Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete. Cells store fatty acids (FAs) as triacylglycerol and package them into cytoplasmic lipid droplets (LDs). New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates. Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g., exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain reactive oxygen species (ROS) within levels compatible with signaling while ensuring robust and reliable energy supply. Discovery consists of seeing what everybody has seen and thinking what nobody has thought.Albert Szent-GyorgyiThe role of lipids in human health, nutrition, and disease is taking center stage. Several circumstances including hotly debated issues concur to explain this unusual interest. Among them, pressing societal and biomedical issues concerning the epidemic proportions of obesity and related diseases in the United States and its increasing prevalence worldwide. Higher food consumption, decline in physical activity and a progressively aging population are among the social and behavioral roots of this phenomenon. Biologically, it adopts the form of a so-called “metabolic syndrome,” a set of comorbidities including upper body obesity, insulin resistance, dyslipidemia, and hypertension that increase the risk for developing type 2 diabetes, coronary artery disease, and stroke  utilization and intracellular signaling, have been broadly termed lipotoxicity , cancer, inflammatory disorders, neurodegeneration, and cardiovascular disease . In oxidative tissues such as the heart, TAG-derived FAs are utilized as an energy source, but they also serve as signaling molecules as well as building blocks for membranes and complex lipids.The FAs released during TAG catabolism are mainly used for β-oxidation and subsequent ATP synthesis via OxPhos in mitochondria . Lipid content is elevated in red compared with white skeletal muscles and increases in response to habitual exercise in both oxidative and glycolytic fibers. The “athlete paradox” consists of IMTG accumulation observed in endurance-trained athletes that retain insulin sensitivity irrespective of the fact that in some cases IMTGs exceed those measured in sedentary obese or T2DM obese patients  accumulation is not strictly a pathologic phenomenon (see below: The protein family of perilipins (Plin) is associated with LDs. As scaffolding proteins perilipins affect the spatial and metabolic interactions between LD and mitochondria Figure . DevelopThe Plin protein family, or PAT for perilipin/ADRP/TIP47, is constituted by Plin1 to Plin5, and droplets may contain various combinations of them  lipolysis and reduced catecholamine-stimulated lipolysis  is crucial for vital functions such as division, differentiation, contractile work and survival amongst others  and tricarboxylic acid (TCA) cycle activity. In turn, the decrease in NADH and acetyl-CoA (AcCoA) levels leads to an increase of the β-oxidation flux  complex by coronary vascular endothelial lipoprotein lipases Figure . Long chUpon entry into the cell, LCFA first gets activated by forming thioesters with coenzyme A (CoA), LCFA-CoA, and is either oxidized in the mitochondria via β-oxidation or forms TAG by esterification Figure . SubsequAfter its formation by CPT1, the long-chain acylcarnitine is translocated across the inner mitochondrial membrane by CACT that involves the exchange of carnitine for acylcarnitine. CACT has extremely high activity in most cell types with active β-oxidation , with acyl-CoA dehydrogenase exhibiting different substrate specificity for short-, medium-, long- and very long-chain acyl-CoAs , DAG, and ceramide] that are responsible for the impairment in insulin action rather than the IMTG pool contained in LDs   derived from β-oxidation in mitochondria. The higher energetic budget provided by the saturated FA palmitate (three times higher than from glucose when ATP/mol substrate is considered) in the form of reducing power provides electrons to antioxidant systems and the mitochondria respiratory/energetic machinery. In agreement with the prominent role of lipids on the intracellular redox status, it was shown that Palm determined a transition from oxidized-to-reduced cellular redox status in cardiomyocytes from type-2 diabetic (db/db) hearts abating ROS levels drastically  coupling as well as energy supply in the heart   .The occurrence of close contact between mitochondria and LD in the heart is remarkable because of its dependence on mitochondrial energetics preferentially fueled by FAs. More noteworthy though is the fact that these close contacts occur in the T2DM heart, where the dependence on fat fueling is even more prominent   of obese and T2DM patients (McGavock et al., Previous reports have linked ROS-mediated mitochondrial dysfunction to DAG and ceramide, two main products of lipid degradation (Coen and Goodpaster, Lipid metabolites can damage the respiratory chain leading to impaired energetic transition in mitochondria through their dual effect as uncouplers and inhibitors (Wojtczak and Schonfeld, 2 reaches a maximum following ADP stimulation (Figure Mitochondria are a main source of ROS but can also be their target. The RE is a major driving force of the crucial energy-redox link of mitochondrial function (Cortassa et al., n Figure . Under sn Figure . In excen Figure .2O2 emission levels 2-fold higher than controls, and exhibited lower respiration (Figure Mitochondria function in more oxidative environments in chronic diseases (Tocchetti et al., n Figure .Recent evidence supports physical and metabolic interactions between LDs and mitochondria mediated by the scaffolding protein Plin 5 (Wang and Sztalryd, Based on the premise of metabolic links extending beyond physical contact between mitochondria and LDs, we propose a model of metabolic channeling for lipid utilization by mitochondria. According to our model, metabolic channeling represents a way mitochondria can manage lipid affluence in an energetically and redox-controlled fashion. Qualitatively, the lipid utilization channeling model postulates that after TAG degradation, lipids are directly delivered for activation, transport and β-oxidation from the LD to the mitochondrion at the contact site Figure . The modFrom a structural standpoint, the model is based on direct and close contact between LDs and mitochondria involving their recruitment and surrounding of the LD. The model also postulates membrane fusion-mediated reorganization of intra-mitochondrial membrane and molecular components (Walther and Farese, Biochemically, the pathway of long-chain FAO to AcCoA is one of the longest unbranched pathways in metabolism, containing 27 intermediates between palmitoyl-CoA and AcCoA Eaton, . That thAn earlier proposal of metabolic channeling in β-oxidation was based on the detection of low concentrations of intermediates (Garland et al., Some aspects of the structural basis for a channeling mechanism in β-oxidation have been described (Ishikawa et al., Mitochondria, cells and organs have developed mechanisms that allow managing heavy influx of FAs within functionally reliable limits. The LD as a dynamic storage of FAs can also be seen as a protective mechanism employed by cells to avoid excessive intracellular concentration of FAs thus hindering their potential deleterious effects on mitochondrial function. The tight and reciprocal regulation of lipid storage and utilization is evidenced by genetic manipulation of perilipins indicating that their reduced expression leads to increased lipid oxidation and reduced accumulation of intracellular fat and adipose mass. On the other hand, however, excessive lipolysis and defective lipid storage promotes insulin resistance through mitochondrial FA overload and ROS overflow.Preservation of the intracellular RE is crucial for vital functions. Mitochondria play a decisive role as the organelle that specifically handles the highest amounts of oxygen processed by the organism thus prone not only to be the source but also the target of oxidative stress. Mitochondrial function needs to sustain energy supply reliably while releasing ROS levels compatible with signaling. However, lipids can derail both of these critical functions. Consequently, the hypothetical lipid utilization channeling model we are proposing herein satisfies the fundamentals of cellular and mitochondrial energetics and redox. In principle, diversion of excess lipids to LDs can be an effective cytoplasmic mechanism for “sequestering” FAs thereby helping to keep low concentration of lipotoxic intermediates resulting from lipid oxidation. Functionally, direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to ensure energy supply and redox control. Such a mechanism would avoid exceeding the lipid storage capacity thus becoming crucial for skeletal muscle or heart subjected to high workload, and therefore, heavy influx of FAs.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.


Peripheral artery disease (PAD) can result in limb loss within six months of diagnosis in a subset of patients who cannot undergo endovascular or surgical revascularization yet continues to maintain a marginal position in cardiovascular research. While a body of literature continues to grow describing the role of danger signaling and innate immunity in cardiac biology, the role of these pathways in the ischemic myopathy associated with PAD has not been extensively studied. The following report will review the current literature on the role of Toll-like receptor (TLR) signaling in cardiovascular biology as well as in nonischemic myopathy. While attenuation of TLR signaling has not been shown to be clinically useful in the treatment of infectious inflammation, it may show promise in the management of severe arterial insufficiency. Peripheral arterial disease (PAD) represents an advanced stage of atherosclerosis that is associated with increased risk of cardiovascular events and can result in clinically significant limb ischemia. In the United States, PAD affects approximately 5 million adults over the age of 40  and is pThe role of innate immunity in promoting angiogenesis and skeletal muscle recovery after ischemic injury and the ways in which it may be modulated to improve outcomes in PAD have not been extensively studied. The innate immune system, including Toll-like receptors (TLRs), is likely to play an important role in angiogenesis in response to limb ischemia from arterial disease. After ischemic injury, release of damage-associated molecular patterns (DAMPs) such as the nuclear protein high mobility group box 1 (HMGB1) from necrotic muscle and endothelial cells alerts the immune system via pattern recognition receptors like TLRs . TLRs meA number of papers have described potential roles for TLR signaling in the pathophysiology of cardiovascular disease, specifically addressing ways in which TLR activity can modulate systemic inflammation after ischemia, development of atherosclerotic plaques, and modulation of cardiac function following ischemic injury –22. OtheJaneway hypothesized that, during pathogen invasion, the host is able to mount an immediate response via preexisting receptors . PatternThe evolutionarily conserved nature of PAMPs allows the innate immune system to quickly recruit immune cells, such as macrophages and leukocytes, remove foreign substances, and initiate processes to protect the host from infection.In addition to PAMPs, DAMPs are a group of tissue or cell-derived molecules that are released following tissue injury that can activate the innate immune system through PRR. Immune responses are therefore initiated by tissue damage, trauma, and ischemia and are independent of the presence of invasive pathogens. HMGB1 is a nuclear protein and DAMP which functions in this way, promoting systemic inflammation following hemorrhage and hepatic ischemia-reperfusion injury , 29, 30.β (TRIF). MyD88 signals through interleukin-1 receptor-associated kinase (IRAK), an enzyme that results in translocation of NFκB to the nucleus in a rapid fashion. TRIF also can result in NFκB translocation but with slower kinetics [The Toll-like receptors (TLRs) are a class of PRRs known to recognize a number of bacterial and viral components, as well as endogenous danger signals , 37. TLRkinetics . TLR2 iskinetics . Both TLkinetics .TLR4 Asp299Gly) in which responsiveness to TLR4 ligands is diminished has been studied quite rigorously as possibly being associated with an attenuated risk of cardiovascular diseases [ TLR4 Asp299Gly and atherosclerotic risk, with the premise that polymorphisms may be protective against disease. The investigators found no definitive link between the polymorphism and attenuated atherosclerosis [The role of Toll-like receptor signaling in the etiology of atherosclerosis as well as in cardiomyocyte function following ischemic injury has been well documented , 42–45. diseases , 53. OneOnce present on a pathologic arterial lesion, TLR4 may mediate plaque activation and rupture . In one An important etiologic factor in the development of atherosclerosis is the incorporation of lipids into inflammatory cells and intimal lesions. TLR4 has been demonstrated to mediate uptake of minimally oxidized LDL (mmLDL) in circulation by monocytes, as well as in tissue by activated macrophages . CytoskeOther TLRs have been posited to play a role in atherosclerotic lesion formation. Citing inflammation as an initial insult for plaque development, Zimmer et al. investigated the role of TLR3, a receptor for viral double stranded RNA that signals through TRIF . TLR3 caToll-like receptors like TLR4 expression have also been demonstrated on cardiomyocytes. In 1999, Frantz et al. demonstrated TLR4 expression in both normal and failing myocardium . In thatIn contrast, activation of TLR4 through endogenous danger signals such as HSP60 has been shown to be proapoptotic and attenuated using antagonists of TLR4 activity . Adminis2O2-) induced cytotoxicity was promoted in cells treated with TLR2 antagonism, suggested by higher levels of annexin-staining cells. TLR2 also was shown to result in NFκB translocation in hamster ovary cells in response to H2O2, suggesting that reactive oxygen species may be a target of TLR2 signaling. In this study, activation of TLR2 was found to be protective in cardiac myocytes [TLR2 has also been shown to play a role in apoptotic pathways within cardiac muscle. In one study by Frantz et al., neutralizing antibodies to TLR2 enhanced oxidative stress in rat ventricular myocytes . Hydrogemyocytes . Others myocytes .κB and release of interleukin-8 in cultured cells. Finally, these researchers demonstrated high levels of TLR3 in inclusion bodies found within myocytes of patients with HIV induced inclusion-body myositis [A role for Toll-like receptor activity has been described in the etiology of myopathy and myositis, distinct from ischemic insults. In 2006, Schreiner et al. evaluated expression of TLRs 1–9 on myoblasts as well as human rhabdomyosarcoma cells. They demonstrated that muscle cells demonstrated low levels of TLRs 1–7 as well as TLR9 by analysis of protein as well as mRNA levels. Interestingly, expression of TLR3 could be upregulated with activation by its own ligand Poly:IC as well as interferon-gamma. Not surprisingly, the expression of TLR3 was largely intracellular, as it is an endosomal receptor for double stranded RNA . Activatmyositis .In one recent study by Zong et al., TLR4 was found to be expressed in the myoplasm of skeletal muscle biopsies taken from both healthy subjects as well as those from polymyositis (PM) and dermatomyositis (DM) patients. While the amount of TLR4 in patients and control subjects was not different, colocalization with major histocompatibility complex-1 (MHC-1) was seen only in PM and DM patients . FurtherIn another study evaluating mouse models of muscular dystrophy, TLR7 appeared to play an important role in inflammatory responses in dystrophin-deficient muscle cells. Specifically, myoblasts harvested from the diaphragm, gastrocnemius, and soleus of dystrophic mice (mdx) expressed a number of Toll-like receptors including TLR2, TLR4, TLR7, and TLR9. Additionally, myoblasts produced cytokines when activated by specific TLR ligands, including single stranded RNA (ssRNA), an activator of TLR7 signaling. When mdx mice were bred with MyD88 knockout mice, they demonstrated improved hindlimb strength, suggesting that this critical mediator of most TLR signaling contributes to the pathophysiology of weakness in dystrophic mice .TLR4 antagonism has not been proposed as a therapy for the management of ischemic muscle injury and its clinical sequelae. Furthermore, the majority of studies have investigated TLR function in the setting of cardiomyocyte ischemia and not the ischemia that affects skeletal muscle induced by peripheral arterial disease. For this reason, our laboratory has been invested in studying how danger signaling and TLR activity modulates responses to skeletal muscle ischemia, using mouse models of induced myocardial injury. If modulation of TLR signaling improves skeletal muscle function in the setting of ischemia, many patients with significant peripheral arterial disease who are not candidates for revascularization, or who are impaired by intermittent claudication, may benefit from this novel line of therapy.The innate immune system is likely to play an important role in angiogenesis, particularly in response to tissue ischemia. Ischemia in brain, muscle, and liver has been shown to result in release of the danger signal HMGB1 from its normal nuclear stores , 66. RelTLR4-mediated inflammation has been shown to be important in arteriogenesis, the maturation of preexisting collaterals in the setting of increased shear stress . This woWe have also demonstrated similar interplay between MyD88 and TRIF. Genetic absence of MyD88 results in diminished IL-6 levels after ischemia and attenuated recruitment of inflammatory cells. In contrast, TRIF absence resulted in a prolonged inflammatory state, with IL6 levels remaining elevated up to a week after the initial injury . FurtherModulation of innate immunity, danger signaling, and Toll-like receptor activity has not been a major focus in the management of PAD. However, inferences from their roles in cardiac pathology in both human disease and animal models suggest that their pathways may present new therapeutic targets for arterial disease. TLR4 antagonism has been tested in sepsis with disappointing results , but it A theoretical concern exists that overwhelming immunosuppression may occur by employing antagonists of TLR function to combat disease. However, antagonism of TLR signaling has been proposed and investigated in a variety of infectious disease processes without such consequences and is reviewed by Savva and Roger . BecauseWhether anti-TLR4 treatments would be effective in managing PAD remains to be investigated, but the suggestion represents a novel approach to treating patients with cardiovascular disease. While data from knockout mice suggest that diminishing TLR4 activity may offer promising results in improving both perfusion and muscle recovery in the short term, further studies employing exogenously administered TLR4 antagonists would be required in preclinical experiments. Modulation of TLR activity in cardiovascular biology remains an intriguing line of investigation, particularly as it relates to patients with severe lower extremity arterial insufficiency.


Classical studies have also shown that plant tissues have a remarkable capacity to undergo de-differentiation and proliferation in vitro, highlighting the fact that plant cell fate is highly plastic. This suggests that the mechanisms regulating fate transitions must be continuously active in most plant cells and that the control of cellular pluripotency lies at the core of diverse developmental programs. Here, we review how pluripotency is established in plant stem cell systems, how it is maintained during development and growth and re-initiated during regeneration, and how these mechanisms eventually contribute to the amazing developmental plasticity of plants.Plants are sessile organisms, some of which can live for over a thousand years. Unlike most animals, plants employ a post-embryonic mode of development driven by the continuous activity of pluripotent stem cells. Consequently, plants are able to initiate new organs over extended periods of time, and many species can readily replace lost body structures by  Summary: This Review discusses how pluripotency is established in plant stem cell systems, how it is maintained during development and growth, and how it is re-initiated during regeneration. To conclude, we discuss how the mechanisms controlling pluripotency might underlie the extraordinary developmental plasticity observed in plants.Over the past few decades, significant progress has been made in deciphering the regulatory mechanisms that control the development of complex multicellular organisms – an intricate process starting with the fusion of the male and female gametes, which form the zygote. This totipotent cell displays the remarkable capacity to self-renew and, after a series of cell divisions and cellular fate transitions, to give rise to all the cell types composing the adult organism. Further along the course of ontogenesis, populations of adult pluri- or multipotent stem cells are set aside, which allow the establishment, homeostasis and regeneration of tissues. Despite multicellularity arising independently in plants and animals, this basic developmental scheme is conserved between the two kingdoms. In line with this, common regulatory mechanisms controlling stem cell activities in a wide range of model organisms as well as among different stem cell niches within the same organism begin to emerge . It has in vitro plant tissue cultures revealed substantial cell fate plasticity and the basis for the regenerative capacity of plants  and the root apical meristem (RAM), are responsible for plant longitudinal growth and are located at the tip of the stem and root, respectively . In addiRecent studies have begun to elucidate the organisation of the SAM and the RAM, and the key mechanisms that regulate these stem cell niches. Whereas these studies have highlighted a number of differences between plant stem cell niches, they have also revealed some key common modules as well as regulatory mechanisms that appear to be shared between plant and animals stem cells.Shoot stem cells are the source of all aboveground tissues of a plant and are embedded in the SAM B. This dWUSCHEL (WUS), which is required for stem cell activity , which encodes a small peptide, and CLV3 in turn signals back to the OC by restricting the WUS expression domain  signalling , a member of the KNOTTED-like homeobox (KNOX) gene family, which has overlapping activities with KNOTTED1-LIKE HOMEOBOX GENE 6 (KNAT6) and BREVIPEDICELLUS (BP) (ASYMETRIC LEAVES 1 (AS1) and AS2, which in turn form a dimer and repress KNOX gene expression to promote cell differentiation  . STM repntiation . TherefoWUSCHEL-RELATED HOMEOBOX 5 (WOX5) activity  expression  and the Trithorax (trxG) families play opposing roles by promoting or restricting chromatin accessibility at gene regulatory regions, respectively. Typically, Polycomb Repressive Complex 2 (PRC2) promotes H3K27 and H3K9 methylation, leading to recruitment of the PRC1 complex, which ultimately promotes chromatin compaction and stable gene repression . HoweverArabidopsis leads to the development of a larger shoot stem cell system together with an additional cell layer of columella stem cells and multiple files of procambium in the root, collectively suggesting a delay in the onset of cell differentiation , which are negative regulators of cytokinin signalling, and thereby promotes its own expression (ISOPENTENYL-TRANSFERASE (IPT) enzymes are required for maintaining SAM cell proliferation potential downstream of STM, which promotes the expression of the gene coding for IPT7 (CYTOKININ OXYDASE/DEHYDROGENASE (CKX) gene family, and the reduction of CKX3 and CKX5 function consequently results in the formation of larger SAMs with a broader WUS expression domain , which interferes with the cytokinin signal transduction pathway and restricts the cytokinin-signalling domain to the centre of the SAM. Accordingly, loss of AHP6 function results in a SAM with stronger cytokinin response at the incipient primordia, which in turn impairs the precise timing of lateral organ growth , which encodes a GRAS domain transcription factor that is necessary and sufficient to cell-autonomously instruct QC fate and is a key player relaying inputs from cytokinin and auxin signals   C. The mo1 (ASB1) .A central function of stem cell niches is to allow the controlled amplification of cell lineages originating from a small number of stem cells. As plant meristems carry sub-populations of cells, which generate the whole plant body and exhibit divergent mitotic activity, precise spatio-temporal control of the cell cycle within meristems is required. Importantly, cells undergoing differentiation in plants do not simply shut down cell cycle activity, but frequently undergo multiple cycles of endo-reduplication, making cell-cycle regulation an essential component of the developmental program throughout the life of a typical plant cell. Recent research into the mechanisms controlling cell cycle progression within meristems has not only identified important molecular players, but has also highlighted that stem cell niches can respond dynamically to internal or external cues in order to adjust their cell proliferation rate.The stem cells at the centre of the dome-shaped shoot meristem (the CZ) divide slowly, with division cycles ranging from 36 h to 72 h, whereas cells in the peripheral zone (PZ) divide much more rapidly, with divisions occurring every 18 h to 48 h . The intCLV3 mRNA levels revealed that CLV3 not only constrains stem cell fate to the CZ but also restricts cell division rates in the PZ  was shown to control stem cell activity within the SAM in a cell-type specific manner. Uncoupling V system . The mecWUS expression, cytokinin stimulates stem cell proliferation in the SAM by promoting the G1-S transition through the regulation of the cell cycle machinery component CYCLIN D3 (CYCD3)  . In addiactivity . Anotheractivity . Althougactivity . HoweverCell cycle control is also important in the root meristem and serves diverse functions at different levels. First, stem cell maintenance at the root tip depends on asymmetric cell divisions, and their precise spatio-temporal control is required for the proper formation of specific tissue layers [reviewed by At the proximal RAM region, cells entering the transit-amplifying zone ramp up their division rate B. In addCYCD1.1 and CYCD3.3 , which, in turn, stimulates QC division through transcriptional activation of PHYTOSULFOKINE PRECURSOR 5 (PSK5), which encodes a member of the small peptide phytosulfokine family (BRASSINOSTEROIDS AT VASCULAR AND ORGANIZING CENTER (BRAVO), which is required for slow QC divisions. Mechanistically, BR signalling leads to phosphorylation of BRI1-EMS-SUPPRESSOR 1 (BES1), which dimerizes with BRAVO to repress BRAVO, thereby constituting a network module with switch-like properties   Heyman . Wherease family . In turne family . Second,operties  (Vilarraoperties . AlthougWUSCHEL-RELATED HOMEOBOX 9 (WOX9) controls stem cell activity by promoting the expression of WUSCHEL. Notably, WOX9 also integrates metabolic signals into stem cell behaviour, as the meristem arrest observed in wox9 mutant plants can be rescued by promoting cell cycle entry with sucrose . Originally identified in human cells, CAF1 is composed of three proteins: p150, p60 and p48. In plants, the CAF1 complex A is compt plants  , which, among other tasks, regulates nucleosome positioning and controls meristem activity   . By contpromoter A . It was originally used to describe the property of embryonic stem cells derived from the inner cell mass of mammalian embryos, which, after culture under appropriate conditions, can generate all cell types constituting the animal body. As stem cells progress towards a fixed lineage, their fate becomes more restricted to give rise to a limited subset of cell types (multipotent) before they finally differentiate.in vivo, suggesting that meristematic cells could indeed be pluripotent.A parallel definition is currently used for plant stem cells located in meristems, as they are able to give rise to all cell types of shoot or root, respectively. Whereas this behaviour is more comparable to multipotency in animals, mutations or ectopic expression of transcriptional regulators are able to overcome this fate limitation in vitro. These cells then can differentiate into a fully functional plant, supporting the idea that many plant cells are pluripotent. However, recent work suggests that callus cells are derived from a small number of stem cell-like cells distributed in all plant tissues, rather than a re-programming of terminally differentiated cells.In another analogy to animal cells, excised plant tissue is able to produce undifferentiated proliferating cells, termed callus, under appropriate phytohormone treatment Thus, whereas the terminology derived from classical studies in animals might not perfectly fit the behaviour of plant stem cells, it still seems a valid concept. In addition, the use of shared terminology greatly facilitates communication between researchers studying both kingdoms.Box 2.1759: First description of the shoot apical meristem by Caspar Wolff1926: Characterization of the phytohormone auxin by Frits Warmolt Went1939: Philip White develops the first plant tissue culture1955: First isolation of the cytokinin kinetin by Miller and colleagues1957: Controlled organogenesis from callus by Skoog and Miller1964-1965: Regeneration of complete plant from single isolated carrot and tobacco cultured cells by Vasil and Hildebrandt1991: Cloning of the shoot meristem maintenance gene KNOTTED1 by Hake and colleagues1993: First description of the Arabidopsis thaliana RAM cellular organization by the Scheres lab1995; 2003: Ablation studies by the Scheres and Kuhlemeier labs show self-organization properties of plant stem cell systems and strict dependence of cell fate on cellular position1998: Cloning of shoot stem cell maintenance gene WUSCHEL by Laux and colleagues2000: Description of the WUS/CLV3 feedback loop of communication by the Laux, Simon and Meyerowitz labs2005; 2008; 2010: Mechanisms of phytohormonal cross-talk underlying stem cell activity identified by the Sabatini and Lohmann labs2010: Identification of distributed callus founder cells in all plant tissues that promote in vitro proliferation and differentiation via a lateral root developmental program by the Meyerowitz labThe reprogramming of animal somatic cells into embryonic-like stem cells  highlights the fundamental capacity of many cell types to re-enter pluripotency from a differentiated state. Strikingly, the concerted activity of only four transcription factors  is sufficient to initiate the molecular reprogramming of animal somatic cells to a pluripotent state in vitro . Whereasents see , more reructures . Furtherructures . Convers tissues . Collecttors see .Box 1.Pin vivo. For example, auxin and cytokinin signalling are crucial for this process, and shoot regeneration is impaired in wus and pin1 mutant plants  function, which controls lateral root development, impairs callus formation (Although all plant tissues can potentially form callus, the question as to whether all plant cell types can be reprogrammed to a pluripotent state has been a matter of debate . Shoot rormation . These formation . FurtherFollowing the detailed description of the molecular mechanisms controlling plant stem cell pluripotency, one might wonder about the relevance of such an elaborate system for plant survival. Against this backdrop, we have to consider that, owing to their sessile mode of life, plants are not only subjected to substantial fluctuations in their direct abiotic environment but are also threatened by herbivores and pathogenic microbes. Consequently, plant development must be robust, yet plastic in face of these challenges, and pools of continuously active pluripotent stem cells obviously represent an ideal cellular toolkit for this kind of lifestyle. However, there is more to it, as even when stem cell systems are ablated physically or genetically, regeneration can take place, suggesting that other cells can acquire stem cell properties, similar to what is observed in a wide range of animal stem cell systems . This dyA final, important aspect to consider is the high degree of evolutionary conservation of the pluripotency network within the plant kingdom. This not only includes sequence conservation of important regulators, such as the WOX genes, between species, but also extends to the cellular and molecular design of the diverse stem cell systems within a given species. The fact that plant stem cell regulation largely relies on multi-purpose building blocks, such as the CLE-WOX-HAM module or the cytokinin signalling system, not only promises that discoveries made in reference plant species will be applicable to crop plants, but also that the experimental strategies limited to individual stem cell systems can inform us about the general mechanisms underlying the control of pluripotency in multiple stem cell niches.


For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes. Transcription is a multistep process and its regulation involves a balanced coordination of several molecular factors. Epigenetic modifications of chromatin, including histone acetylation, represent priming events in the cascade leading to gene expression and are governed by the antagonistic activity of two families of enzymes: the histone acetyltransferases (HATs) and histone deacetylases (HDACs)  and its expression was negatively correlated with a degree of skeletal muscles re-innervation and functional outcome   suppressed HDAC4 nuclear translocation, whereas a pro-apoptotic CaMK inhibitor stimulated HDAC4 nuclear accumulation. Moreover, as expected, an ectopic expression of the nuclear-localized HDAC4 led to neuronal apoptosis and repressed the transcriptional activities of survival factors in neurons like: MEF2 and cAMP response element-binding protein (CREB). In contrast, inactivation of HDAC4 by small interfering RNA or HDAC inhibitors suppressed neuronal cell death  to be approved for the cancer therapy of advanced cutaneous T-cell lymphoma  concurrent with an increased expression of HDACs   or by a direct binding followed by proteosomal degradation (class IIa) Figure . CrucialThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In both asthma and COPD, in the respiratory tract, TLRs are the primary proteins of interest associated with the innate and adaptive immune responses; hence, multiple treatment options targeting TLRs are being explored in an effort to reduce the severity of the symptoms of these disorders. TLR-mediated pathways for both COPD and asthma have their similarities and differences with regards to cell types and the pro-inflammatory cytotoxins present in the airway. Because of the complex TLR cascade, a variety of treatments have been used to minimize airway hypersensitivity and promote bronchodilation. Although unsuccessful at completely alleviating COPD and severe asthmatic symptoms, new studies are focused on possible targets within the TLR cascade to ameliorate airway inflammation.Asthma and chronic obstructive pulmonary disease (COPD) have both been historically associated with significant morbidity and financial burden. These diseases can be induced by several exogenous factors, such as pathogen-associated molecular patterns (PAMPs) . Endogenous factors, including reactive oxygen species, and damage-associated molecular patterns (DAMPs) recognized by toll-like receptors (TLRs), can also result in airway inflammation. Asthma is characterized by the dominant presence of eosinophils, mast cells, and clusters of differentiation (CD)4 Asthma and chronic obstructive pulmonary disease (COPD) are two respiratory diseases characterized by an accumulation of inflammatory cells in the respiratory tract, which leads to subsequent airflow obstruction  may be associated with the aberrant stimulation of immune responses, possibly contributing to the chronic inflammation seen in asthma  , hydrogen peroxide (H2O2), singlet oxygen (O2(a1Δg)), hydroxyl radical (∙OH) and superoxide , and molecular hydrogen (H2), may be an effective adjuvant treatment . The owner of this application is Max Planck Society. All other 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.


Calmodulin (CaM) is one of the most extensively studied Ca2+-sensing proteins and has been shown to be involved in transduction of Ca2+ signals. After interacting with Ca2+, CaM undergoes conformational change and influences the activities of a diverse range of CaM-binding proteins. A number of CaM-binding proteins have also been implicated in stress responses in plants, highlighting the central role played by CaM in adaptation to adverse environmental conditions. Stress adaptation in plants is a highly complex and multigenic response. Identification and characterization of CaM-modulated proteins in relation to different abiotic stresses could, therefore, prove to be essential for a deeper understanding of the molecular mechanisms involved in abiotic stress tolerance in plants. Various studies have revealed involvement of CaM in regulation of metal ions uptake, generation of reactive oxygen species and modulation of transcription factors such as CAMTA3, GTL1, and WRKY39. Activities of several kinases and phosphatases have also been shown to be modulated by CaM, thus providing further versatility to stress-associated signal transduction pathways. The results obtained from contemporary studies are consistent with the proposed role of CaM as an integrator of different stress signaling pathways, which allows plants to maintain homeostasis between different cellular processes. In this review, we have attempted to present the current state of understanding of the role of CaM in modulating different stress-regulated proteins and its implications in augmenting abiotic stress tolerance in plants.Intracellular changes in calcium ions (Ca The targets of CaM comprise a disparate group of proteins such as metabolic enzymes, kinases, transcription factors, etc., and have been reviewed extensively  is a prominent feature in most CaMs  that down-regulated CaM-KMT, the expression of this gene was shown to increase in response to auxin, salt-, and water stress , a highly conserved protein among eukaryotes  because higher concentration of this ion is toxic for phosphate-based energy systems  concentrations and fungal elicitor was observed to enhance the expression of soybean Ca2+-ATPase encoding SCA1 gene, whereas, addition of mannitol and KCl had no apparent effect  is an ubiquitously found non-protein amino acid. Characterized as a neurotransmission inhibitor of central nervous system in animals  apyrase, PsNTP9, localized to nucleus and also present extracellularly  in Arabidopsis, only the former showed interaction with CaM. The differential regulation of different isoforms by Ca2+-CaM may imply distinct role of these proteins in plants that warrants further elucidation. Overexpression of pea apyrase, besides resulting in enhanced growth and phosphate transport in transgenic plants , Beta vulgaris (BvM14-GlyI), Brassica juncea (GlyI) and rice (GlyII) has been reported to confer enhanced tolerance to salt-, metal-, osmotic- and oxidative stress in transgenic plants . This study revealed the presence of up to three different putative CaMBDs in several members of GlyI and GlyII protein families in Arabidopsis and rice , one of the ROS, is a secondary signal molecule that constitutes an important component of signal transduction pathways that enable the plants to respond to changes in external stimuli  homologs, respectively]  encoding different proteins have been identified in Arabidopsis  and approximately two- and three-thousand genes encoding these proteins have been identified in human and Arabidopsis AtCAMTA5  at both N-terminus (amino acid residues 73–90) and C-terminus  in plants may be the result of an adaptive strategy to regulate the cellular responses under conditions that lead to an alteration in Ca2+ signal. On the contrary, the presence of Ca2+-dependent CaM-dissociation domain in an isoform-specific manner suggests that different members of CAMTA proteins family may be playing distinct roles in Ca2+/CaM pathway, thereby providing versatility to plants in responding to different environmental conditions. We also speculate that since OsCBT shows 98.7% identity to another CAMTA protein in rice  was demonstrated to regulate expression of CBF2 by binding to a conserved DNA-binding motif CM2 or CG-element (vCGCGb) present in the ZAT12 promoter region of the latter  that are implicated in cold acclimation  showed enhanced resistance to virulent strain of Pseudomonas syringae. The atsr1 plants depicted early induction of PR1 (PATHOGENESIS RELATED 1) gene, after 6 h inoculation of P. syringae as compared with 24 h in wild type plants  gene that encodes a positive regulator of salicylic acid synthesis. Du et al.  that binds to AtSR1 and facilitates ubiquitination and degradation of the latter upon pathogen challenge , with 100–150 members reported in rice , in rice imparted drought tolerance without any associated yield penalty  was enhanced after Ca2+-dependent interaction with CaM , revealed that CaMBD (comprising of amino acid residues 471–512 in CBNAC) is not conserved among different members of this family. The selective presence of CaMBD among NAC proteins suggests that different members of this family are regulated differentially by CaM and perform distinct regulatory functions. Experimental analysis is required to determine the CaM-binding property of different NAC proteins so that the role of these proteins can be established in Ca2+/CaM signal transduction pathway.Plants contain another large family of TFs that are characterized by the presence of NAC domain  of AtMYB2 protein, abrogated the binding with GmCaM1. On the contrary, the interaction of AtMYB2 with GmCaM4 was inhibited only when both L69 and I78 were replaced with Arg  and G3  present in the C-terminus of AtWRKY7 is distinct from the classical CAMBDs described until now and is conserved in several group G2d members  responsible for CBP60g-induced drought tolerance in the transgenic plants and the role of Ca2+/CaM in its regulation are not known and need to be explored further. Apart from that, whether the ABA-hypersensitivity of transgenic plants was due to an increase in endogenous ABA or because of changes in the expression of proteins of ABA signaling pathway also needs to be addressed for deciphering the molecular basis of these observations. To conclude, these studies suggest that regulation of different TFs through Ca2+/CaM pathway is a crucial aspect of abiotic stress response in plants and unraveling of these mechanisms may lead to novel strategies for developing stress tolerance in different crops.Another plant-specific family of TFs that bind to CaM consists of CBP60 proteins , acts as a negative regulator of WUE since loss of function mutation in this gene in Arabidopsis resulted in enhanced tolerance to water stress  homolog PtaGTL1 suppressed the drought tolerance  following its binding to GT2-box (GGAAT) in the promoter of the latter  and TMM (Too Many Mouths) proteins  that binds to Arabidopsis GT-1-like transcription factor, AtGT-3b, is also observed in the promoter region of a soybean CaM gene, SCaM-4 . However, in silico and empirical analysis of promoter regions of different CaM genes for the presence of GT-1 elements and their regulation by GTL TFs in different plant species is required to validate this speculation.One of the most desirable features for drought stress adaptation in plants is to maximize water use efficiency  and tobacco CBKs was downregulated by CaM  CBK (ZmCaMK) but its substrate phosphorylation activity showed obligated requirement for Ca2+-CaM , a cytoplasmic RLK in Arabidopsis, was upregulated by salt- and cold stress, ABA, and H2O2 treatments , with at least 600 RLK homologs predicted in  Hardie, , is also Hardie, , whereas Hardie, . These p Hardie, . MembersOsMKP1; Katou et al., Arabidopsis  and TMKP1 , a different class of kinases that have been reviewed earlier (Pedley and Martin, er Table . The CAMer Table . Recent er Table , suggestArabidopsis and rice, respectively (Nover et al., Global warming is projected to result in an increase in average temperature (Angilletta, 2+]cyt, and Ca2+/CaM signal transduction pathway plays a crucial role in regulating the response of plants to thermal stress (Gong et al., 2+ signatures and CDPKs, followed by an activation of mitogen-activated protein kinases (MAPKs; Sangwan et al., 2+ has also been implicated in increased DNA-binding activity of HSFs through direct interaction (Mosser et al., 2+ in multiple regulatory pathways for controlling the heat shock response in plants. The role of Ca2+ in heat shock response has been further validated by the use of Ca2+-channel blockers, which provided evidence in favor of heat stress-induced influx of Ca2+ from the apoplast (Bush, Imposition of heat stress leads to elevation in cyt in plants, reported to occur within 4 and 7 min in wheat and rice, respectively, precedes the induction of CaM genes (Liu et al., 2+/CaM pathway in the regulation of HSPs. Wu et al. (2+]cyt, and expression of OsCaM1-1 and OsHSP17 in rice was abrogated by CaM antagonists, chlorpromazine and trifluoperazine. Although, this aspect needs to be validated independently, these findings suggest that Ca2+ homeostasis and expression of CaM genes may be under the control of feedback regulation (Figure In the absence of heat stress, HSPs in the cell are maintained at basal levels through repression of transcription of genes. Heat stress-induced increase in [Cau et al.  recentlyArabidopsis have provided evidence that H2O2 acts upstream of NO (Wang et al., AtCaM3 and functions upstream to Ca2+-CaM in the signal transduction pathway under heat stress (Xuan et al., 2+ (Liu et al., AtCBK3 in heat stress adaptation, Liu et al. (cbk3 mutants of Arabidopsis exhibited reduced thermotolerance and overexpression of AtCBK3 rescued the mutant plants (Table Arabidopsis exhibits Ca2+-dependent binding to CaM, and mutation in AtPP7 resulted in decreased thermotolerance (Kutuzov et al., Recent studies in u et al.  observedts Table . Another2+-dependent manner (Virdi et al., 2+/CaM pathway since the heat stress-induced increase in HSP90 levels was abrogated in the presence of exogenous Ca2+-channel blockers and CaM-antagonists (Virdi et al., 2+-CaM with HSP90, thereby releasing the HSF to activate the transcription of HSP genes (Virdi et al., Arabidopsis (Yamada et al., HSP genes was shown to be enhanced by exogenous application of a specific inhibitor of HSP90, geldanamycin, even in the absence of heat shock. Further evidence for validation of the proposed model was also provided by recent studies that reported enhanced expression of AtCBK3, AtPP7, AtHSF, and AtHSP genes in absence of heat stress in the transgenic Arabidopsis that overexpressed OsCaM1-1 (Wu et al., AtHSP90.3 lowered the expression of AtHsfA1d, AtHsfA7a, AtHsfB1, AtHsp101, and AtHsp17, leading to impaired thermotolerance of transgenic Arabidopsis (Xu et al., Heat shock response in plants also appears to be regulated by CaM through interaction with HSPs such as HSP70 (Sun et al., cis-trans isomerase activity (Schreiber, Arabidopsis, AtFKBP62 or ROF1, is heat-inducible and forms a complex with HSP90, which is then translocated from cytosol to nucleus following exposure to thermal stress (Meiri and Breiman, In addition to HSPs, plants are also reported to express heat-specific isoforms of FK506-binding proteins, FKBPs, which show peptidyl prolyl 2+ levels in response to unfavorable conditions is one of the important components of signaling pathways that allow plants to adapt to changing environmental conditions. Of the various Ca2+ sensors, CaM is one of the most well-characterized proteins that decodes Ca2+ signals and regulates activities of diverse proteins. Approximately, 3% of the proteome in Arabidopsis has been reported to be involved in Ca2+ signaling (Reddy et al., 2+ but also regulates its intracellular levels by modulating the activity of Ca2+-ATPases. Detailed investigations into the specificity of different CaM isoforms for different Ca2+ pumps may reveal the role of these interactions in generating stimulus-specific signals. In addition to Ca2+ transport, CaM also affects uptake of heavy metal ions through modulation of channel proteins such as NtCBP4. Engineering of these proteins offers a promising alternative for developing transgenic plants that are able to tolerate toxic levels of heavy metal ions. Further, how CaM regulates activities of apyrases and Gly proteins, that confer tolerance to xenobiotic compounds, is still a matter of speculation. Understanding the physiological implications of interaction of CaM with apyrases and Gly enzymes may unravel strategies for enhancing stress tolerance in crops by transgenic technologies (Table Modulation of intracellular Caes Table .2+-CaM, and regulation of NADPH oxidase and NAD kinase through Ca2+/CaM signaling pathway are indicative of complex feedback mechanisms that may allow the cells to maintain H2O2 homeostasis. Since ROS are also involved in biotic stress response, studies are required to determine the role of Ca+2-CaM in regulating cross-talk between biotic- and abiotic stress pathways that enable the cells to maintain appropriate levels of ROS. Regulation of TFs by Ca+2-CaM appears to be a crucial factor in stress adaptation response of plants. CaM-regulated TFs are involved in both activation and suppression of stress responses. For instance, CAMTA3 acts as a suppressor of plant immunity, whereas GTL1 functions as a negative regulator of drought tolerance (Table 2+-CaM-regulated TFs. Studies are also needed to understand the significance of different domains that facilitate interaction of TFs, such as NAC, with CaM in Ca2+-dependent and Ca2+-independent manner. This will provide insights into the mechanisms that regulate the interaction of CaM with these proteins, and may also allow engineering of specific domains for improving stress tolerance of crop plants. As of now, very few stress-regulated CaM-binding TFs have been identified but a growing body of data suggests that many more such proteins could exist (Table Production of ROS under stress conditions is one of the important factors that cause damage to cellular components. Relieving autoinhibition of catalase by Ca2+ and H2O2 homeostasis, and heat shock response by CaM appears to be mediated through complex feedback mechanisms involving interaction of several different pathways. It is evident that CaM is acting as a hub for integration of different signal transduction pathways that enable cells to respond to different stimuli and maintain homeostasis. System biology approach would, therefore, be helpful in developing a deeper understanding of these mechanisms. Another aspect that needs to be explored further is to understand the cross-talk between regulation of different stress-modulated CaMBPs and phytohormones. With advances in protein microarray, transcriptome, and genome sequencing technologies, the number of stress-regulated CaMBPs that are identified in economically important crops is expected to increase further. Analysis of these proteins by using functional genomics approaches will, therefore, be an important factor in unraveling novel candidate genes for improving stress tolerance of crops by biotechnological interventions.Regulation of several processes such as maintenance of CaThe 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.


Rapamycin, a FDA-approved pharmaceutical, has received significant attention as a possible anti-aging agent since the groundbreaking discovery in 2009 that rapamycin treatment significantly extends the lifespan of mice . ExcitinRictor, an essential protein subunit of mTORC2, in either the whole body of an adult mouse or specifically in the liver mimicked the effects of rapamycin, producing glucose intolerance and hepatic insulin resistance.In order to better understand the mechanisms underlying both the beneficial and deleterious effects of rapamycin, we focused our attention on the mechanism by rapamycin affects the control of glucose homeostasis. We determined that chronic treatment of mice with rapamycin caused hepatic insulin resistance, and using genetic models determined that disruption of mTOR complex 1 (mTORC1), the canonical target of rapamycin, was not the cause of this effect . This su−/−S6K1, as well as yeast and C. elegans with reduced levels of ribosomal subunits and translation initiation factors, have extended longevity . HoweveAging Cell, that the deletion of Rictor in all three models is deleterious for the longevity of males, but surprisingly does not negatively impact female lifespan [Rictor deletion might be a result of glucose intolerance, which we had previously observed in mice lacking hepatic Rictor, but surprisingly this was independent from the role of Rictor in lifespan. While we cannot yet rule out an mTORC2-independent role for Rictor, these results suggest that even partial inhibition of mTORC2 signaling, as observed in mice heterozygous for Rictor, is likely to impair the health and longevity of males. As outlined in Figure We demonstrate in our latest work, now published in lifespan . We initRictor deletion, and understanding this effect should permit the development of mTOR inhibition strategies that are equally effective in both sexes. Further, although it is clear that inhibition of mTORC2 results in premature mortality in males, the actual cause of death in these animals is unknown. Further complicating the picture, it remains possible that partial inhibition of signaling downstream of mTORC2 may even be beneficial in some contexts – it was recently shown that mice heterozygous for the mTORC2 substrate Akt1 have extended lifespan [C. elegans, the mTORC2 substrate SGK-1 can alternately promote or retard longevity depending upon the cellular and environmental context [Our findings leave open many questions regarding the role of mTORC2 and lifespan. Most significantly, we do not understand the basis for the sexually dimorphic effect of lifespan , while i context . A full


The plasma membrane contains diverse and specialized membrane domains, which include tetraspanin-enriched domains (TEMs) and transmembrane adaptor protein (TRAP)-enriched domains. Recent biophysical, microscopic, and functional studies indicated that TEMs and TRAP-enriched domains are involved in compartmentalization of physicochemical events of such important processes as immunoreceptor signal transduction and chemotaxis. Moreover, there is evidence of a cross-talk between TEMs and TRAP-enriched domains. In this review we discuss the presence and function of such domains and their crosstalk using mast cells as a model. The combined data based on analysis of selected mast cell-expressed tetraspanins  or TRAPs  using knockout mice or specific antibodies point to a diversity within these two families and bring evidence of the important roles of these molecules in signaling events. An example of this diversity is physical separation of two TRAPs, LAT and NTAL, which are in many aspects similar but show plasma membrane location in different microdomains in both non-activated and activated cells. Although our understanding of TEMs and TRAP-enriched domains is far from complete, pharmaceutical applications of the knowledge about these domains are under way. The plasma membrane, as well as other cellular membranes, is a very complex structure composed of a plethora of proteins and a variety of lipids organized into two asymmetrical leaflets. The proper function of cellular membranes depends on the composition of the leaflets and intermolecular communication of the membrane components. This is especially important in such complex processes as signal transduction from plasma membrane receptors into the cytoplasm and nucleus. Cellular membranes play a key role in signal transduction in both directions, inside-out and outside-in. For years it has been thought that the lipid composition of the membrane allows formation of signaling platforms that are critical for membrane functioning and that membrane lipids and proteins play key roles as membrane organizers  or MC lines. MCs are effector cells of the immune system that are able to react to external stimuli by rapid release of numerous allergy mediators from cytoplasmic granules and/or by production and secretion of a variety of cytokines and chemokines. Activation of MCs is initiated by binding of ligands  to plasma membrane receptors or their complexes . This binding initiates cell activation events, which involve a number of signal transduction molecules forming functionally and spatially connected units, called signalosomes. Receptor-mediated responses vary in strength and duration. For example, aggregation of FcεRIs by multimeric Ag-IgE complexes leads to phosphorylation of several proteins, followed by CaTetraspanins are an evolutionarily conserved superfamily of transmembrane proteins with characteristic features. They have four transmembrane domains and two extracellular loops, a small one (SEL) and a large one (LEL). LEL possesses a conserved CCG motif and at least two other cysteine residues that form disulfide bonds inside the LEL domain Figure . There aTetraspanins are known regulators of cell migration , whereas others are restricted e.g., to leukocytes . Only a few tetraspanins  have their distribution limited to specific tissue  are abundantly expressed on the plasma membrane of MCs and/or secretory vesicles Table  and sinc2+ release and tyrosine phosphorylation of several proteins including TRAP NTAL and dephosphorylation of ezrin/radixin/moesin (ERM) family proteins  cells, clone 2H3, also caused degranulation, but its F(ab)2 fragment not  did not affect migration toward Ag, suggesting that CD9 is not involved in this process. However, the possibility was not excluded that residual CD9 on the cell surface is involved in the proper Ag-induced migration  in vivo makes CD63 a possible therapeutic target  and KO MCs into mice of MC-deficient strain Kitw∕w−v and found out that mice reconstituted with CD63 KO MCs exhibited significantly decreased degranulation and PCA. CD63-specific antibody, unlike CD9-specific antibody, was unable to inhibit MC migration toward IL-16 , mAb specific for CD81 was found to down-regulate FcεRI-mediated degranulation in RBL-2H3 cells without affecting initial tyrosine phosphorylation of signal-transduction proteins, calcium response and synthesis of LTC4. The inhibitory effect of anti-CD81 antibody was confirmed Despite the fact that production of CD81 KO mice was described almost 20 years ago 2 domain-containing cytoplasmic as well as membrane-associated proteins and cytoskeletal components. As was already mentioned, most of the TRAPs possess a juxtamembrane palmitoylation motif that determines their solubility in non-ionic detergents, distribution in the plasma membrane, and some functional properties. The role of TRAPs in MC and leukocyte signaling has been recently extensively reviewed  kinase upon activation and serve as binding sites for SH2 domain-containing proteins including growth factor receptor-bound protein 2 (GRB2), phospholipase C (PLC)γ1, guanine nucleotide exchange factor VAV, ubiquitin ligase CBL, SH2 domain-containing leukocyte protein of 76 kDa (SLP-76), and GRB2-related adaptor downstream of SHC (GADS) , LYN, and c-KIT itself , production of cytokines and chemokines, and also decreased chemotaxis    and the actin cytoskeleton through the actin-binding domain (Abd) at the C-terminus. This binding is a highly dynamic process dependent on ERM 567/564/558 threonine phosphorylation/dephosphorylation. ERMs are released from the membrane when their inhibitory threonine is dephosporylated and ERMs are transformed from “open” phosphorylated to “closed” dephosphorylated conformation (McClatchey, Both tetraspanins and TRAPs were found to function as direct or indirect linkers of the plasma membrane and cytoskeleton. Co-immunoprecipitation studies showed that tetraspanins CD9 and CD81 are associated with ERM proteins, which directly interact with the cytoskeleton (Sala-Valdés et al., in vitro conditions. However, one needs to understand more on how TEMs and TRAPs-enriched domains function under in vivo conditions. This issue involves not only the influence of various soluble factors that are absent in cell culture media, but also the interaction with other cells and extracellular matrix components that could influence functions of the tetraspanins and their interaction partners. Such type of studies in the case of MCs will deepen our understanding of the cellular and molecular mechanisms underlying allergic diseases.Although knowledge about tetraspanins and TRAPs at the level of proteins and the corresponding genes and their regulators is increasing, their functioning as platforms of plasma membrane signalosomes and their mutual crosstalk are far from understood. The exact composition of TEMs and TRAPs-enriched domains is also poorly defined. This is in part due to highly dynamic nature of the membrane domains and the large number of various lipids involved. Lipids function not only as a matrix in which tetraspanins, TRAPs, and other membrane proteins are anchored, but also as modifiers of various proteins. When focusing specifically on signal transduction in MCs, there are also many poorly explored areas, which include potential roles of various post-translational modifications on topography and function of the tetraspanins and TRAPs and their interaction partners. An important area to explore is the role of miRNAs, noncoding RNAs, and other regulators of tetraspanins and TRAPs expression (Zhang et al., Both authors 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.


Low Grade Central Osteosarcoma (LGCO) is a rare subtype of osteosarcoma that is less aggressive than conventional osteosarcoma. The importance of LGCO lies in the fact that regarding microscopic and radiographic features, it occasionally simulates some benign jaw lesions and would consequently be misdiagnosed in many patients.The present study was conducted to collect the information and descriptive analyses related to ten cases reported between 1987 and 2010, including a sample reported by the authors emphasizing on diagnostic errors and the prevailing misdiagnosis. The aforementioned reports were gathered in full-texts through Google and PubMed search engines. The results of this study showed that the pathologists should exactly evaluate the clinical, radiographic, and histopathologic features in order to observe the evidence of invasion. Osteosarcoma is the most common primary malignant bone tumor with nonhematopoietic origin in children and adolescents-6 in whiThe significance of LGCO lies in the fact that regarding microscopic and radiologic features, it occasionally simulates some benign jaw lesions and is usually misdiagnosed as a fibrous dysplasia or sometimes other gnathic benign proliferations;-37 thus A limited amount of study has been published on gnathic LGCO. With respect to rarity of this lesion in any large series of investigating skeletal osteosarcomas, data relTherefore, this study reviewed the literature to collect the information and descriptive analyses related to 10 rare cases reported from 1987 to 2010 including a reported sample by the authors in 2010, with empEpidemiologic FeaturesThe investigated gnathic LGCO samples were in a wide age range from 18 to 69 years with the mean age of 35., 31-38MoClinical FeaturesSome studies have shown an equal frequency of gnathic osteosarcomas in both jaws,, 46 whilIn the investigated LGCO samples, mandibular involvement was twice as much as the maxilla (3.7= maxilla/mandible), 34-38 aThe main symptoms of conventional osteosarcoma are pain and swelling, 48-50 aRadiographic FeaturesLike other body bones,, 51-53 gBased on the radiographic findings, in two cases out of all investigated samples, there were misdiagnosis of a giant cell granuloma and a be24,32-34,36-38 were in favor of malignancy on the onset, but occasionally these important features were neglected  with a variable osteoid production that may be seen in abundant layers of irregular calcified or scattered layers of osteoid., 36With respect to the quality of osteoid distribution, the amount of present collagen, presence of myxoid changes, and the benign lesion it mimics, there are many patterns describing this tumor, including fibrous dysplasia-like, osteoblastoma-like, desmoplastic fibroma-like, parosteal-like, chondromyxoid fibroma-like; however, their occurrence is rare., 54-60The LGCO was diagnosed initially based on incisional biopsy in 5 cases , 35-36 oIn two investigated samples the lesion that had been first diagnosed as a fibrous dysplasia turned to LGCO with focal area of high-grade osteosarcoma in later recurrences with lesion development in adjacent structures.The proliferation of spindle cells with defined atypia and production of osteoid, chondroid, and formation of irregular osteoid trabeculae were observed., 37 One Differential Diagnoses and MisdiagnosisThe most important feature for correct diagnosis of gnathic LGCO and precluding the misdiagnosis with benign lesions is the observation of clinical symptoms as well as radiographic and histopathologic features of invasion. These features include poor margination of lesion, cortical bone destruction, and invasion into soft tissues. However,Evaluation of cases in this study showed that in most cases (80%) the pathologists were suspicious of a malignant lesion based on radiographic features ; althougRelatively, low cellular fibroblastic stroma in fibrous dysplasia and LGCO contained spindle cells that produce collagen; however, spindle cells in LGCO have a tendency to arrange in form of crossover groups which are not shown typically in fibrous dysplasia. Although cellular atypia is minimum in LGCO, it holds the most important diagnostic features , since fThe most important factor for differentiation of LGCO from fibrous dysplasia is to observe an infiltrative growth pattern. These patterns are described as surrounding pre-existed bone trabeculae with tumor, tumoral cells infiltration into bone marrow, cortex destruction by tumor, and tumor invasion into soft tissues., 57 BaseFibrous dysplasia-like type includes irregular spicules of woven bone that sometimes resembles the classic pattern of Chinese script writing., 57 HoweTherefore, while radiographic features suggest an aggressive lesion, the biopsy should contain peripheral areas of the tumor or the overlying cortical bone.Chondromyxoid fibroma-like osteosarcoma is a completely rare subgroup of low-grade osteosarcoma., 55 SimiSolid areas of an aneurismal bone cyst might sometimes be mistaken for LGCO. Aneurismal bone cyst is a benign lesion that hardly ever occurs in craniofacial area. Solid type of this lesion comprises only 5% of all cases and its occurrence in jaws is extremely rare. Aneurismal bone cyst is more cellular than LGCO and has a prominent mitotic activity.For early diagnosis of gnathic LGCO and preclusion of misdiagnosis as a benign lesion, the pathologists should exactly evaluate the clinical and radiographic features in order to observe the peripheral border, cortical bone destruction, and invasion to the soft tissues.An excisional biopsy, which includes overlying soft tissue, cortical bone, and the medullary portion of the lesion is needed and curettage should not be done. By thorough evaluation of various sections of specimen, two important features should be taken into account: 1- Osteoid production by tumor cells 2- Any observable infiltrative pattern. Therefore, the general histomorphologic appearance of the lesion might be more helpful than surveying cellular features.


Plasmodium, the agent of malaria, which kills around a million people each year, mostly young children in Africa. Most successful is Toxoplasma, which parasitizes nearly a third of the human population, making those people at risk of life-threatening complications, primarily encephalitis or pneumonia, in case of immunosuppression. Other apicomplexans of human importance include Cryptosporidium, Isospora, and Sarcocystis, which are opportunistic pathogens that cause severe diarrhea often associated with AIDS. Several apicomplexan parasites cause heavy losses in livestock, particularly Theileria and Babesia in cattle and Eimeria in poultry.Apicomplexans form a large phylum of parasitic protists, some of which cause severe diseases in humans. Most notorious is Most apicomplexans are obligate intracellular parasites. Their extracellular stages, called zoites, display several conserved features: they are elongated and polarized cells, their shape is maintained by a set of microtubules running longitudinally, and their anterior pole contains secretory vesicles, called micronemes and rhoptries, which secrete their content at the anterior tip of the parasite. Most zoites also share two unique properties among eukaryotic cells. They move on substrate by a gliding type of motility, i.e., without overt deformation of the cell shape, at speeds of several microns per second. They also typically invade host cells by forming a ring-like junction with the host cell membrane. Zoites slide through the junction into an invagination of the host cell surface that becomes the parasitophorous vacuole (PV) after pinching off from the host cell plasma membrane, in a process that takes less than a minute. Once inside the PV niche, the zoite can multiply into multiple new zoites that eventually egress the infected cell to infect new host cells.Plasmodium and Toxoplasma parasites.Much work has been performed since the late 1970s to understand the cellular and molecular bases of host cell invasion by apicomplexans, using various zoites as models. The overall invasion process encompasses several steps, including loose followed by intimate attachment, reorientation relative to the host cell surface, and organelle discharge with junction formation. The ultimate step, sliding through the junction inside the PV and called here internalization, is commonly viewed as powered by the zoite submembrane actin-myosin motor. The junction is thought to act as a traction point for the motor, to bridge the cortical cytoskeletons in the two cells, and to be made of parasite proteins conserved in the apicomplexan phylum. In this review, we confront these established notions with genetic data recently obtained in Plasmodium merozoites and their target cells, erythrocytes The first observation of a junction between an apicomplexan zoite and its host cell was made using Eimeria sporozoites. They showed that several activities at the zoite surface were dependent on parasite actin, including the posterior translocation (capping) of various surface ligands and beads Eimeria sporozoites was continuous with extracellular gliding ToxoplasmaPlasmodiumStudies in the 1980s focused on the highly motile Toxoplasma tachyzoites, which can be made to invade host cells at high frequency and synchronicity. The host cell was initially described as displaying no detectable actin reorganization and playing no active role during tachyzoite invasion Toxoplasma tachyzoites induced, specifically at the junction, host actin polymerization and recruitment of the Arp2/3 complex, an actin-nucleating factor, which is important for tachyzoite entry Toxoplasma protein that sequesters actin monomers in vitro The role of the host cell during zoite invasion has been studied mainly with Toxoplasma and Plasmodium has allowed the identification of some of the main players of the apicomplexan motor. The first proposed motor-substrate link was the thrombospondin-related anonymous protein (TRAP), a transmembrane protein of Plasmodium sporozoites conserved in the phylum that was found to be essential for sporozoite gliding Toxoplasma tachyzoites Plasmodium TRAP and its MIC2 ortholog in Toxoplasma with actin The motor is located in the space (∼20 nm) between the zoite plasma membrane and the inner membrane complex (IMC), a continuous layer of flattened vesicles apposed onto the microtubule structure typical of alveolates  [12]. ThPlasmodium merozoite Toxoplasma, called gliding-associated protein 45 (GAP45) Actin polymerization in apicomplexans has been studied in some detail. In these parasites, which contain a limited repertoire of actin-binding factors Plasmodium sporozoites exert on the surface during gliding indicate that zoite movement is not continuous, as predicted by the linear motor, but follows a stick-and-slip pattern The motor is still typically viewed as linear, i.e., as “linear arrangements of transmembrane proteins transducing the force generated by the actin-myosin motor and posteriorly capped,” as originally proposed by King Plasmodium merozoites have been described as being released from apical organelles, important for invasion and found at the junction. This is the case of several members of the micronemal erythrocyte binding like (EBL) family of proteins, such as Plasmodium falciparum erythrocyte-binding antigen 175 (EBA175) P. knowlesi Duffy binding protein (DBP) P. falciparum reticulocyte-binding like (RBL) homologue PfRh1 Plasmodium merozoite, typically relying on antibody inhibition and negative transfection experiments. In Toxoplasma, one member of the micronemal MIC family of proteins, MIC8, was shown to be specifically crucial for junction formation Numerous proteins in Plasmodium sporozoite and MIC2 in the Toxoplasma tachyzoite Toxoplasma tachyzoite, inactivation of MIC2 impairs but does not preclude motility or invasion Plasmodium motile ookinete stage that does not invade host cells, were shown to be important for gliding motility Since the junction is viewed as a traction point for the motor, other candidates for junction components were the transmembrane proteins involved in gliding motility, i.e., the TRAP family of proteins including TRAP, TLP, and TRAP-related protein (TREP) in the Toxoplasma tachyzoites, called rhoptry neck proteins (RON), which specifically marked the constriction around invading zoites in a ring-like manner  or knock-out (AMA1KO) zoites constructed are still invasive. AMA1KDP. berghei sporozoites invade hepatocytes 3-fold better than the wild type (WT) in vitro and in vivo KOToxoplasma tachyzoites and P. berghei merozoites are internalized into host cells indistinguishably from the WT, i.e. systematically form normal RON rings and are internalized at normal speed KOToxoplasma tachyzoites and P. berghei merozoites display reduced invasion efficiency KO tachyzoites might be secondary to a failure to form a normal junction leading to parasite detachment from the cell, based on immunofluorescence (IF) assays of rhoptry secretion KO tachyzoites formed an abnormal junction before detaching. AMA1KO tachyzoites observed by real-time imaging did not display abortive invasions and their attachment defect (upright instead of flattened positioning relative to the cell surface) concerned the entire population, irrespective of invasion Plasmodium, AMA1KO merozoites were 15-fold less adhesive to erythrocytes than controls after only 3 minutes incubation, which cannot be accounted for by failed invasions given that merozoite invasion efficiency is less than 5% Toxoplasma tachyzoites Plasmodium merozoites Plasmodium AMA1 binds erythrocytes In contrast, all Toxoplasma genome encodes paralogs of AMA1 and RON2 in specific combinations. In the tachyzoite, RON2 interacts with AMA1 or AMA2 and RON2L1 with AMA4 L2 interacts with AMA3 in a manner mutually exclusive with tachyzoite paralogs KO tachyzoites L1–AMA4 pair KOPlasmodium, the compensation theory appears particularly unlikely. The AMA1KD Flp/FRT sporozoites undergo AMA1 excision after parasite selection and yet are 100% invasive Plasmodium expresses no AMA1 or RON2 paralog. The protein most closely related to AMA1 is the trans-membrane protein MAEBL, with which it shares the presence of a cysteine-rich domain but differs by an unrelated cytoplasmic tail and the absence of RON2-binding ability. MAEBL was shown by gene targeting in both P. bergheiP. falciparumToxoplasma, and MAEBL in Plasmodium form a family of stage-specific, host cell–binding proteins.Recent work revealed that the L2 binding alters AMA3, including allosterically in its membrane-proximal domain If AMA1 primarily mediates zoite intimate binding to host cell surfaces, irrespective of RON2 interaction and junction assembly, what could be the role of the conserved and therefore important AMA1–RON2 interaction? AMA1 might still bind to RON2, possibly to help further stabilize the zoite prior to internalization, although direct evidence for such a step is still lacking. Alternatively, AMA1–RON2 interactions might serve to process AMA1 at the junction during internalization of the AMA1-covered zoite. For example, interaction with RON2 might serve to disengage the AMA1–host cell receptor interaction and help the zoite slide free inside the PV, separated from the vacuole membrane. In agreement with this, RON2 binding induces conformational changes in AMA1 TheileriaThe contribution of the apparently essential RON proteins is also unclear. They might be structural components of the junction, by linking it to the host cell cytoskeleton  allowed the generation of knock-down mutants and the functional dissection of individual components of the motor  and the release of the motor complex in the cytosol, does not abolish host cell entry MIC8 does not affect gliding motility but completely blocks host cell invasion due to an inability to form a junction The he motor . As alreToxoplasma, can invade host cells through a junction KO tachyzoites, in which the IMC detaches from the parasite membrane and MyoA and MLC1 become cytosolic, remain motile and also invade The current adaptation of a conditional recombination system based on dimerizable Cre has allowed the construction of a series of tachyzoite mutants completely lacking individual components of the motor complex, including MyoA, GAP45, MLC1, and Act1 +/H+ antiporters have been implicated in invasion and egress of host cells by Toxoplasma tachyzoites ToxoplasmaHow could tachyzoites with a deficient actin-myosin motor invade host cells? Until recently, actin polymerization and actin-myosin contraction were thought to underlie force generation during movement. However, this view is currently being challenged by new models, in which hydrodynamic forces generate changes in cell shape during motility Theileria sporozoites and merozoites, which lack an IMC and subpellicular microtubules and are not motile, invade host cells in any orientation, without a junction, and by a mechanism of circumferential zippering of parasite and host cell membranes Cryptosporidium sporozoites, are motile but rest on the host cell surface and induce the formation of host cell membrane folds that progressively encapsulate the “epicellular parasite” inside the PV +/glucose cotransporter and aquaporin 1, which generate localized water influx and are required for parasite invasion Another possibility that cannot be excluded is that the force for parasite internalization might originate from the host cell. If zoite internalization is powered by the host cell or by hydrodynamic forces, then the junction would no longer be connected to the parasite motor. In this case, the junction might serve as a membrane “seal,” possibly regulating protein processing upon entry into the PV, facilitating membrane dynamics, fluidity and curvature, and/or ensuring correct formation of the PV (New mutagenesis data question the current view that apicomplexan zoites invade host cells by a unique pathway involving their motor and AMA1–RON2 interactions as traction points at the junction. AMA1 appears not to be involved in junction function and the RON proteins are the only parasite proteins known to functionally associate with the junction. Whether the RON complex transmits force at the junction remains uncertain, though the evidence of a link between the RON proteins and the host cell cytoskeleton points to this direction. The conservation of the RON proteins in apicomplexans and of their essential role in invasion suggests a conserved molecular kit for junction formation. Still, there is no definitive evidence for such a conserved apicomplexan junction core, and at least part of its structure might be stage-specific. Whether the zoite provides all pieces of the junction, or whether the host cell also provides receptors, possibly located in specific microdomains, is also unclear.Toxoplasma, be generated in a motor-independent manner. Whether this holds true for other apicomplexan genera remains to be seen. In any event, apicomplexan invasion of host cells appears more complex than previously thought. Dissecting the process and its possible versatility will require establishing novel experimental approaches, including biophysical, and investigating unconventional force-generation means in zoites, as well as in host cells, that might facilitate, or even replace, the activity of the parasite motor.Moreover, it now appears that the force required for gliding motility and host cell entry might, at least in


The repair of infected bone defects is still challenging in the fields of orthopedics, oral implantology and maxillofacial surgery. In these cases, the self-healing capacity of bone tissue can be significantly compromised by the large size of bone defects and the potential/active bacterial activity. Infected bone defects are conventionally treated by a systemic/local administration of antibiotics to control infection and a subsequent implantation of bone grafts, such as autografts and allografts. However, these treatment options are time-consuming and usually yield less optimal efficacy. To approach these problems, novel biomaterials with both antibacterial and osteoinductive properties have been developed. The antibacterial property can be conferred by antibiotics and other novel antibacterial biomaterials, such as silver nanoparticles. Bone morphogenetic proteins are used to functionalize the biomaterials with a potent osteoinductive property. By manipulating the carrying modes and release kinetics, these biomaterials are optimized to maximize their antibacterial and osteoinductive functions with minimized cytotoxicity. The findings, in the past decade, have shown a very promising application potential of the novel biomaterials with the dual functions in treating infected bone defects. In this review, we will summarize the current knowledge of novel biomaterials with both antibacterial and osteoinductive properties. The repairing rate of a bone defect mainly depends on the size of a bone defect /nHA  composite. This composite exhibited a series of positive physicochemical and biological properties, such as good osteoconductivity, an elasticity for surgical press-fitting, and an attractive release profile for proteinaceous drugs  (PDLLA), as a sequential drug delivery coating with three distinctly different release profiles: (1) a burst release of gentamicin; (2) a burst release of IGF-I followed by a sustained release and (3) a slow release of BMP2 [in vitro evaluation suggested that the orchestrated delivery of various factors might prevent infections and stimulate bone healing [Over the past decades, metallic implants have been widely used in the fields of orthopedic and dentistry. Although most of them are modified via changing the roughness and hydrophilicity of titanium , metallirin/BMP2   and poly(acrylic acid) (MW ~ 450 kDa); and an overlying antibacterial layer by dipping into a sodium acetate solution containing gentamicin, poly(β-amino esters) (Mn ~ 11 kDa) and poly(acrylic acid) (MW ~ 1.25 MDa). On each layer, polymer/clay barrier layers were deposited using a programmable spray-LBL technique to provide a physical separation of the two components and control interlayer diffusion. Cationic chitosan or poly (MW ~ 200–300 kDa) and anionic laponite clay were alternately sprayed onto both osteoinductive and antibacterial layers. The clay barriers could lead to an about 50% reduction in bolus doses and a 10-fold increase in the time span of release. The temporal separation between the release of gentamicin and BMP2 was further enhanced by the laponite barrier, which resulted in a more physiological dosing of BMP2 [Using a layer-by-layer (LBL) principle, Min  of BMP2 .in vitro osteoblastogenesis and an in vivo osteogenesis. The antibacterial and osteoinductive drugs can be incorporated into co-delivery system through the following modes: (A) superficial adsorption/binding with a chemical bond; (B) an internal encapsulation; (C) a mixed carrying mode with a superficial adsorption and an internal encapsulation; and (D) a surface coating (The repair of infected bone defects remains a formidable challenge in the fields of oral implantology, maxillofacial surgery and orthopedics. Due to the less optimal efficacy of current clinical treatments, novel biomaterials with both antibacterial and osteoinductive properties have been developed in order to provide a viable treatment option. In comparison with the clinically used antibiotics, many novel antibacterial biomaterials showed very promising application potential due to their broader bactericidal spectrum, nearly no resistance and good biocompatibility. BMPs, particularly BMP2, are the most potent osteoinductive drugs to induce an  coating . By mani