DNA accessibility is primarily determined by the presence or absence of nucleosomes, differences in nucleosome composition or dynamics may also regulate accessibility. Methods for mapping nucleosome positions and occupancies genome-wide (MNase-seq) have uncovered the nucleosome landscapes of many different cell types and organisms. Conversely, methods specialized for the detection of large nucleosome-free regions of chromatin  have uncovered numerous gene regulatory elements. However, these methods are less successful in measuring the accessibility of DNA sequences within nucelosome arrays.Here we probe the genome-wide accessibility of multiple cell types in an unbiased manner using restriction endonuclease digestion of chromatin coupled to deep sequencing (RED-seq). Using this method, we identified differences in chromatin accessibility between populations of cells, not only in nucleosome-depleted regions of the genome , but also within the majority of the genome that is packaged into nucleosome arrays. Furthermore, we identified both large differences in chromatin accessibility in distinct cell lineages and subtle but significant changes during differentiation of mouse embryonic stem cells (ESCs). Most significantly, using RED-seq, we identified differences in accessibility among nucleosomes harboring well-studied histone variants, and show that these differences depend on factors required for their deposition.Using an unbiased method to probe chromatin accessibility genome-wide, we uncover unique features of chromatin structure that are not observed using more widely-utilized methods. We demonstrate that different types of nucleosomes within mammalian cells exhibit different degrees of accessibility. These findings provide significant insight into the regulation of DNA accessibility.The online version of this article (doi:10.1186/1471-2164-15-1104) contains supplementary material, which is available to authorized users. Eukaryotic genomes are wrapped around histone octamers to form nucleosome arrays, which are further packaged into the nucleus. Although chromatin compaction facilitates storage of large quantities of DNA within small nuclear compartments, it drastically reduces the accessibility of genomic DNA to proteins that require access. Nucleosomal DNA is relatively inaccessible to DNA binding proteins due to both the occlusion of approximately half of its surface by contacts with histones, as well as the distortion of the normal B-form structure that occurs when DNA is wrapped around a histone octamer . Consequin vivo.Although protection of DNA from nuclear factors by the formation of tight interactions with histones appears to be the major method by which DNA accessibility is regulated, many different isoforms of the histone octamer exist within most eukaryotes, each with distinct biochemical and biophysical properties –8. TheseAlong with differences in chromatin structure within distinct genomic regions in individual cell types, cell type-specific chromatin structural differences facilitate gene expression patterns specific to cells of different lineages . In embrMethods have been developed to study DNA accessibility based on either the protection of nucleosomal DNA from general endonuclease digestion or the differential solubility properties of open and closed chromatin. Deoxyribonuclease I (DNase I) , 19 prefet al. developed a genome-wide method to probe chromatin structure using restriction enzymes, finding that chromatin accessibility correlated broadly with gene expression in hematopoietic cell lineages and became progressively restricted during differentiation , plotted as in Figure Additional file 2:a GEO:GSE0254, ploSequences of barcoded and biotinylated adaptors.(PDF 42 KB)Additional file 3:Sequences of qPCR primers for DHSs.(PDF 40 KB)Additional file 4:Sequences of qPCR primers for CTCF binding sites.(PDF 48 KB)Additional file 5:


Lung cancer is difficult to treat with a poor prognosis and a five year survival of 15%. Current molecularly targeted therapies are initially effective in non-small cell lung cancer (NSCLC) patients; however, they are plagued with difficulties including induced resistance and small therapeutically responsive populations. This mini review describes the mechanism of resistance to several molecularly targeted therapies which are currently being used to treat NSCLC. The major targets discussed are c-Met, EGFR, HER2, ALK, VEGFR, and BRAF. The first generation tyrosine kinase inhibitors (TKIs) resulted in resistance; however, second and third generation TKIs are being developed, which are generally more efficacious and have potential to treat NSCLC patients with resistance to first generation TKIs. Combination therapies could also be effective in preventing TKI resistance in NSCLC patients. The focus of current lung cancer treatment has been shifted from more traditional options to newly developed molecularly targeted therapies. Many of the molecularly targeted therapies are utilized to target specific biomarkers that are commonly overexpressed and have important roles in tumorigenesis; these biomarkers contribute to cancer-related processes such as cell proliferation, survival and migration. While initially effective, many targeted therapies have been associated with increased drug resistance after their initial use. Acquired resistance to current molecularly targeted therapies in lung cancer presents a major clinical challenge. Current research focuses on identifying potential novel biomarkers and mechanisms involved in resistance to these therapies. There are several clinical challenges associated with current molecularly targeted therapies including the induction of various types of resistance mechanisms, which are not clearly defined, and the lack of effective combinatorial therapies designed to prevent and overcome the problem of drug resistance in lung cancer.Common molecularly targeted therapies target receptor tyrosine kinases (RTKs) including hepatocyte growth factor receptor (HGFR/c-Met), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), and endothelial growth factor receptor (VEGFR), which are commonly mutated in NSCLC cases . Recentlc-Met is a RTK for the ligand hepatocyte growth factor (HGF), which is secreted by mesenchymal cells and cancer cells . There hEpidermal growth factor receptor (EGFR) is a transmembrane receptor that plays an essential role in regulating cell proliferation, survival, and growth . EGFR TKThe anaplastic lymphoma kinase (ALK) is a RTK typically expressed in the central and peripheral nervous system regions ,20. ALK Overexpression of vascular endothelial growth factor (VEGF), an angiogenic factor, and its receptors are related to poor prognosis in NSCLC patients . BevacizBRAF  is a member of the RAF serine/threonine protein kinases family. Mutations in BRAF have been shown to be associated with tumor development in NSCLC with a frequency of 2–3%. Recently, a BRAF inhibitor dabrafenib, the first drug of its class, is shown to be effective for the treatment of advanced NSCLC patients with BRAF V600E mutation in a phase II clinical study . HoweverAlthough current molecularly targeted therapies are very effective for NSCLC patients, almost all patients eventually acquire resistance to these therapies. To combat this resistance against first generation TKIs, second and third generation TKIs have been developed. These new generations of TKIs are either completing clinical trials or have been FDA approved to treat NSCLC patients. However, their therapeutic potential needs to be further validated and established. Various secondary mutations and alternative signaling pathways have been identified as distinct resistance patterns for several TKIs targeting EGFR, c-Met, and ALK. However, further studies are required to determine the specific mechanisms of acquired resistance to HER2, VEGFR and BRAF. Combinatorial strategies could be effective in overcoming TKI resistance in lung cancer patients. These strategies may require targeting both mutations involved in resistance and alternative signaling pathways.


Xanthomonas citri subsp. citri, three Candidatus Liberibacter spp and Citrus leprosis virus C (CiLV-C). In plant-pathogen interactions, the role of salicylic acid (SA) in activating defense related genes is well recognized  seedlings grown in test tubes containing MS culture medium. The presence of the transgene will be evaluated by PCR using specifics primers that amplify part of the ubiquitin promoter and part of the gene. SABP2 expression levels in transgenic plants will be assessed through qPCR. After bud multiplication, transgenic plants will be evaluated for their response to citrus canker, HLB and leprosis.A total of 620 explants in three independent experiments were introduced and approximately 336 shoots were regenerated. The GUS histochemical test was performed and confirmed the transformation of 30 positive shoots. These shoots are being grafted onto Carrizo citrange [


I first overview motor neuron developmental biology to provide some context for reviewing recent studies interrogating pathways that influence the generation of MN diversity. I conclude that motor neurogenesis from PSCs provides a powerful reductionist model system to gain insight into the developmental logic of MN subtype diversification and serves more broadly as a leading exemplar of potential strategies to resolve the molecular basis of neuronal subclass differentiation within the nervous system. These studies will in turn permit greater mechanistic understanding of differential MN subtype vulnerability using in vitro human disease models.Resolving the mechanisms underlying human neuronal diversification remains a major challenge in developmental and applied neurobiology. Motor neurons (MNs) represent a diverse pool of neuronal subtypes exhibiting differential vulnerability in different human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The ability to predictably manipulate MN subtype lineage restriction from human pluripotent stem cells (PSCs) will form the essential basis to establishing accurate, clinically relevant  Human neurodegenerative disorders represent a spectrum of progressive and untreatable clinical diseases, characterized by selective loss of neurons, usually in a region-specific  and/or subtype-specific  fashion. There is a great experimental need for renewable sources of clinically relevant, region-specific, and subtype-specific neurons. Lineage restriction and the generation of neuronal diversity within the developing neuraxis are consequences of the interplay of multiple developmental signals, which are regulated in a spatiotemporal manner. Precise cellular and molecular mechanisms through which these complex sequential and progressive developmental processes are orchestrated remain unresolved. The ability to generate defined neuronal cell types from PSCs offers a unique experimental opportunity to study the developmental mechanism(s) underlying generation of neural diversity during human embryogenesis , 2 Figu. In turn in vitro with fidelity and precision , 1312, 1 postmitotically is a key determinant of neuronal subtype diversification [Experiments involving intercolumnar fate switching have demonstrated a consequent and congruent change in axonal trajection. For example, ectopic expression of Hoxc10 (lumbar) at thoracic levels causes a fate change to LMC MNs, which then project into the lower limb . These efication , 53, 54.fication , 54. Sucfication . ExperimAgainst the background of these studies, it is clear that the descriptive term “MN” is an oversimplification and the numerous motor neuronal subtype differences described above  begin to demonstrate some of the necessary complexity inherent in MN diversification. The developmental biology that underpins MN differentiation is relatively well understood and thus provides a rational basis for using human stem cell-based systems to allow further elucidation of mechanisms responsible for generating MN subtype diversity. in vitro. PSCs respond predictably to developmental cues such that their fate can be systematically manipulated to differentiate into myriad cell lineages from any of the 3 germ layers. There are 3 principal properties that characterize PSCs: (i) the ability to self-renew, (ii) pluripotency  [ in vitro culture conditions for the propagation of undifferentiated vertebrate tumor cell lines in the 1970s [ in vitro fertilization clinics [There are different sources of species-specific stem cells including embryonic, fetal, and adult varieties. Embryonic stem cells (ESCs) are a type of PSC thus possessing the greatest developmental potentialderived) , and  also represents a potential problem because this cannot, at present, be predictably altered using extrinsic signals. This tissue specific “multipotency”  is a relative disadvantage when studying cell fate specification, where the pluripotent state represents an ideal investigative tool. Attempts to derive PSCs by different methods have partially tempered the ethical controversy in which the human ESC field is immersed . These e neurons . These dβ signaling superfamily permits highly efficient neural conversion of PSCs and represents the most widely adopted method employed to date [Predictable and scalable directed differentiation of PSCs to the neural lineage is necessary for studying human neural development, modeling disease, and drug discovery. Several well established methods can robustly achieve neural conversion of PSCs in chemically defined conditions –98. Effi to date .The elucidation of developmental inductive cues and transcriptional programmes for MN specification  have bee in vitro work using human PSCs suggest that, soon after neural induction, precursors initially assume a rostral and dorsal positional identity through the combined actions of the BMP, WNT, and FGF signaling pathways, which have unique spatiotemporal influences on positional identity and cell fate decisions [ in vitro [Insights from developmental studies across different species and fromecisions , 6. Mousin vitro , 103. On versus simultaneous administration of morphogenetic signals is another interesting subject, which merits discussion here. In the case of motor neurons, for example, the first directed differentiation of MNs from mouse ESCs employed simultaneous administration of RA and Shh [ in vivo motor neuron lineage restriction.Important future studies would include systematic analyses of the requisite time for neural patterning prior to terminal differentiation, which has yet to be definitively addressed. Some studies have suggested that accelerated neural conversion and patterning protocols are possible. The question of sequential and Shh , whereas and Shh  the cuesThere is an increasing wealth of literature around the mechanisms underlying neurodevelopment, revealing a remarkable and previously unrecognized extent of neuronal diversity. Functionally relevant differences in molecular phenotype, axonal projection, dendritic arborization, and electrophysiological attributes have been demonstrated between different neuronal subtypes throughout the neuraxis –110. TheTo date, the vast majority of studies using ESCs have focused on deriving MNs generically, while comparatively few studies address the issue of motor neuronal subtype diversification. Most protocols for motor neuron specification from PSCs (either ESCs or iPSCs) utilize the application of a simplistic programme of morphogenetic signals to achieve neural patterning, followed by standard terminal differentiation conditions. Signaling mechanisms and transcriptional events involved in the postmitotic diversification of motor neuronal subtypes from human ESCs remain poorly characterized. Currently, no study has systematically investigated the influence of a morphogenetic signal during both MN precursor “patterning” and terminal differentiation in order to establish their relative contributions to subtype choice during these distinct developmental stages. in vivo studies [MNs are a diverse collection of neuronal subtypes displaying differential vulnerability in different human neurodegenerative diseases. During embryogenesis, retinoid signaling contributes to caudal precursor specification generically and subsequent MN subtype diversification. RA typically results in a cervical or brachial positional identity , 106. Ag studies . Therefo studies . Collect studies , 111–113 studies  (a small studies .Separately, the use of suspension culture , 116 ver in vitro. Access to human PSCs allows questions around early cell fate acquisition to be addressed. Developmental competence to extrinsic morphogenetic signals during embryonic patterning is both spatially and temporally restricted. Human PSCs faithfully recapitulate the key milestones of neurodevelopment and thus permit studies that will improve our understanding of the relative contributions of extrinsic signals, cell-intrinsic transcriptional programmes, and intercellular/paracrine communication to direct cell fate decisions. This reductionist model system, together with the use of a fully defined cell culture medium, provides a unique experimental opportunity to understand the relevance of how signaling pathways function individually or combinatorially to direct lineage restriction at different developmental stages. In turn, such knowledge will permit more predictable manipulation of PSCs to generate desired progeny for experimental study. PSCs therefore represent an unparalleled opportunity to study human neurodevelopmental processes. It is likely that, for future strategies aimed at generating distinct subtypes of MN, controlled extrinsic morphogenetic instruction during both precursor specification and terminal differentiation will be key determinants of success. As a final remark, although there is a considerable degree of conservation in neuraxial systems between rodents and humans, important differences in architecture, computational power, and functional capacity exist. Such evolutionary divergence strongly reinforces the indispensability of human experimental systems to complement, but not replace, existing rodent-based approaches.Elucidating efficient protocols to generate enriched populations of MN subtypes has important biotechnological implications for disease modeling, drug discovery, and potentially cell-based therapy. Such approaches would permit comprehensive mechanistic studies of differential MN subtype vulnerability


Peromyscus leucopus) utilized space and depredated two incidental prey items: almonds  and maple seeds . We estimated mouse population densities with trapping webs, quantified mouse consumption rates of these incidental prey items, and measured local mouse activity with track plates. We predicted that 1) mouse activity would be elevated near full feeders, but depressed at intermediate distances from the feeder, 2) consumption of both incidental prey would be high near feeders providing less-preferred food and, 3) consumption of incidental prey would be contingent on predator preference for prey relative to feeders providing more-preferred food. Mouse densities increased significantly from pre- to post-experiment. Mean mouse activity was unexpectedly greatest in control treatments, particularly <15 m from the control (empty) feeder. Feeders with highly preferred food (sunflower seeds) created localized refuges for incidental prey at intermediate distances (15 to 25m) from the feeder. Feeders with less-preferred food (corn) generated localized high risk for highly preferred almonds <10 m of the feeder. Our findings highlight the contingent but predictable effects of locally abundant food on risk experienced by incidental prey, which can be positive or negative depending on both spatial proximity and relative preference.Abundant, localized foods can concentrate predators and their foraging efforts, thus altering both the spatial distribution of predation risk and predator preferences for prey that are encountered incidentally. However, few investigations have quantified the spatial scale over which localized foods affect predator foraging behavior and consumption of incidental prey. In spring 2010, we experimentally tested how point-source foods altered how generalist predators (white-footed mice,  Predator foraging behaviors, and the resulting distribution of predation risk within a landscape, are influenced by what prey are available and where they are located. Optimal foraging theory provides a framework for predicting predator choice of prey on the basis of energetic profitability , as wellZea mays) spatially concentrate foraging by raccoons (Procyon lotor), increasing predation risk for nearby nests of wild turkeys  and turtles /11 = 0.44. This subtle but potentially important reduction in risk is an important consideration when interpreting results showing elevated risk of generalist predation near artificial food sources [Regarding our second prediction, we did not observe a general pattern of depressed track activity at intermediate distances from either filled or empty feeders. This lack of result is likely related to the difference in spatial areas: for example, the annulus between radii of 10 and 25 m has an area 21 times larger than the circular area within 5 m of the feeder. Thus, the shift of a fixed amount of mouse activity from the annulus to the circle would cause an increase in activity density near the center 21 times greater than the corresponding decrease in the annulus. Such a subtle decrease in activity is likely to require very high sample size to reliably detect. However, even subtle modifications in predator activity, and thus predation risk, over large areas can disproportionately increase prey survival rates. Concentrating predation risk in space generally increases overall survival of relatively sessile prey because depletion of prey in high-risk areas quickly generates a negative spatial correlation between prey abundance and risk , 61. Jen sources , 63, 64.Regardless of the cause of spatial variations in mouse activity, we expected that consumption rates of incidental prey would reflect the local risk of discovery, as indicated by mouse activity, mediated by predator preference for these prey relative to the provided food treatment. Based on these expectations, our third prediction was that consumption rates for both incidental prey items would be elevated near feeders providing a less-preferred food (corn). This prediction was partially supported for almonds but not for maple seeds. On the other hand, sunflower seeds have higher energy density and protein content than corn, so we predicted that feeders providing sunflower seeds would elevate local consumption of almonds but depress consumption of less-preferred maple seeds. However, consumption of both almonds and maple seeds was depressed near feeders providing sunflower seeds. Taken together, these deviations from our predictions regarding consumption rates imply that the incidental prey items we deployed were consistently devalued relative to the food provided in feeders. Incidental prey may be devalued by handling time cost imposed by seeds being embedded in wax. However, predation by small mammals (mainly white-footed mice) was much greater for freeze-dried gypsy moth pupae affixed to burlap with beeswax than for naturally occurring gypsy moth pupae at the same microsites and times , so wax Sciurus niger) over-utilized poor-quality habitat patches [The findings of this study may be applied to other generalist consumers and their prey . Abundant food sources can decrease rodent predator activity levels , 58, inf patches  and decr patches . DifferePanthera leo), deviated from optimal foraging expectations by choosing suboptimal prey based on prey group size, prey distance from the hunting group, and prey group composition [The results of this investigation may be broadly applied to predator and prey interactions. Optimal foraging theory provides a general predictive framework for predator foraging behavior and choice of prey. However, generalist predators can deviate from optimal expectations by altering their space use and consuming suboptimal prey. Large predatory mammals, like African lions (position . Avian cposition . Differe


HIV transmission occurs predominantly across mucosal surfaces. An ideal preventive strategy would be to target HIV at mucosal entry sites to prevent infection. We developed a novel epithelial stem cells-based AIDS preventive approach in female macaques. This approach is based on the ability of therapeutic lentiviral vectors integrated in mucosal epithelial stem cells to induce virus-specific cellular immune responses at mucosal sites of viral entry. We first intended to expose the cervicovaginal tract to conditions used for intravaginal vaccine delivery and non-invasively image local tissues to determine the vaccination effects on epithelial integrity and generation of antigen-specific mucosal immune responses.Experimental cervicovaginal vaccinations were carried out on 12 uninfected female macaques, in conjunction with deliberate abrasion of epithelium using Depo-Provera, 4% nonoxynol-9 treatments, or gentle abrasions to reduce vaginal epithelial height and cell layers number. Longitudinal study was performed for baseline levels of hormones, antibodies, cytokine profiles during normal cycling with/without vaccination. Endoscopic colposcopy followed by optical coherence tomography (OCT) helped monitor macaque cervical-vaginal epithelium pre-, post-, without treatment to measure epithelial thickness changes. Colposcopy help visualizing the vagina and cervix. Blood samples and biopsies were collected at various time-points to evaluate immune responses to vaccination.OCT imaging provided quantitative measurements of epithelial changes and detected minute changes in epithelial thickness and morphology. Colposcopy and OCT imaging correlated with hormone levels and biopsies imaging. Depo-Provera gave better results in epithelium thinning but naturally cycling macaques showed clearer thickness differences. All collected secretions, biopsies and blood samples gave a better understanding of the correlation between menstrual cycle, hormonal level, epithelial thickness changes. Optimal conditions for vaccine delivery were determined and revealed virus-specific T cell response in all vaccinated animals.OCT is well suited for the examination of superficial mucosal layers and close underlying stromal structures of tissues. In this study, we demonstrated the feasibility of using epithelial stem cells as mucosal antigen-presenting cells to induce viral specific immune responses at mucosal sites, and improved our knowledge of the role of mucosal surfaces.


Granulomatosis with polyangiitis is a systemic disease resulting in necrotizing vasculitis of small- and medium-sized vessels. Cardiac involvement is rare and when present usually manifests with pericarditis and coronary artery vasculitis. We report here a case of granulomatosis with polyangiitis involving the native coronary arteries, bypass graft, and pericardium with interesting imaging findings on contrast-enhanced CT and MRI. A 57-year-old man with a history of chronic headaches presented to the emergency room with syncope. Contrast-enhanced CT demonstrated extensive soft tissue attenuation around the native coronary arteries and bypass graft. Contrast-enhanced MRI demonstrated enhancing nodular soft tissue surrounding the coronary arteries, bypass graft, and pericardium. Pericardial biopsy revealed a necrotizing granulomatous pericarditis with vasculitis concerning for granulomatosis with polyangiitis. The patient demonstrated MPO-positive and PR-3 negative serologies. After being discharged on rituximab and prednisone, follow-up CT 3 years later showed significant improvement of the soft tissue thickening surrounding the coronary arteries, bypass graft, and pericardium. Granulomatosis with polyangiitis (GPA) is a form of systemic vasculitis with necrotizing granulomatous inflammation of the upper and lower respiratory tracts and kidneys . GPA invThe literature concerning cardiac involvement is limited. The few case reports and general reviews show that the two most common histologic cardiac manifestations are pericarditis and coronary arteritis. The most frequent clinical manifestation is cardiac arrhythmias, typically supraventricular tachyarrhythmias. We report an unusual case of GPA initially presenting with cardiac involvement affecting the coronary arteries, bypass graft, and pericardium.A 57-year-old white male with history of Graves' disease with ophthalmopathy and coronary artery disease status after 3-vessel CABG presented to the ER after a syncopal episode during a doctor's office appointment. He had been having severe frontal headaches for several months with workup prior to this admission revealing an elevated ESR and bilateral temporal artery biopsies which were negative for giant cell arteritis. A lumbar puncture revealed elevated protein, increased opening pressure, elevated WBC, IgG index, and oligoclonal bands. A bone marrow biopsy performed for microcytic anemia was unremarkable.Given his history of syncope, a CT angiogram of the chest was performed to exclude a pulmonary embolism. No evidence of pulmonary embolism was seen; however, soft tissue attenuation around the coronary arteries, bypass graft, and pericardium raised concern for vasculitis Figures  and 2. FA pericardial biopsy demonstrated dense scar tissue associated with a mononuclear infiltrate comprised mostly of nodular aggregates of monocytes and macrophages . Within Myeloperoxidase associated ANCA vasculitis with orbital pseudotumor and pericardial involvement was considered to be the most likely diagnosis. He was discharged after being placed on prednisone and rituximab. Subsequent contrast-enhanced chest CT 3 years later showed significant improvement of the soft tissue thickening around the coronary arteries, bypass graft, and pericardium .GPA affects multiple organ systems and may involve any part of the body. The upper respiratory tract is involved in nearly all patients. In addition, a vast majority of patients with GPA will also have pulmonary (90%) and renal (80%) involvement . ElevatiCardiac involvement is relatively rare in GPA even though autopsy results show that GPA related cardiac abnormalities are present in one-third of patients . CardiacThe coronary arteries are frequently involved in systemic arteritis. The inflammatory infiltrate damages the intima and may trigger the occurrence of coronary thrombosis. Morbini et al. report an extreme example of an elderly female with intimal inflammation in multiple sites of a coronary tree with and without atherosclerosis which triggered coronary thrombosis. She died after cardiac arrest from a clinically unrecognized systemic autoimmune-inflammatory disorder with necrotizing arteritis. Autopsy showed findings typical of GPA and systemic arteritis with fibrinoid necrosis and systemic arteritis. Although there were no clinical signs of cardiac involvement, the coronary arteries showed inflammation associated with multiple mural and occlusive thrombi .Ohkawa et al. reported a case of generalized GPA with extensive cardiac involvement at autopsy. Necrotizing angiitis and severe granulomatous inflammatory foci affected the common bundle of His and right bundle branch in addition to the myocardium .Cardiac valvular involvement is an uncommon manifestation of GPA. Espitia et al. reported the case of a 60-year-old woman with severe inflammatory aortic and mitral valvular involvement characterized by GPA with typical histopathological valvular lesions. Cardiac valvular involvement is a rare and potentially fatal complication of GPA and may misleadingly suggest infectious endocarditis .Currently, multiple imaging modalities are increasingly used as first-line noninvasive diagnostic tools to assess target-organ involvement in GPA, although biopsy with pathological testing represents the gold standard . In our To the best of our knowledge this is the first case report showing involvement of a bypass graft, native coronary arteries, and pericardium as the initial manifestation of GPA.In conclusion, cardiac involvement of GPA is rare. It must be included in the differential diagnosis when soft tissue thickening involves the coronary arteries and pericardium, even when no pulmonary or airway findings are identified.


On the evening of 13 November 2015, three terrorists equipped with military-grade firearms and explosive jackets penetrated Bataclan, a Paris music hall containing 1500 people [Immediately, RAID , the French national police counter-terrorism team, and the BRI (Research and Intervention Brigade) were engaged. As previously reported , 3, thesFirst, RAID police officers and tactical physicians proceeded to zoning. Priority was given to police operation and safety . They deWhile police operators were getting into position within the theater and thus repelling terrorists, two RAID tactical physicians performed triage in the combat zone , 4. TheyIn the combat zone, RAID tactical physicians applied tourniquets to 15 invalid patients [Once salvage therapies were performed , more thTwo tactical physicians joined the operation theater. They perform damage control resuscitation to casualties within the dressing station . SeveralThe initial tactical physicians then joined the assault team to act as forward medical officers. The remaining two terrorists committed suicide, detonating their bombs during a final assault, without causing additional fatalities.Because the environment remained under the threat of explosives, despite terrorists’ neutralization, conventional rescue teams were maintained out of the exclusion zone until the end of mine-clearing operations. All five physicians continued to perform damage control resuscitation on invalid patients until they were transferred to the casualty receiving station. When conventional rescue teams received clearance to penetrate the theater, all living casualties had already been extracted. The teams discovered 89 fatalities.Owing to the mismatch between the number of casualties and tactical physicians, the latter first decided to secure non-invalid casualties before treating invalid patients with severe but accessible lesions. The tangle of numerous dead bodies might have hidden living casualties from tactical physicians’ view, preventing the former from receiving care in time.Not all the concepts of damage control resuscitation were performed. Some of the casualties did not even receive damage control resuscitation, owing first to the aforementioned mismatch between the number of casualties and tactical physicians and second to an insufficient amount of available medical equipment.Maintaining conventional rescue teams out of danger was consistent with prehospital disaster plans. This appeared a safe option because mine-clearing operators discovered a bag filled with explosives. Of note, despite dynamic adaptation of the exclusion zone boundaries to the threat, post hoc analysis revealed that the distance between the dressing station within the theater and the casualty receiving station was excessive.


RECIST criteria use changes in tumour diameters to quantitatively obtain response assessments for traditional chemotherapeutic cancer treatments: Positive responses are identified by reductions in tumour size while tumour growth signifies non-response.transarterial chemo embolization (TACE) can be used alone or in combination. Local treatment, radiation therapy, immunotherapy and targeted therapy can each result in an increased tumour diameter in spite of treatment response at the cellular level and increased survival times. As a result, tumour diameter can no longer stand alone when assessing oncological treatment strategiesTraditional chemotherapies work primarily by damaging cells that are undergoing rapid growth and division. Immunotherapies work by stimulating the immune system to reject and destroy tumour cells. Targeted cancer therapies block the growth of cancer cells by interfering with specific molecules needed for tumour growth and carcinogenesis. These oncological treatments as well as stereotactic radiation therapy and local treatments, such as image-guided ablations and Tumour heterogeneity and contrast enhancement often change during treatment, and tumour enhancement combined with tumour size has been shown to be successful in assessing treatment response in gastrointestinal stromal tumours (CHOI criteria). Modified CHOI criteria could potentially be used for monitoring the effect of oncological treatment strategies in metastatic renal cell cancer and hepatocellular carcinoma.Dynamic contrast-enhanced imaging  uses changes in tumour enhancement following the intravenous injection of a contrast media to create a time-versus-signal curve. From such curves, reliable quantitative estimates of blood flow, blood volume and permeability can be obtained. Diffusion-weighted MRI and PET can also be used to obtain quantitative measures of physiological processes. A major advantage of DWI-MRI and PET is the possibility of whole body coverage, while DCE imaging is limited to a single tumour or a comparatively small region.Although quantitative assessments of oncological treatment response using physiological parameters have been shown to be superior to size-based response in several studies, the methods mentioned are not yet standardized, and randomized multicentre studies have not yet been performed. When planning such studies, it is important to note that clinical endpoints such as progression free survival and overall survival are superior to morphological imaging results.In the routine assessment of oncological treatment responses, it is becoming increasingly important for the radiologists to know exactly what kind(s) of treatment that the patient has received. Simply reporting changes in tumour size using RECIST is no longer sufficient considering the large percentage of patients who receive advanced and often combined treatment regimens.


Our patient presented dramatically with a previously unrecognized FAP complicated by heart failure requiring heart transplantation at the age of 49 years and liver transplantation at the age of 51 years. Direct DNA sequencing of the TTR gene showed a heterozygous Glu89Lys mutation in the proband and her daughter (published in Transplantation 2011).Longitudinal follow-up with clinical scores with ancillary testings.After her double transplantation, the patient reported over the 8 subsequent years slowly progressive increasing pain and loss of sensation in the feet, slow bowel habit, and delayed urine flow. On examination, we found orthostatic hypotension, sensory loss, muscle weakness, and mild atrophy in the distal lower extremities with reduced Achilles tendon reflexes. Nerve conduction studies revealed a mild decrease of amplitude of motor and absent sensory action potentials and normal velocities except for bilateral slowing within the carpal tunnels. The sympathetic skin response and Sudoscan responses to electrical stimuli was normal in the palms but not in the soles. No complications were seen, such as acute rejection, portal vein thrombosis, or infectious diseases resulting from administration of immunosuppressive drugs.As already described, some late-stage patients continue to show FAP progression even after liver transplantation, and longstanding disease is correlated with increased morbidity related to continuing amyloid fibril formation.


TARVA is an NIHR HTA funded portfolio randomised controlled trial (RCT) comparing total ankle replacement (TAR) and arthrodesis (fusion) surgery in NHS patients aged 50-85 with end-stage ankle arthritis. 328 patients will be randomly allocated to TAR or arthrodesis on an equal basis.Clinician and patient treatment equipoise is critical to recruit surgeons and patients successfully.The TARVA Trial team has developed novel surgeon and patient engagement techniques involving technology and multi-media tools to achieve our aims. Examples include an award-winning video, a white-labelled patient information brochure, professional newsletters and blogs, and a particular focus on the use of social networking tools to engage both investigators and patients.http://anklearthritis.co.uk).The impartial trial information video featuring consultant foot and ankle surgeons and patients who have undergone TAR or fusion surgery can be accessed through the trial website (The pilot phase began with the randomisation of the first patient in March 2015. An overview of our techniques alongside recruitment data accumulated until November will be presented at the ICTM conference.


Planning malaria interventions requires the prediction of likely impacts of different intervention strategies. Simulation models can provide such predictions but weak information about pre-control levels of transmission, intervention coverage and access to care often makes it challenging to correctly parameterize them. We consider a number of low malaria transmission sites in Madagascar, with available historical prevalence and entomological inoculation rate (EIR) estimates (by mosquito sampling), giving disparate estimates of historical exposure. Information about implementation of Long Lasting Insecticide Nets (LLINs) and Indoor Residual Spraying (IRS), and access to healthcare, collated from malaria surveys and on-going cross-sectional studies were used to parameterise simulations of malaria transmission, prevalence and burden within the OpenMalaria platform. Multiple parameterisations were considered using various sources of data for pre-intervention transmission level, intervention coverage and access to healthcare. In some sites the simulated impact of existing vector control programs matches reasonably well the malaria prevalence measured in a recent national survey. In others it predicts lower than observed prevalence, very likely because the models do not capture residual local transmission foci. The simulations suggest that the most cost-effective vector control strategy would be to scale-up LLINs or IRS only, depending on the transmission level. Indeed, preliminary results show no additional benefit of IRS where LLINs were used. These preliminary results suggest that historical prevalence data, combined with current coverage information are potentially adequate for planning intervention strategies. The outcome of intervention scale-up is essentially unpredictable if baseline information is poor. Reproducing the observed epidemiology of malaria through simulations both provides confidence in the use of the model but serves as a basis for prospective studies that support decision-making, including cost-effectiveness analyses.