Scientific studies have shown that non-conscious stimuli and representations influence information processing during conscious experience. In the light of such evidence, questions about potential functional links between non-conscious brain representations and conscious experience arise. This article discusses neural model capable of explaining how statistical learning mechanisms in dedicated resonant circuits could generate specific temporal activity traces of non-conscious representations in the brain. How reentrant signaling, top-down matching, and statistical coincidence of such activity traces may lead to the progressive consolidation of temporal patterns that constitute the neural signatures of conscious experience in networks extending across large distances beyond functionally specialized brain regions is then explained. During early childhood, our brain learns to perceive and represent the physical world. Such knowledge is generated progressively over the first years of our lives and a long time before we become phenomenally conscious of the Self and its immediate or distant environment . StatistBrain representations have been conceptually divided ,7,8 intoTheoretical models have tried to explain how such a selective process may work by suggesting that non-conscious sensorial and representational processes interact, through working and long-term memory, to generate brain learning and, ultimately, enable conscious experience ,11,12,13The following section presents evidence which supports the general idea defended here that non-conscious brain representation enables a selective process for either making representations accessible to, or suppressing them from, immediate consciousness. Then, SPA [Non-conscious processes in emotional, perceptual and cognitive function cover a wide range of observations, such as subliminal psychodynamic activation and non-conscious perception in hypnosis, subliminal semantic priming, effects of stimuli that are not consciously perceived on recognition processes, implicit learning, the perceptual integration of subliminal luminance or color targets , and phenomena of blind-sight in patients with striate cortical lesions, non-human primates, and normal observers Subliminal psychodynamic activation or SPA  describeSPA ,18. So-cSPA . Follow-SPA . ExplanaSPA . In otheSPA . i.e., neither drive- nor affect-related, stimuli to establish individual subjective thresholds for SPA [Theory and findings regarding SPA effects have received critical feed-back raising issues relating to the appropriateness of control and threshold stimuli in the various experiments ,24, the  for SPA . However for SPA . Partial for SPA .The implHypnosis and hypnotic suggestibility are phenomena that are not yet fully understood scientifically, but merit nonetheless attention. Hypnotic induction is not as such a subliminal process since the psychodynamic effects in this case are mediated via essentially supraliminal verbal suggestions. Hypnotic phenomena may reflect states of altered consciousness , and theMeasurable consequences of hypnosis intervention on cognitive function were also reported. With highly susceptible observers, hypnosis may produce an inhibition of correct responses in perceptual tasks with conflicting stimuli , correlaartifacts such as placebo, current knowledge points towards the general agreement that pain and distress perception is significantly lowered through hypnosis, in acute as well as chronic pain patients with high hypnotic susceptibility [A particular example showing how supraliminal perceptions or representations may become subliminal through guided shifts in awareness induced by hypnotic suggestions is the hypnotic control of physical pain, or hypnotic analgesia ,38. Resetibility . Recent tibility  in highltibility . Apart fEffects where a person’s conscious feelings, judgment, or choices are changed by non-conscious processing of images or messages have also been reported. Such is supposed to happen every time when we watch television or look at colorful adverts in a magazine or in the street . In a BBResearch on the influence of non-conscious perception on cognitive processes such as recognition, memory, and learning harks back to the experimental studies by Marcel, who investigated effects of visual masking on word recognition. These early findings  showed tversus-no-shock aversive conditioning) to non-consciously perceived faces were compared to activities triggered by aversive responses to consciously processed faces [Neurophysiological studies have provided insight into the brain correlates of semantic priming, using a combination of behavioral task and brain-imaging technique . It was ed faces . Specified faces . Similared faces . SubjectEvaluative conditioning is a particular case of emotional priming. Changes in emotional responses to stimuli that are supposed to be affectively neutral at the beginning can be primed in either a positive or negative direction, as in the controversial experiments by Underwood mentioned earlier here, by introducing a subliminal associative stimulus. After repeated association with stimuli carrying strongly negative or positive emotional connotations, the initially neutral stimuli then elicit emotionally biased responses. Some studies using evaluative conditioning have shown that the conscious evaluation of objects judged “neutral” at the beginning changed towards “negative” or “positive” judgments after a series of trials where the presumed neutral objects have been associated repeatedly with either a positive or negative, non-consciously perceived stimulus . Such obAccounting for the effects of non-conscious sensory stimuli on conscious behavior requires making a clear distinction between the sensory threshold, that is the psychophysical or statistical threshold for the detection of a stimulus as defined by Signal Detection Theory , and othEvidence for a shift from non-conscious to conscious sensory processing as a function of visual context has been found in psychophysical experiments with supraliminal contrast lines and subliminal contrast targets collinear with the lines. In these experiments, small vertical contrast lines (targets) had to be detected at fixed locations. In some conditions, the targets were presented together with a clearly visible, spatially separated collinear line (context); in others, the targets were presented alone (no context). While the contrast intensities of these targets were mostly subliminal, or non-detected without the context, they became detectable when presented with the context ,67,68. SHowever, neural pathways other than those projecting to striate cortex seem to be involved in generating the non-conscious processing of visual signals. In patients with cortical blindness caused by lesions to their primary visual cortex (striate cortex V1), residual responses to visual objects are found while observers are unable to report what they actually see . Such paNon-conscious brain processes are presumed to have the capacity of processing a majority of incoming signals and to hold them available for further processing, after selection, at the conscious level, which is limited in capacity ,12,13. VAdaptive resonance theory  conceiveEarlier cognitive theories had suggested that perceptions and sensations may feed into functionally separate processing streams, operating within or outside consciousness ,82. KihlThe idea of a strict functional segregation between the cognitive unconscious and conscious experience may have to be reconsidered. The brain appears to process information through circuits which interact at multiple levels of integration and across large distances in the brain, well beyond intrinsic functional specialization ,85,86,87Attempting to solve this problem, Grossberg  defined (1)Bottom-Up Automatic Activation is a mechanism for the processing and the temporary storage of perceptual input outside conscious experience. Through Bottom-Up Automatic Activation, a group of cells within a given neural structure becomes supraliminally active whenever it receives the necessary bottom-up signals. These bottom-up signals may or may not be consciously experienced. They are then multiplied by adaptive weights that represent long-term memory traces and influence the activation of cells at a higher processing level. Grossberg  original(2)Top-down Representation Matching is a mechanism for selectively matching bottom-up representations of incoming signals to learnt memory representations. Subliminal representations may become supraliminal when bottom-up signals or representations are sufficiently relevant at a given moment in time to activate statistically significant matching signals. These would then temporally match the bottom-up representations (coincidence). A positive match confirms and amplifies ongoing bottom-up representation, whereas a negative match tends to invalidate ongoing bottom-up representation . Top-dowi.e., a negative instead of positive coincidence index. Results from certain observations in motor behavior, which operates mostly outside awareness [The matching rules address the so-called attention-pre-attention interface problem  by allowwareness , highligwareness . This coDresp-Langley and Durup  suggesteSeveral approaches have suggested functional properties to explain how groups of neurons could produce specific temporal signatures through timing-dependent mechanisms where bottom-up processing is represented by the temporal firing activity of a specific coding assembly for a specific temporal window or duration. The activity traces of long-term memory representations would then consist of unique combinations of many such temporal sequences , generatJohn  suggesteThe temporal activity matching of non-conscious representations for the generation of conscious experience results from intra-cortical reverberation and may correlate with brain mechanisms which establish arbitrary but non-random departures from different functional regions or topological maps, which may be subject to functional re-organization. Thus, conscious experience is constructed on the basis of selective matching of non-conscious representations. This requires reentrant brain circuitry, long-range inter-cortical connectivity and, most importantly, functional plasticity. Such brain properties should make it possible to retrieve any given temporal signature through any set of coding cells. The neural basis of conscious experience is then identified with specific temporal properties of resonant activity patterns, arbitrarily determined through brain learning. stability versus plasticity dilemma [Reverberant circuits or loops in the brain have their own intrinsic functional topology ,97 and w dilemma . A candi dilemma .A multitude of sensory, somatosensory, and proprioceptive signals can be perceived simultaneously in a single conscious moment. The integration of such a variety of signals into a unifying conscious experience originate relies on the temporal linking of non-conscious representations, which have to be stable, yet, possess functional plasticity to enable the continuous updating of representations in response to changes in context. This allows the brain to learn and integrate new facts, events, and event properties. Clinical observations and case studies of the “phantom limb” syndrome  are consIt seems that during brain learning, the progressive selection of coincident activity traces of non-conscious representations builds some kind of access code for conscious experience. This is achieved on the basis of purely statistical criteria and progressively leads to fewer and fewer consolidated patterns for the increasingly complex signal coincidences the brain is to learn throughout its epigenetic development. When we are born, all brain activity is more or less arbitrary, but not necessarily random. During brain development, temporal activity patterns elicited by events in biophysical time will be linked to a variety of particular conscious experiences in a decreasingly arbitrary manner. Frequently activated patterns are progressively consolidated through a process of developmental selection ,13. The I prefer to think that non-conscious representations are encoded and decoded in the brain through mechanisms of neural learning which, although they may well be universal , expressNon-conscious brain representations are the basis upon which all conscious experience is built. The capacity of the human brain to generate such experience is a result of evolution, expressed through continuous interaction between the brain and its environment from early childhood on, progressively enabling conscious experience on the basis of the temporal matching of the neural activity traces of non-conscious representations. These matching processes take place in physiologically determined biophysical time, while psychological time associated with a conscious experience is entirely subjective. The brain learning process which ensures the continuity and the stability of representations and therefore that of conscious experience relies, as suggested by the model approaches discussed here above, on the progressive development of dedicated resonant circuits capable of reentrant signaling and space-time signal de-correlation. The latter ensures that the temporal activity traces of non-conscious representations are maintained in the brain independently from functional specialization or spatial cortical maps. The dedicated resonant circuits that are necessary to achieve this are progressively and arbitrarily formed in the brain. Although their intrinsic functional properties are universal and pre-wired, their expression strongly depends on epigenetic factors. The latter determines the amount of long-range connectivity between neural structures activated by bottom-up signals at a given moment in time, and distant structures not directly activated by bottom-up input. When a critical amount of such long-range circuitry is consolidated, reentrant signaling will trigger conscious experience. This happens whenever non-conscious representational traces statistically match the temporal signatures of learnt and sufficiently stable long-term memory representations. Further investigation of experience related temporal activities in the thalamo-cortical and cortico-cortical pathways of the brain might one day allow tracing such mechanisms.


Bone is an integral part of the osteoarthritis (OA) process. We conducted a systematic literature review in order to understand the relationship between non-conventional radiographic imaging of subchondral bone, pain, structural pathology and joint replacement in peripheral joint OA.A search of the Medline, EMBASE and Cochrane library databases was performed for original articles reporting association between non-conventional radiographic imaging-assessed subchondral bone pathologies and joint replacement, pain or structural progression in knee, hip, hand, ankle and foot OA. Each association was qualitatively characterised by a synthesis of the data from each analysis based upon study design, adequacy of covariate adjustment and quality scoring.In total 2456 abstracts were screened and 139 papers were included . BMLs, osteophytes and bone shape were independently associated with structural progression or joint replacement. BMLs and bone shape were independently associated with longitudinal change in pain and incident frequent knee pain respectively.Subchondral bone features have independent associations with structural progression, pain and joint replacement in peripheral OA in the hip and hand but especially in the knee. For peripheral OA sites other than the knee, there are fewer associations and independent associations of bone pathologies with these important OA outcomes which may reflect fewer studies; for example the foot and ankle were poorly studied. Subchondral OA bone appears to be a relevant therapeutic target.CRD 42013005009PROSPERO registration number: The online version of this article (doi:10.1186/s13075-015-0735-x) contains supplementary material, which is available to authorized users. Osteoarthritis (OA), the most common form of arthritis, is a major cause of chronic pain and disability. OA confers a huge burden on both individuals and health economies , 2. TherThe subchondral bone in particular is intimately associated with hyaline cartilage and therefore a tissue of great potential interest. Conventional radiographs are known to be relatively insensitive to the structural features of OA , in partWe therefore wished to comprehensively review the literature on subchondral bone structure assessed with all non-conventional radiographic imaging modalities, examining the common sites of peripheral OA and describing the relationships between imaging-detected subchondral bone features and joint replacement, structural progression and pain.A systematic literature search of Medline from 1950), EMBASE (from 1980) and the Cochrane library databases until September 2014 was performed. A full description of the search terms used is recorded in Additional file 950, EMBAThe articles identified by the preliminary search were screened by two reviewers  for relevance and for references not identified by the preliminary search, although no additional citations were found. Discordance in opinion was resolved by a third reviewer (SK). We applied the methods for reporting meta-analyses of observational studies in epidemiology that are recommended by the Cochrane collaboration , 16.Data extraction was performed by two reviewers  as described in the Supplementary methods ‘data extraction’ , as described in Supplementary methods ‘Quality assessment’  and its association with pain or structural progression and joint replacement was provided based on the study design, adequacy of adjustment for confounders  and quality score as described in the Supplementary methods ‘Best evidence synthesis’  or negative (−) accordingly. If no association or inconclusive findings were described this was reported as no association (NA) or no conclusion (NC) respectively.The Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram in Fig. In only 12 studies did the mean age fall below 50 years –29. MostConcordance of opinion in quality scoring was observed in 2,040 (89 %) of the 2,242 scoring items assessed, which are recorded in Additional file The association of bone features with structural progression and joint replacement are described in Tables MRI : in prospective cohorts with high- quality, well-adjusted analyses the presence and increasing size of baseline BMLs and incidence of BMLs conferred greater odds of structural progression , 70–73. MRI : in one prospective cohort with high quality and well-adjusted analysis, the increasing size of osteophytes conferred greater odds of structural progression of OA . In loweMRI : one prospective, well-adjusted, but below-average-quality cohort analysis found an association with baseline attrition severity and structural progression that became insignificant after covariate adjustment . The unaMRI : in prospective cohorts with high quality well-adjusted analyses, greater baseline tibial plateau bone area conferred greater odds of structural progression of OA and incidence of TKR , 112. ThMRI and CT  studies: two prospective cohorts with well-adjusted but below-average-quality analyses of cysts reported no association with structural progression of OA before or after adjustment , 93. TwoMRI : one prospective cohort, unadjusted, below-average-quality analysis reported increasing bone volume fraction, trabecular number and thickness and decreasing trabecular spacing were associated with structural progression . The samDXA and CT : two prospective cohorts with well-adjusted but below-average-quality analyses reported that increasing tibial subchondral BMD is associated with structural progression of OA , 68. In Scintigraphy : prospective cohorts with high quality analyses found greater late-phase bone signal was associated with structural progression of OA, with no or inadequate covariate adjustment , 38, butOne cross-sectional, well-adjusted analysis identified an association between greater femoral and tibial bone width and elevating tibial plateau, and greater structural severity . In summThe association between bone features and pain is described in Tables MRI : in 3 prospective cohort, well-adjusted, high quality analyses the baseline or longitudinal increase in size of BMLs was associated with longitudinally increasing knee WOMAC pain severity , 72, 124MRI : one prospective cohort, unadjusted, below-average-quality analysis reported increasing baseline osteophyte size was associated with increasing WOMAC pain severity score . In wellMRI ; cross-sectional analyses found greater attrition was associated with greater pain severity, without covariate adjustment , 138, buMRI : one prospective, well-adjusted, high quality analysis found the femoro-tibial articulating surface mismatch was associated with incident frequent knee pain . One unaMRI : one prospective cohort, unadjusted, low quality analysis found no association between bone cyst size and increasing WOMAC pain score . In mostOne inadequately adjusted cross-sectional analysis found an association between the elevation of the lateral tibial plateau and severity of pain . In summThe association between bone features and structural progression is described in Tables MRI : one well-adjusted, high quality analysis of a prospective OA case series, found that increasing BML number and size in the interphalangeal joints at baseline conferred greater odds of structural progression of OA . Two adjOne cross-sectional, adjusted analysis found greater MRI attrition or MRI osteophyte number and size was associated with greater structural severity . HoweverThe association between bone features and pain is described in Tables MRI : one well-adjusted, high quality analysis of a prospective OA case series, found that BML number and size at baseline was not associated with longitudinal change in hand pain . One adjOne cross-sectional, adjusted analysis found no association between bone features, osteophytes, attrition or cysts observed on MRI, and pain severity . In summScintigraphy : one cross-sectional unadjusted analysis found no significant association between bone signal in the hands and severity of pain. In summary, bone scintigraphy signal is not associated with severity of pain in hand OA.The association between bone features, and structural progression and joint replacement is described in Tables MRI : one well-adjusted  and one One unadjusted cross-sectional analysis found greater MRI bone volume fraction, trabecular thickening, trabecular number and lower trabecular spacing were associated with greater structural severity of OA . In summDXA : one well-adjusted  and one Hip bone shape : in two prospective cohort, well-adjusted, high quality analyses increasing asphericity of the femoral head  was associated with total hip replacement (THR)  or with The association between bone features and pain is described in Tables MRI : two cross-sectional, unadjusted analyses found that increasing semi-quantitative BML scores were associated with greater severity of pain , 152. InOne cross-sectional, unadjusted analysis found that increasing semi-quantitative cyst scores on MRI were associated with greater severity of pain . In summThe association between bone features and structure is described in Table Scintigraphy : one well-adjusted  and one This systematic review is the first to have incorporated quality scoring alongside statistical adjustment in the comprehensive examination of the relationship of subchondral bone pathology with both structural progression of OA and pain for all non-conventional types of radiographic imaging of peripheral joints with OA. This systematic review has concluded that there are independent associations between imaging-assessed bone pathology and structural progression and pain in the knee, hand, and hip.Subchondral bone pathology may lead to cartilage degeneration by altering the biomechanical force distribution across joint cartilage, or disruption of the osteochondral junction and release of soluble biomediators influencing the cartilage , 154. InOsteophytes represent subchondral bone hypertrophy typical of OA. They represent endochondral and direct bone formation and create a circumferential increase in bone area around each knee cartilage plate, particularly on the medial side in OA , which cIn terms of bone morphology, knee OA is associated with shallow trochlear patellar grooves in multiple epiphyseal dysplasia . These fWe found that bone attrition and cysts were associated with structural progression or severity, but not after covariate adjustment, which included other OA subchondral bone features. This suggests these bone features are an epiphenomenon of the pathogenic process of structural progression rather than a primary cause. This hypothesis is supported by bone cysts and attrition frequently occurring synchronously with BMLs , 138 andIncreasing bone volume fraction, trabecular number and thickness, but decreasing trabecular spacing on CT and MRI studies were associated with structural progression. These specific associations concur with numerous histological analyses of peripheral joint OA –171.Subchondral bone, particularly BMLs, have been found to be associated with pain in knee, hip and hand OA. However, some analyses, in which pain was measured using heterogenous pain outcomes, report an absence of longitudinal or cross-sectional association with BMLs , 173. FuThe independent association between a mismatch of the femoral and tibial articulating surface areas and incident frequent knee symptoms indicates that bone shape may predict not only the incidence of radiographic knee OA , but alsIn terms of limitations, stratifying observational studies by quality may artificially create relatively high quality studies from a collection of generally low quality studies. However the distribution and summary statistics of quality scores indicate a suitably broad range of quality, particularly in the influential cohort studies with a mean of 54 % and range of 22−83 %. The decision to exclude articles reporting analysis of association that included fewer than 20 patients with OA may seem arbitrary. However, several papers report associations with the presence or absence of pain or structural progression based upon small numbers of patients. Our threshold decision reflects the absence of specific guidelines on how to exclude such papers, with inherent risk of imprecision, in the context of heterogenous populations and statistical analyses. Had these papers been included there would have been no change in any of the conclusions in Table Publication bias could not be assessed with a funnel plot as there were insufficient results for odds and relative risk ratios. The heterogenous nature of the measures of bone features and structural or pain outcomes precluded a meta-analysis or calculation of an effect size. This was because there were insufficient analyses describing the same association between the same bone features and outcome measure pair.In conclusion subchondral bone plays an integral role in the pathogenesis of OA. BMLs, osteophytes identified on MRI and tibial bone area are independently associated with structural progression of knee OA. BMLs and tibial bone area are independently associated with TKR. BMLs are independently associated with structural progression of hand OA and 2D hip bone shape is associated with progression of structural hip OA and THR. BMLs are independently associated with longitudinal change in severity of pain and femorotibial articulating area mismatch is independently associated with incident frequent knee pain. These bone features may be used in the future for targeting treatment, stratifying patients into those most in need of OA modification and measuring treatment response.Additional file 1:Supplementary material: supplementary methods and results. 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Arabidopsis thaliana. Emerging from these studies is a picture whereby complex crosstalk and induced hormonal changes mold plant health and disease, with outcomes largely dependent on the lifestyle and infection strategy of invading pathogens. However, recent studies in monocot plants are starting to provide additional important insights into the immune-regulatory roles of hormones, often revealing unique complexities. In this review, we address the latest discoveries dealing with hormone-mediated immunity in rice, one of the most important food crops and an excellent model for molecular genetic studies in monocots. Moreover, we highlight interactions between hormone signaling, rice defense and pathogen virulence, and discuss the differences and similarities with findings in Arabidopsis. Finally, we present a model for hormone defense networking in rice and describe how detailed knowledge of hormone crosstalk mechanisms can be used for engineering durable rice disease resistance.Phytohormones are not only essential for plant growth and development but also play central roles in triggering the plant immune signaling network. Historically, research aimed at elucidating the defense-associated role of hormones has tended to focus on the use of experimentally tractable dicot plants such as  Plant hormones are small signaling molecules that are essential in the regulation of plant growth, development, reproduction, and survival. They not only orchestrate intrinsic developmental programs but also convey environmental inputs and drive adaptive responses to a wide variety of biotic and abiotic stresses. Plants typically respond to pathogen infection or herbivore attack with a complex scenario of sequential, antagonistic, or synergistic action of different hormone signals leading to defense gene expression . This inArabidopsis thaliana. In this model species, the production and joint role of salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) upon pathogen attack is well studied and these three hormones are considered to be the key players in the regulation of the disease signaling pathways. Following microbe perception, plants produce a complex blend of SA, JA, and ET, with the exact combination seemly depending on the infection strategy and lifestyle of the invading pathogen. Although there are exceptions, SA is usually effective against biotrophic pathogens that feed on living plant tissues, whereas cell death-provoking necrotrophic pathogens are commonly deterred by JA- and ET-dependent defenses  are starting to provide important new insights, often revealing unique complexities  and effector-triggered immunity (ETI). PTI is triggered by perception of invariant pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs). Several PAMPs have been identified thus far, including bacterial flagellin, lipopolysaccharides (LPSs) and elongation factor Tu (EF-Tu), fungal chitin and oomycetes cellulose-binding elicitor proteins . PAMPs aArabidopsis which are impaired in the biosynthesis, perception or signaling of specific hormones have demonstrated the central importance of plant hormones in the regulation of these downstream immune events. Upon pathogen attack, plants synthesize a complex blend of hormones, leading to the activation of distinct sets of defense-related genes  that do not change significantly upon pathogen attack , but increase by two orders of magnitude following infection biotrophic bacterial leaf blight pathogen Xanthomonas oryzae pv. oryzae (Xoo) and the necrotrophic root pathogens Pythium graminicola and Hirschmanniella oryzae . Arabidopsis PAD4 encodes a lipase-like protein that functions in ETI and basal immunity against biotrophic pathogens (Xoo and the hemibiotrophic leaf streak pathogen X. oryzae pv. oryzicola (Xoc) does not involve SA-responses, but is associated with the accumulation of JA and the expression of JA-responsive genes.Considerable differences between rice and athogens . AtPAD4 athogens . Recent athogens . Unlike Arabidopsis, including the master regulatory protein NPR1. During SAR, SA-induced redox changes reduce the intermolecular disulphide bonds that normally keep NPR1 in an inactive oligomeric state in the cytosol  is the closest homolog of AtNPR1 . Ectopic and Xoo . By contreatment .Arabidopsis where nearly 99% of all BTH-responsive genes are controlled by NPR1 biotrophic pathogens e oryzae . Althougext cell .Rhizoctonia solani. OsWRKY30 biotrophic and necrotrophic rice pathogens, several reports indicate that SA–JA antagonism is conserved in rice. In roots, SA attenuated JA-induced expression of the rice r OsERF1 . Furtherr OsERF1 . FurtherahG rice .Arabidopsis counterpart, overexpression of OsNPR1 is characterized by strong activation of SA-responsive genes and concomitant suppression of JA marker genes , showed increased resistance to both Magnaporthe oryzae and R. solani, whereas silencing of ET biosynthesis genes or the central ET signal transducer OsEIN2b rendered plants more susceptible against Magnaporthe oryzae and the bacterial pathogen Burkholderia glumae  strongly promotes disease development in this interaction, whereas genetic or pharmacological disruption of ET signaling resulted in enhanced resistance , and CKs, were historically best studied for their role in growth and development and only recently emerged as additional players in plant–microbe interactions. Although their precise role and function in orchestrating plant defense is still elusive, recent data are now beginning to unveil how these ‘developmental’ hormones modulate host immunity, and how microbe-induced perturbations of these classic growth regulators contribute to virulence.Arabidopsis imply that auxin attenuates (hemi)biotroph resistance but enhances plant defenses toward necrotrophic pathogens , are a major class of plant hormones that control a range of cellular processes, including apical dominance, tropistic growth, lateral root formation, vascular tissue development, and regulation of plant senescence. Thus far, studies on athogens . In comp disease . Like ma disease . In plan in rice . Up to n and Xoc .Arabidopsis, auxin is widely believed to antagonize SA-mediated defenses against biotrophic pathogens .In addition, trade-offs may be circumvented by engineering transgenic rice lines that are designed to neutralize microbial hormone intervention strategies. Such proactive response necessitates the identification and precision engineering of core pathogen-modulated hormone signaling elements and re-wiring these components to promoters specifying precise, temporally and spatially controlled responses to pathogens . InterfeTo prevent microbial manipulation of these pathways, one could envisage creating a dominant hormone-insensitive phenotype, either via local and timely disruption of hormone perception or through ectopic expression of re-engineered negative regulators of hormone signaling such as ABA-repressing Clade A protein phosphatase 2Cs (PP2C). Upon ABA binding, a family of cytosolic ABA receptors commonly known as PYLs (PYRABACTIN RESISTANCE LIKE) bind to and inhibit the active site of PP2Cs. This alleviates negative regulation on the PP2C target sucrose non-fermenting related kinase 2 (SnRK2), leading to activation of ABA signaling . InteresA similar strategy could be followed for SLR1 and Aux/IAA proteins, which function as the central repressors of GA and auxin signaling, respectively. Upon hormone perception, these negative regulators are targeted by cognate F-box proteins for polyubiquitination and subsequently degraded by the 26S proteasome, thus relieving their repressive effect. Structural and predictive modeling have revealed the domains and residues involved in SLR1 and Aux/IAA protein–protein interactions . TherefoArabidopsis and other dicot plants. However, as illustrated throughout this review, the conceptual framework emerging from these studies does not always translate to monocot systems (Table 1). While underscoring the importance of using alternative models systems, the unique complexities associated with defense networking in rice call for a re-evaluation of overly generalized defense models.Over the past decade, significant inroads have been made in our understanding of hormone defense signaling in Figure 1). Most conspicuously, although hyperactivation of one can attenuate the other, synergistic SA–JA interactions seem to prevail in rice and the two hormones are effective against both hemibiotrophic and necrotrophic rice pathogens. Moreover, unlike in dicots, we are unaware of any reports showing negative effects of SA or JA on rice pathogen defenses. Therefore, it is not inconceivable that both hormones function as endogenous priming agents that amplify infection-induced defense reactions regardless of the lifestyle of the invading pathogen. In contrast, ET can have both positive and negative effects on rice disease resistance that are seemingly independent of the pathogen’s parasitic habits.Contrary to the classic binary defense model with SA and JA playing opposite roles in biotroph and necrotroph resistance, respectively, innate immunity in rice appears to be controlled by a much more complicated signaling network that supports no clear dichotomy between the effectiveness of most hormone pathways and the overall infection biology of the invading pathogen biotrophic rice pathogens, while CK signaling can cascade either to the detriment or the benefit of plant. GAs, on the other hand, appear to play opposite roles in rice and Arabidopsis. Finally and consistent with their ambivalent role in dicot immunity, BRs and ABA can both promote and suppress rice immunity depending not only on the type of pathogen, but also on the type of tissue, and even spatial and temporal conditions.The impact of developmental hormones is equally complex. As was reported in Despite the recent progress, much remains to be learned about the role of hormones in the regulation of the rice defense signaling network. For instance, it is still unclear how SA and JA are perceived in rice and how their signaling pathways interact at the molecular level, there is little information available about the impact of viruses, insects and nematodes on the rice hormone signaling network, and there is still much to be learned about the hormone intervention strategies used by rice pathogens to inflict disease. Moreover, few studies have investigated the spatiotemporal dynamics of a given hormone during rice-pathogen interactions and none addresses the kinetics and signature of the blend of hormones released upon pathogen attack. Finally, there is a paucity of knowledge on the molecular players orchestrating pathway crosstalk and signal integration in the rice signaling circuitry. Deepening our knowledge in this area is especially important since defining synergies and trade-offs may help identify appropriate contexts for the optimal deployment and commercial acceptance of hormone-based rice disease resistance.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.


Apoptosis has been reported to induce changes in the remodelling of membrane lipids; after death receptor engagement, specific changes of lipid composition occur not only at the plasma membrane, but also in intracellular membranes. This paper focuses on one important aspect of apoptotic changes in cellular lipids, namely, the redistribution of the mitochondria-specific phospholipid, cardiolipin (CL). CL predominantly resides in the inner mitochondrial membrane, even if the rapid remodelling of its acyl chains and the subsequent degradation occur in other membrane organelles. After death receptor stimulation, CL appears to concentrate into mitochondrial “raft-like” microdomains at contact sites between inner and outer mitochondrial membranes, leading to local oligomerization of proapoptotic proteins, including Bid. Clustering of Bid in CL-enriched contacts sites is interconnected with pathways of CL remodelling that intersect membrane traffic routes dependent upon actin. In addition, CL association with cytoskeleton protein vimentin was observed. Such novel association also indicated that CL molecules may be expressed at the cell surface following apoptotic stimuli. This observation adds a novel implication of biomedical relevance. The association of CL with vimentin at the cell surface may represent a “new” target antigen in the context of the apoptotic origin of anti-vimentin/CL autoantibodies in Antiphospholipid Syndrome. Apoptosis or programmed cell death (PCD) constitutes a physiological phenomenon that concerns any nucleated cell but is particularly important in multicellular organisms, where it can be paradoxically considered a vital process. Apoptosis is critically important for fundamental processes, such as cell turnover, hormone-dependent atrophy, embryonic development, chemical-induced cell death, and immune system homeostasis –4.Distinct morphological features and energy-dependent biochemical mechanisms characterize apoptosis versus other forms of cell death , 3. In pStudies on transbilayer lipid movements during apoptosis have shown that PS translocation results from downregulation of the adenosine triphosphate-dependent aminophospholipid translocase and activation of a nonspecific lipid scramblase , both ofThus, after death receptor engagement, specific changes in the lipid composition occur not only at the plasma membrane, but also in intracellular membranes. In particular, the most critical changes during apoptosis take place in mitochondria, where they promote the permeabilization of the outer mitochondrial membrane (OMM) to release apoptogenic factors into the cytoplasm –18. scenario, membrane lipids, including CL, diacylglycerol (DAG), and lysolipids, play an essential role in facilitating the changes in membrane traffic induced by Fas stimulation in sensitive cells.Indeed, it is well known that apoptosis is accompanied by mitochondrial perturbations, such as reduction of mitochondrial transmembrane potential and increase of mitochondrial generation of superoxide anion –18. BothHowever, relatively little is known about the mechanisms and intracellular pathways regulating CL membrane translocation.CL is considered to be a specific component of mitochondria, since it is synthesized exclusively within the inner mitochondrial membrane (IMM), where it constitutes about 20% of the total lipid composition . CL is r c (Cyt c) from mitochondria , 8014, 8 in vivo trigger for the production of autoantibodies.The presence of autoantibodies in some systemic diseases may arise from abnormal exposure of autoantigens on apoptotic cells. In fact, in many autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) or APS, it is possible to detect the presence of high amounts of apoptotic cells compared to the control samples . In thisTranslocation of CL on the surface of apoptotic cells and its interaction with protein cofactor(s) such as vimentin produce a new twist in the ever evolving APS field, because it represents a novel potential trigger for “antiphospholipid antibodies.” Vimentin/CL complex as a “new” target antigen in APS unveils possible lines of therapeutic intervention in those patients with clinical signs suggestive of APS, who are persistently negative for the conventional tests but positive for anti-vimentin/CL antibodies , 104. In


Throughout their life, tumor cells proliferate, migrate, overcome obstacles and survive. All these actions require multiple interactions between tumor cells and their extracellular surroundings through specialized cell-surface molecules termed matricellular receptors. We define the matricellular receptors as being receptors that bind extracellular matrix (ECM) structural proteins or soluble factors that dynamically act on ECM homeostasis. Matricellular receptors mediate signalings from the extracellular environment to cell nucleus and drive main biological functions that are cell growth, survival and migration. Numerous data from the last decade provide evidence that matricellular receptors are biosensors that allow to a tumor cell to answer to microenvironmental variations. In this sense they are important contributors to tumor cell malignancy.Ricard-Blum and Vallet review on matricryptins and their receptor(s) and co-receptor(s), which form a complex network at the surface of tumor and stromal cells. They describe their roles in angiogenesis, tumor growth and metastasis, and their anti-cancer drug potential.Tumor development is associated with an intense remodeling of ECM that generates biologically active fragments, termed matricryptins. Blandin et al. summarize the current knowledge about integrin involvement in tumor progression and specifically provide informations about β1 integrins as therapeutic targets to disrupt hallmarks of cancer.Interaction between cells and the ECM largely involves the well-known cell-surface receptors integrins. Data accumulation during the last 20 years demonstrated that these heterodimeric proteins act as sensors of cell microenvironment by transducing intracellular signals regulating cell fate. They are now considered as critical players in cancer progression. Rammal et al. pinpoint the roles of DDR1 and DDR2 in the successive phases of a cancer development. Finally, the authors review pharmacological approaches to inhibit DDR1 and DDR2, which might represent valuable targets for anti-cancer therapies.Beside integrins that bind various ECM macromolecules, the tyrosine kinase receptors Discoidin Domain Receptors (DDR) specifically interact with collagens. Collagens, mainly the fibrillar type I collagen, are major components of the tumor stroma. After summarizing biochemical data on DDR, Scandolera et al. describe the role of EDP in tumor development and focus their review on the main elastin receptor, an heterotrimer named the Elastin Receptor Complex (ERC), unique by its composition and operating mechanism. They propose anti-ERC therapeutic strategies and describe ERC involvement in cancer-associated processes such as diabetes and thrombosis.Elastin is the longest-lived protein in vertebrate and provides elasticity to tissues with high mechanical constraints such as lung or skin. Its degradation during cancer progression not only affects its mechanical properties but also generates elastin-derived peptides (EDP) that are actively involved in the development of cancer. Cheng et al. discusses the current state of knowledge of syndecans expression and implication in the field of cancer, with a special and exciting focus on syndecans binding with PDZ domain-containing proteins. The regulation of PDZ binding by phosphorylation of the syndecan cytoplasmic tail is notably debated. Consistently, the experimental data reported by Kashyap et al. focus on syntenin, a scaffold protein containing two PDZ domains and known as an intracellular adaptor for syndecans. To evaluate the potential benefit of anti-syntenin strategies, the authors report the effects of syntenin depletion on various cancer cells from distinct origins. Their results show that syntenin loss of function leads to a significant decrease in tumor cell proliferation, growth and migration in each cancer cell model with a noteworthy defect in the cell-surface expression of active β1-integrin. The authors conclude that syntenin may constitute a molecular target of pharmacological interest in the tumor context.Syndecans are transmembrane proteoglycans expressed at the cell-surface of various cell types. Syndecans are now considered as key regulators of tumorigenesis and cancer progression, especially as being involved in the control of cell proliferation, migration and angiogenesis and in cell-matrix interaction and dynamics. In this regard, the review by Appert-Collin et al. describe the regulation of Erb activity and their role in epithelial-mesenchymal transition. They illustrate the dedicated therapeutic strategies allowing their inhibition with an interesting focus on peptides which mimick transmembrane domains. Beside their role in cancer progression, TKR are involved in the development of various fibrotic diseases. In this regard, these diseases also benefit from advances in the pharmacological strategies developed to fight cancer. Particularly, VEGFR, PDGFR, FGFR, and EGFR kinases appear as potential targets for anti-liver fibrosis therapies. Qu et al. summarize the anti-liver fibrosis effects of multitargeted TK inhibitors and molecular mechanisms. with a specific focus on anti-cancer drugs such as sorafenib and erlotinib.Growth factors receptors are recognized as critical players in tumor progression by regulating diverse biological activities such as proliferation, migration or survival through their binding on Tyrosine Kinase Receptors (TKR). Among this large family, Erb receptors are often overexpressed, amplified, or mutated in many forms of cancer, making them important therapeutic targets. In their review, Gonias and Hu gives a synthetic overview of uPAR expression and function in cancer and provides a relevant schematic representation of uPAR-related mechanisms at both sides of the cell membrane. The authors also address the role of uPAR in the tumor cell resistance to anti-cancer drugs. This part is quite new and attractive and constitutes an exciting area to explore for the future.The urokinase receptor (uPAR) is a key cell-surface receptor generating pericellular proteolysis involved in tissue remodeling processes and triggering intracellular signaling pathways to support various cancer-related events. The mini review by Van Gool et al. provide an overview of this complex receptor, with a particular focus on the multiple roles played by LRP-1 in cancer progression. Furthermore, the authors present recent (pre)clinical data that suggest applications of LRP-1 as therapeutic tool  and diagnostic/prognostic tool. The amount of LRP-1 at the cell surface is strictly regulated by a proteolytic process termed shedding, which is itself controlled, notably by cell cholesterol level. Dekky et al. present original data that highlight the importance of cell cholesterol distribution in the modulation of LRP-1 shedding. Their results suggest an inverse correlation between intracellular cholesterol concentration and LRP-1 shedding efficiency.While numerous matricellular receptors only exhibit signaling properties, the low-density lipoprotein receptor-related protein-1 (LRP-1) further has endocytic capacities. Jeanne et al. focus on the CD47 and CD36 molecules that function as cell-surface receptors for thrombospondin-1, a large matricellular glycoprotein highly overexpressed within tumor stroma where it promotes an aggressive phenotype. The authors review the various therapeutic options, including antibody-based approaches, therapeutic gene modulation and TSP-1-derived peptides and mimetics. Interestingly, the authors also discuss in detail the more recent and innovative approaches including combination strategies to improve radiotherapy and chemotherapy.As we have mentioned, these matricellular receptors may constitute relevant targets to fight against malignant diseases. As examples, Through (mini) reviews and original reports, this Research Topic highlights matricellular receptors that could represent valuable targets for the development of original anti-cancer strategies. We would like to thank all the authors for their important contribution in these exciting fundamental and applied research fields. We are also grateful to the reviewers and editors for their constructive comments that allowed our issue to reach a high standard quality.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The capacity of synaptic networks to express activity-dependent changes in strength and connectivity is essential for learning and memory processes. In recent years, glial cells (most notably astrocytes) have been recognized as active participants in the modulation of synaptic transmission and synaptic plasticity, implicating these electrically nonexcitable cells in information processing in the brain. While the concept of bidirectional communication between neurons and glia and the mechanisms by which gliotransmission can modulate neuronal function are well established, less attention has been focussed on the computational potential of neuron-glial transmission itself. In particular, whether neuron-glial transmission is itself subject to activity-dependent plasticity and what the computational properties of such plasticity might be has not been explored in detail. In this review, we summarize current examples of plasticity in neuron-glial transmission, in many brain regions and neurotransmitter pathways. We argue that induction of glial plasticity typically requires repetitive neuronal firing over long time periods (minutes-hours) rather than the short-lived, stereotyped trigger typical of canonical long-term potentiation. We speculate that this equips glia with a mechanism for monitoring average firing rates in the synaptic network, which is suited to the longer term roles proposed for astrocytes in neurophysiology. At a high level of abstraction, the brain is essentially an organ that detects environmental stimuli, processes the received sensory information, and initiates an appropriate motor response. From this perspective, the primary role of the brain is information processing, and the computational processes associated with transforming input to output are centred on the network of trillions of synapses through which the signals are relayed. The train of action potentials initiated in sensory neurons must be transduced by the central synaptic networks in such a way as to reliably trigger a pattern of action potentials in the motor neurons that effect the necessary coordinated activation of muscles needed to evoke a behavioural response. It is thus widely accepted that, despite defying human comprehension, there must be a particular spatiotemporal pattern of network activity reliably associated with generating a given response to a given external cue.To cope with a complex and changing environment, the synaptic network must also be adaptable, such that experience can refine and reorganize the spatiotemporal patterns of network activity in response to, for example, injurious stimuli. This adaptability requires controlled alteration of synaptic strength, a phenomenon termed synaptic plasticity .The forms and mechanisms of synaptic plasticity have been extensively studied for many decades in many brain regions –6 and caOver the last few decades, the view of glial cells in the brain has developed from passive, homeostatic components to active signalling elements. Unsurprisingly, much of the evidence supporting a computational role for astroglia comes from the effects of astrocyte signalling on synaptic transmission and synaptic plasticity; clearly, if astroglia are able to modulate synaptic plasticity, then they are functionally implicated in information processing. Less attention has been focussed on a tangential question: can astrocyte signalling networks themselves exhibit activity-dependent changes in strength? Do pathways for neuron-glial transmission also vary in connectivity and strength in response to defined patterns of activity; do astrocytes exhibit plasticity that could allow them to directly mediate encoding of memory processes?In this review, we summarize the current evidence for plasticity in neuron-glial transmission (with an emphasis on astroglia), the different forms that this plasticity can take and speculate on the potential computational properties of known forms of glial plasticity. We argue that neuron-glial plasticity has several strikingly different features from synaptic plasticity, which are better suited to the temporal scale over which astrocyte calcium signals operate and the neurophysiological roles in which glia are implicated.As electrically passive cells, astrocytes were once thought to depolarize solely as a result of the changes in extracellular potassium concentration associated with neuronal activity, reflecting a passive potassium conductance. This view was overturned by experiments performed in neuron-free astrocyte cultures, in which direct depolarization in response to excitatory and inhibitory neurotransmitters were recorded, demonstrating that astrocytes expressed ionotropic neurotransmitter receptors , 10. TheThe next key advance in understanding of neuron-glial transmission was the discovery of metabotropic receptors linked to second messenger signalling pathways. An important first step was the use of astrocyte-enriched cultures to demonstrate turnover of radiolabelled inositol phospholipids in response to acetylcholine or noradrenaline administration , indicatIn 1990, Cornell-Bell et al.  culturedIn addition to heterogeneity within cultures from individual brain regions, astrocyte cultures obtained from the cortex or cerebellum displayed different response characteristics to those observed in hippocampal cells. The glutamate analogue quisqualate produced calcium responses in approximately one-quarter of cerebellar and cortical astrocytes, but less than one-tenth of hippocampal cells responded to this treatment , suggest in situ tissue slice preparations where synaptic release could be directly triggered experimentally.These key discoveries from cultured astrocytes, bolstered by many other demonstrations of calcium-evoked responses to neurotransmitters (see ), establThe first demonstration of astrocyte calcium signalling in response to electrical stimulation of neurons came from the hippocampus . HippocaSubsequent investigations confirmed activity-dependent astroglial calcium responses in neuromuscular junction , retina  ex vivo rat retina preparation is a model system to which a natural stimulus—light—can be applied in a controlled manner, to examine cellular events in intact networks. Constant illumination triggered calcium transients in Müller cells , and flickering light increased the frequency of the calcium oscillations in the glia [ in situ.The final step in confirming neuron-glial transmission as a fundamental aspect of neurophysiology was demonstrating glial responses to sensory input. Thethe glia . The gen in vivo. Cortical astrocytes were shown to exhibit spontaneous calcium signals, which correlated with neuronal firing frequency, and spread through astrocyte networks [Calcium imaging studies of astrocyte responses to sensory stimuli have also been performednetworks . The barnetworks . Similarnetworks  indicatinetworks .This body of work has shown that, in common with neuronal transmission, the modes of neuron-glial communication vary in their anatomy, molecular mechanisms, and spatiotemporal kinetics. In some contexts, specialized terminals between neurons and glia are known , 42, witThe concept of neuron-glial transmission as a ubiquitous feature of neurophysiology is now widely accepted . The phyOne of the earliest reports of plasticity in glial cell signalling was related to metabotropic glutamate receptor (mGluR) evoked calcium signalling in cultured visual cortex astrocytes . Repetit in situ investigation in hippocampal slices [This initial discovery was followed by anl slices . Here itl slices . Collectq/11 protein; so called dynamic uncoupling [The detailed mechanism for priming has not been determined, but the intracellular signalling network that regulates mGluR5-evoked calcium oscillations in astrocytes has been characterized in detail –52. The coupling , 54. Thecoupling . These mcoupling .In addition to mGluR5 activation following Schaeffer collateral stimulation, Perea and Araque  reportedHonsek et al.  took a d+ concentrations (5 mM) to increase firing rate. This caused a decrease in the responsiveness of astrocytes to mGluR agonists, suggesting bidirectional changes in the strength of mGluR-evoked calcium signals depending on the rate of neuronal firing. This plasticity in mGluR response was also selective, as responsiveness to activation of other Gq coupled receptors was unaffected [Xie et al.  have alsaffected .Collectively, these studies demonstrate that the strength of neuron-glial transmission via activation of mGluR and mAChR can vary in response to alterations in neuronal firing rates, but these changes are initiated by different patterns of activity to those that trigger synaptic plasticity.Bergmann glial cells are astroglia of the cerebellar cortex with a characteristic morphology . Radial  in situ (in acutely isolated slices) was confirmed [Cultured Bergmann glia were first shown to express calcium-permeable AMPA receptors in 1992 , and sooonfirmed . In 1997onfirmed  and paraonfirmed  inputs tGlial AMPAR currents were found to show rapid kinetics consistent with local vesicular delivery, rather than diffusion of glutamate from distant sites , 64. SigEctopic transmission to Bergmann glia exhibits both short-term plasticity and long-term plasticity. Short-term plasticity mirrors the plasticity observed at the adjacent synapses—paired pulse depression at climbing fibres, and paired pulse facilitation at parallel fibres—but in both cases the magnitude of plasticity is greater at Bergmann glia than Purkinje neurons , 67. FacAt climbing fibres, the opposite phenomenon, paired pulse depression, reduces AMPAR currents by around half. For ectopic transmission to glia, depression is more pronounced, with >90% of AMPAR current being lost , 68. TheWhile short-term plasticity resembles the synaptic pattern in many respects, long-term plasticity is strikingly distinct. Many forms of LTP and LTD are known at parallel and climbing fibre synapses with both presynaptic and postsynaptic mechanisms , 70. In The mode of neuron-glial plasticity that most closely resembles synaptic plasticity is found in NG2 cells. These cells have been variously described as oligodendrocyte precursor cells, polydendrocytes, synantocytes, and NG2 cells, and their precise nature or subclassifications is still an active area of debate . These cPostsynaptic currents in NG2 cells showed similar short-term plasticity (paired pulse facilitation) to adjacent Schaeffer collateral to CA1 pyramidal neuron synapses in hippocampal slices . In contThe mechanisms of NG2 cell plasticity have since been investigated in more detail in other regions—cerebellum and optic nerve . The levThe neuromuscular junction (NMJ) is surrounded by perisynaptic Schwann cells (PSCs), which are nonmyelinating glia that functionally resemble astrocytes of the central nervous system . Todd etα-bungarotoxin and by chronic stimulation of the nerve [The plasticity of the calcium responses in PSCs has also been explored, by suppression of synaptic transmission with he nerve . The reshe nerve . CollectRecently, this capacity for PSCs to utilize calcium responses as a mechanism for detecting differences in synaptic strength at the NMJ has been proposed as a means for influencing selection between competing presynaptic terminals during development .Another mechanism for plasticity, which can be viewed as distinct from frequency-evoked changes in transmission strength, is the modulation of transmission by concurrent activation of parallel signalling pathways. Crosstalk between pathways is well known in synaptic transmission, through activation of neuromodulatory receptors coupled to second messenger signalling cascades, with the classic examples being monoamine transmitters such as adrenaline, noradrenaline, 5-HT, and dopamine . SimilarInterpretation of the effects of neuromodulators on astrocyte calcium signalling is complex, however, because many of the physiological receptor agonists can directly stimulate calcium responses in the astroglia. Nevertheless, evidence is accumulating that in addition to direct effects, coapplication of several neuromodulators with other transmitters generates different calcium responses in the glia compared to transmitter alone.Nitric oxide can directly activate calcium influx in astrocytes at high concentrations , 82, butAdenosine has also been shown to mediate complex crosstalk with calcium signalling pathways in astrocytes. A1 receptor activation potentiates both mGluR  and mAChα1 receptors. Many studies have shown direct activation of calcium responses by α1R activation, in cultures, ex vivo slices, and in vivo [α1R activation also causes modulation of responses to other calcium mobilizing agonists. In cultured cells, coapplication of the α1 agonist phenylephrine with the mGluR1 agonist DHPG dramatically suppressed calcium oscillations (and associated glutamate release) that were evoked by DHPG alone [α- and β-adrenoceptors, with β receptor antagonists blocking the calcium responses evoked by phenylephrine and ATP, suggesting a tonic, permissive effect of β receptor activity.One of the most intriguing examples of complex crosstalk in astrocyte responses is the effect of noradrenaline acting through  in vivo , 90, 91.PG alone . In contPG alone . The pot in vivo. In awake mice, wide ranging calcium signals recorded in cortical astrocytes appear to predominantly arise from noradrenergic transmission from locus coeruleus projections [ ex vivo preparations or anaesthetized animals, where local excitatory network activity engages mGluRs in astrocytes, suggesting distinct modes of operation linking sensory input to glial calcium responses depending on level of consciousness. Similar NA-evoked astrocyte responses have been described in cerebellar Bergmann glia and visual cortex astrocytes in awake mice [Similar complex adrenoceptor interactions have also been reportedjections , 93. Thiake mice , suggestake mice  also shoake mice .Collectively, these studies demonstrate that the responsiveness of astrocytes to numerous neurotransmitters could be altered, both positively and negatively, by coincident activation of modulatory receptors. This represents a form of gain modulation of glial responses, akin to that observed in synaptic networks.We have so far focussed on forms of plasticity in neuron-glial transmission linked to receptor-mediated calcium signalling pathways, on the assumption that these mechanisms represent an analogue for synaptic transmission. However, several other forms of plasticity in neuron-glial connectivity have also been reported which could impact on signal conditioning.+ influx associated with uptake may have a signalling role [In addition to receptor-mediated signalling, many neurotransmitters also generate inward currents in astrocytes through electrogenic uptake. While this phenomenon is clearly important for termination of synaptic transmission, there is also evidence that the Naing role . Severaling role . Similaring role , 98. In ing role . In the ing role , which wAnother form of plasticity that could impact on information processing in glial networks is the modulation of gap-junctional coupling between astroglial cells. Both short-term and long-term modulation of connexin function and expression by neuronal activity has been reported in both cultured cells and in intact preparations such as the optic nerve –102. DynThe accumulating evidence for neuron-glial plasticity indicates that signal processing through these routes for transmission can be altered in an activity-dependent manner, suggesting that memory processes could be accommodated within the network. However, it is striking that the computational properties of glial plasticity differ from those typical for induction of synaptic plasticity. The canonical example of synaptic plasticity is hippocampal LTP , which iFor both the “priming” of mGluR responses in hippocampal neurons , 58 and To date, most computational models of the role of astrocytes in network processing have focussed on gliotransmission at the level of the tripartite synapse . Glia haIn many respects these long-term shifts in glial sensitivity match well with the time frame over which information can feasibly be encoded into intracellular calcium oscillations. The frequency of spontaneous calcium signals observed in glia operates in the sub-Hz range , 85, andAt present, the study of plasticity in neuron-glial transmission is in the discovery stage. Stimulation paradigms have been found that can cause lasting changes in glial responsiveness to neuronal activity, but we currently lack a deeper understanding of the molecular mechanisms underlying—and the detailed computational rules governing—induction, maintenance, and reversal of glial plasticity. Without this knowledge it will be difficult to hypothesize about feasible roles for glia in short-term information processing and long-term neurophysiological processes such as memory and learning.A future goal to advance this understanding would be to determine the input-output relationship between synaptic stimulation and astrocyte calcium responses at what has been termed the tripartite synapse . The fid


Ovarian cancer is the leading cause of death among gynecologic malignancies. Since ovarian cancer develops asymptomatically, it is often diagnosed at an advanced and incurable stage. Despite many years of research, there is still a lack of reliable diagnostic markers and methods for early detection and screening. Recently, it was discovered that cell-free microRNAs (miRNAs) circulate in the body fluids of healthy and diseased patients, suggesting that they may serve as a novel diagnostic marker. This review summarizes the current knowledge regarding the potential clinical relevance of circulating cell-free miRNA for ovarian cancer diagnosis, prognosis, and therapeutics. Despite the high levels of ribonucleases in many types of body fluids, most of the circulating miRNAs are packaged in microvesicles, exosomes, or apoptotic bodies, are binding to RNA-binding protein such as argonaute 2 or lipoprotein complexes, and are thus highly stable. Cell-free miRNA signatures are known to be parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles. Since it is well established that the dysregulation of miRNAs is involved in the tumorigenesis of ovarian cancer, cell-free miRNAs circulating in body fluids such as serum, plasma, whole blood, and urine may reflect not only the existence of ovarian cancer but also tumor histology, stage, and prognoses of the patients. Several groups have successfully demonstrated that serum or plasma miRNAs are able to discriminate patients with ovarian cancer patients from healthy controls, suggesting that the addition of these miRNAs to current testing regimens may improve diagnosis accuracies for ovarian cancer. Furthermore, recent studies have revealed that changes in levels of cell-free circulating miRNAs are associated with the condition of cancer patients. Discrepancies between the results across studies due to the lack of an established endogenous miRNA control to normalize for circulating miRNA levels, as well as differing extraction and quantification methods, are the pitfalls to be resolved before clinical application. There is still a long way, however, before this can be achieved, and further evidence would make it possible to apply circulating cell-free miRNAs not only as biomarkers but also as potential therapeutic targets for ovarian cancer in the future. Ovarian cancer is the leading cause of gynecological cancer-associated deaths in developed countries. In the United States, ovarian cancer is the fifth leading cause of cancer death in females, with an estimated incidence of 14,180 deaths in 2015 . For examiRNAs are endogenously expressed, single-stranded non-coding RNAs that are typically 19–25 nucleotides in length. They are initially generated as long primary miRNAs (pri-miRNAs) by RNA II polymerase-mediated transcription in the cell nucleus. The primary miRNAs are cleaved into approximately 70 nucleotide-long precursor miRNAs, which are subsequently transported into the cytoplasm and further cleaved into mature miRNAs . miRNAs Since high levels of endogenous nucleases are present in body fluids, freely circulating RNAs were expected to be rapidly degraded. However, recent evidence has revealed that miRNAs are secreted from cells into circulation where they exist stably, and sometimes can be functionally transferred to recipient cells , 30. CirThe expression profile of circulating miRNAs is highly affected by the methodologies of sample preparation , 64. HowIn most studies, the extracted miRNAs are subjected to next-generation sequencing (NGS) or miRNA microarrays to obtain large-scale profiles of circulating miRNAs and determine candidate miRNAs for further quantification. Each method has certain advantages and limitations. NGS has a potential to identify novel miRNAs but is less cost-effective and less efficient compared with microarrays. Thereafter, the candidate miRNAs are generally subjected to further validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in larger cohorts. Establishment of endogenous controls for miRNA normalization remains the bottleneck for the reliable quantification of miRNAs. While RNU-6B, RNU-48, and miR-16 are commonly used as endogenous controls, no definitive control gene has been established , 81. RecDiagnostic potential of circulating miRNAs in ovarian cancerApproximately 20 studies have been published on the diagnostic potential of circulating miRNAs in ovarian cancer. Taylor et al. first reported that eight exosomal miRNAs  from sera were elevated in ovarian cancer patients compared to benign controls, which had been reported to be overexpressed in ovarian cancer tissues. These miRNAs were overexpressed even in patients with early stages of ovarian cancer. The miRNA signatures from exosomes were parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles . FollowiPotential of circulating miRNAs in ovarian cancer as prognostic biomarkersCurrent management of ovarian cancer relies on clinicopathological factors including tumor histology and stage. Recent studies have revealed that changes in the levels of circulating miRNAs are associated with the prognosis of ovarian cancer patients –77, 80, Since 2008, numerous studies have demonstrated the clinical relevance of circulating miRNAs as diagnostic and prognostic biomarkers for a variety of cancer types, using blood plasma or serum. Cancer-associated circulating miRNA expression profiles were determined and have been shown to be related to tumor development, disease progression, and metastases. This section describes the potential roles of circulating miRNAs as novel biomarkers in regard to diagnosis and prognosis in ovarian cancer.Several research groups have studied the ability of miRNAs to predict the sensitivity to treatment. Kapetanakis et al. demonstrated the pre/post-treatment variations of plasma miR-200b in ovarian cancer as a potential prognostic predictor. Plasma samples were collected from a total of 33 ovarian cancer patients prior to and after primary treatment including surgery and chemotherapy. CA125 returned to normal plasma concentrations within the first month of treatment in almost all patients even in the cases with unresectable tumor, whereas there was a remarkable mix of variation in the concentrations of plasma miR-200b. The patients with a negative miR-200b variation had a longer PFS than those patients with a positive variation, and the risk of disease-progression was significantly higher in patients with a positive variation of miR-200b compared to those with a negative variation . Benson While a variety of molecular targeted therapies   have beevia a Toll-like receptor 7 (TLR7) [He WA, et al. reported cancer-secreted microvesicles contain an elevated expression of miR-21 and induce myoblast apoptosis, which lead to cancer cachexia of patients 7 (TLR7) . They pr7 (TLR7) . Based o7 (TLR7) . AlthougIn recent years, emerging evidence has suggested that circulating miRNAs may hold great potential as promising biomarkers for early detection, prognosis, and sensitivity to chemotherapy of ovarian cancer. However, to date, most of the studies appear to be preliminary, because they simply identified altered levels of circulating miRNAs in ovarian cancer patients with relatively small cohort sizes. They lack direct comparison or in combination with conventional diagnostic procedures, such as CA125 and ultrasonography, particular for early stage diseases. In addition, the lack of standardized protocols including sample collection, RNA extraction, and the selection of suitable internal control makes it difficult to compare the results between studies reported. There have been inconsistent findings about circulating miRNAs from the same tumor reported by different studies. Nevertheless, circulating miRNAs have potential as novel non-invasive and highly useful biomarkers of ovarian cancer, as shown in various types of disease such as cardiovascular disease, diabetes mellitus, and cancer of other organs . Further


There isa misbelief that mini-IVF severely compromises pregnancy and live birth rates. Anappraisal of the literature pertaining to studies on mini-IVF protocols was performed.The advantages of minimal stimulation protocols are reported here with a focus onthe use of clomiphene citrate (CC), gonadotropin releasing hormone (GnRH) ago-nist trigger for oocyte maturation, and freeze-all embryo strategy. Literature reviewand the author’s own center data suggest that minimal ovarian stimulation protocolswith GnRH agonist trigger and freeze-all embryo strategy along with single embryotransfer produce a reasonable clinical pregnancy and live birth rates in both goodand poor responders. Additionally, mini-IVF offers numerous advantages such as: i.Reduction in cost and stress with fewer office visits, needle sticks, and ultrasounds,and ii. Reduction in the incidence of ovarian hyperstimulation syndrome (OHSS).Mini-IVF is re-emerging as a solution for some of the problems associated withconventional IVF, such as OHSS, cost, and patient discomfort.Minimal stimulation  Some of the reasons for this increase include: i. High doses of gonadotropins increased the number of oocytes retrieved in good and poor responders, and ii. It allowed the formation of more embryos providing excess embryos for cryopreservation , freeze-all embryo, and GnRH agonist trigger. In addition, references from all relevant articles were reviewed. Titles and abstracts of all citations identified in the search were reviewed. The full-text article was retrieved if the citation was potentially relevant to miniIVF. 2) level of <75 pg/mL. Minimal ovarian stimulation is started with an extended regimen (from day 3 of the cycle until the day before triggering) of CC  in conjunction with gonadotropin injections starting on days 4-7 of the cycle with 75-150 IU of human menopausal gonadotropins (hMG) daily. Patients usually receive both CC and low dose gonadotropins, and the dose given depends on the ovarian reserve status and the body mass index (BMI) of the patient. The final maturation of oocytes is usually induced by either intramuscular hCG or GnRH agonist   . When panasally)  have repAt our institution  retrieved oocytes are fertilized and subsequently cultured until the cleavage stage or preferably the blastocyst stage. Figure 1 represents a summary diagram that summarizes a protocol that has been used at our institution over the last five years and used by Kato et al.  and Tera2, low BMI, young, and good responders . Rather 4), leading to worse perinatal outcomes compared with frozen-thawed embryo transfers in a more neutral physiological environment. There seems to be a less receptive endometrium in cycles with ovarian stimulation, and children born from the transfer of frozen-thawed embryos had better outcome compared with children born from cycles with fresh embryo transfer. Several recent studies have shown that the success rates of frozen-thawed embryo transfer are similar, if not better, to the success rates of fresh embryo transfer  collected data on assisted reproductive technology (ART) success rates of all American fertility clinics from 1997 to 2011. According to those data, success rates of both fresh and frozen-thawed embryo transfer cycles (donor eggs not included) have increased over the past 14 years for women of all ages. Interestingly, the increase in success rates seems to be greater for frozen-thawed embryos compared with fresh embryos . Furthertransfer ,43. Whettransfer ,45. There is still resistance to use of minimal stimulation protocols because of the fear of having few oocytes. There is also a misbelief that minimal stimulation severely compromises pregnancy and live birth rates. It is clear that IVF treatment is stressful and costly to lots of patients. Multiple office visits including injections, blood draws, and ultrasounds can add to the stress. Additionally, stress could emanate from the high cost of IVF medications and procedures, as well as IVF outcomes that include complications of multiple pregnancies . Although severe OHSS is rare, it constitutes a real threat for high-risk patients. Interestingly, there is a lack of literature pertaining to the outcome of mini-IVF in obese older women, especially those with diminished ovarian reserve. We have recently shown that female adiposity might impair oocyte number and maturity in conventional IVF but not in minimal stimulation IVF, suggesting that gentle ovarian stimulation might yield healthier oocytes in obese women. Thus, future studies are needed to address the optimal IVF protocol in this patient population. There is no doubt that minimal stimulation protocols is disadvantageous to oocyte donation and elective oocyte cryopreservation, and that it limits the number of available embryos. However, molecular differences at the level of the oocyte seem to be real between conventional IVF versus mini-IVF. Additionally, molecular differences between frozen-thawed embryos and freshly cultured human embryos have been reported. Interestingly, success rates after frozen-thawed embryo transfer are now nearing the success rates of fresh embryo transfer supporting the hypothesis of so called freeze-all embryo strategies in IVF to optimize success rates. Finally, there is a critical need for high quality randomized controlled trials to determine which cryopreservation protocol is best and whether a freeze-all embryo strategy is justified in IVF treatments.


Epicardial adipose tissue thickness (EATT) is suggested as a novel marker of subclinical atherosclerosis. Despite increased carotid intima-media thickness (CIMT) in autosomal dominant polycystic kidney disease (ADPKD) patients, the extent of the relationship between CIMT and EATT is unknown. The main purpose of our study was to evaluate the relation between EATT and CIMT in normotensive ADPKD patients with well-preserved renal function. Fifty-five normotensive ADPKD patients with normal renal function and 50 healthy control subjects were included in the study. EATT and CIMT were measured by echocardiography in all subjects. Correlation between EATT and CIMT was evaluated in ADPKD patients, while multivariate linear regression analysis was performed to determine factors predicting EATT and CIMT. ADPKD patients had significantly higher levels CIMT  and EATT  as compared with control subjects. Significant positive correlation was found between EATT and CIMT . Higher CRP levels  and having ADPKD  were the only independent factors associated with a higher EATT. A higher age  tended to be independently associated with a higher EATT. In conclusion, our findings suggest that EATT, being simply measured by echocardiography and correlated with CIMT, can be used to detect subclinical atherosclerosis in normotensive ADPKD patients. Autosomal dominant polycystic kidney disease (ADPKD), one of the most common hereditary diseases, is an important cause of end-stage renal disease (ESRD) Schrier , while fEndothelial dysfunction (ED) is an early and reversible manifestation of atherosclerosis with multifactorial etiology. Arterial stiffness with increased vascular smooth muscle tone and intima media thickness (IMT) is related to ED , hyperlipidemia, hypertension, or any cardiovascular disease, a measured office blood pressure ≥140/90 mmHg and usage of antihypertensive drugs were the exclusion criteria. After a detailed explanation each patient signed an informed consent form in accordance with the declaration of Helsinki. The local ethics committee of Uludag University approved the study.Between July 2013 and July 2015, 115 ADPKD patients who were registered by the Uludag University School of Medicine in the Turkish Nephrology Society Cystic Kidney Disease Working Group Registry were evaluated for the study. Fifty-five normotensive ADPKD patients with normal renal function  and 45 age- and sex-matched healthy subjects  were included in the study. ADPKD was diagnosed and defined according to the ultrasonographic criteria published by Pei et al.  and all 2)], vital signs , blood biochemistry , left ventricul ejection fraction , left ventricular mass , CIMT (mm) and EATT (mm) were recorded in patient and control groups. Correlation between EATT and CIMT was evaluated in ADPKD patients, while multivariate linear regression analysis was performed to determine factors predicting EATT and CIMT.Data on patient demographics, anthropometrics , LVM , CIMT , and EATT  as compared with control subjects   analysis showed that an EATT of 51.5 mm or higher was 69 % sensitive and 70 % specific to distinguish between patients with ADPKD and controls Fig. .Fig. 2ReOur findings in a cohort of normotensive ADPKD patients with well-preserved renal function revealed higher levels for LVEF, LVM and serum uric acid levels in patient than in controls. Additionally, hs-CRP, CIMT and EATT levels were higher in ADPKD patients as compared with controls. Besides a significant positive correlation between CIMT and EATT levels, presence of ADPKD was determined to be an independent predictor both increased EATT and CIMT levels, while increased EATT also predicted the increased CIMT levels.As mentioned earlier, our ADPKD patients have higher levels of LVM, even though they have similar arterial BP levels compared to the control group. This finding is supported by several other studies, and development of LVH in normotensive ADPKD patients may have caused by several reasons including; renin-angiotensin-aldosterone system activation, adrenergic stimulation, endothelial dysfunction and diastolic dysfunction (Ecder and Schrier Likewise, numerous clinical reports confirmed the association between the echocardiographic EATT and cardiovascular risk factors, both traditional and novel, as well as with atherosclerotic disease (Kocyigit et al. Our findings are consistent with data from past studies indicating presence of increased CIMT among both hypertensive and normotensive patients with ADPKD compared with healthy individuals (Widlansky et al. Accordingly, being considered amongst markers of ED and thus of early atherosclerosis, increased levels for CIMT and EATT in our ADPKD patients with well-preserved renal function emphasize that during ADPKD, subclinical organ damage starts earlier than renal impairment (Ecder and Schrier In this regard, our findings emphasize the potential value of echocardiographic EATT measurements in evaluating subclinical target organ damage, and thus the likelihood of implementing strategies to control unfavorable cardiovascular risk factors and the development of future CVD in patients with increased EATT (Ecder and Schrier Besides, on the basis of the documented correlation of eGFR to CRP in patients with CKD (Tong et al. On the basis of several advantages such as simplicity, low cost, reliability, easy accessibility, rapid applicability, and good reproducibility echocardiographic EATT measurement has been suggested to offer a routine way of evaluating atherosclerotic and cardiovascular risk in a clinical setting with likely correlation with cardiometabolic risk factors and potential relevance in CAD and atherosclerotic vascular disease (Iacobellis and Willens Certain limitations to this study should be considered. First, small sample size might be disadvantage in achieving the statistical significance about the independent correlates of EATT and CIMT as well as to apply results of the present regression models to the entire population. Secondly, with the exception of hs-CRP, our study was lacking other oxidative stress markers. Thirdly, in our study, we only include patients with normotensive ADPKD with normal renal function, and excluded any other form of ADPKD. Another limitation is lack of long-term follow-up of patients in terms of cardiovascular events. Finally, the cross-sectional design made it impossible to establish any cause and effect relationships.In conclusion, our findings indicate presence of early atherosclerotic changes in ADPKD patients with well-preserved renal function based on identification of increased EATT and CIMT. Our findings suggest that EATT, being simply measured by echocardiography and correlated with CIMT, can be used as a first-line measurement to detect early atherosclerosis in normotensive ADPKD patients. Further studies in large randomized populations are needed to improve our understanding pathophysiological mechanisms involved in early onset of ED in ADPKD patients with more robust and convincing evidence regarding the diagnostic and predictive properties of echocardiographic EATT to be considered as a routine method of evaluating cardiovascular risk in a clinical setting.


Cancer cells have long been known to exhibit metabolic reprogramming which involves a shift towards glycolysis. The enhanced glycolysis of cancer cells not only impose nutrient restriction in the tumor microenvironment, but also contribute to the acidic environment which is hostile to the invading anti-tumor immune cells. Hence, targeting the glycolysis dependency of tumor cells has been exploited for therapy. The glucose anti-metabolite, 2-deoxyglucose (2DG), a competitive inhibitor of glucose transport and glucose phosphorylation by hexokinase, has been extensively tested in various animal models and clinical trials. Although 2DG as anti-cancer agent showed a limited efficacy, its combined use with other treatment modalities, including chemotherapy and radiotherapy, has shown encouraging results. In particular, it has been shown that the combination of 2DG and cytotoxic agent etoposide resulted in enhanced antitumor immune responses, suggesting the therapeutic potential of combining chemotherapy, immunotherapy and glycolysis inhibition. We set out to study how metabolic inhibition alters the tumor microenvironment and how it can be utilized to augment the efficacy of chemo-immunotherapy. We found that glycolysis inhibition alone was detrimental to adoptive T-cell therapy (ACT). However, a rational combination of chemotherapy, ACT and 2DG led to tumor eradication and long-term survival in mice. The underlying mechanism of this synergy will be discussed.


Osteoarthritis (OA) is a chronic degenerative disease affecting articular cartilage in joints, and it is a leading cause of disability in the United States. Current pharmacological treatment strategies are ineffective to prevent the OA progression; however, cellular therapies have the potential to regenerate the lost cartilage, combat cartilage degeneration, provide pain relief, and improve patient mobility. One of the most promising sources of cellular regenerative medicine is from mesenchymal stem cells (MSCs). MSCs can be isolated from adipose tissue, bone marrow, synovial tissue, and other sources. The aim of this review is to compile recent advancement in cellular based therapy more specifically in relation to MSCs in the treatment of osteoarthritis. Osteoarthritis (OA) is a chronic degenerative disease of articular cartilage that is the leading cause of joint disease in the United States. OA is characterized by the inability of chondrocytes to produce adequate functional matrix to compensate for matrix damage and depletion. Comorbidities such as aging, obesity, heart disease, diabetes, and mechanical stress become prevalent concerns in patients with osteoarthritis; in 2013, the center for disease control and prevention (CDC) found that 52.5 million adults over the age of 18 had self-reported physician-diagnosed arthritis, which is 22.7 % of the adult population [OA is a chronic degenerative condition with no cure. Patients often experience pain, stiffness, swelling, loss of mobility, loss of flexibility, and weight gain secondary to reduced mobility/activity. Conventional OA therapeutics are directed toward symptomatic treatment, mainly pain management. Current treatment modalities for OA such as exercise, anti-inflammatory medication, and surgery are summarized below in Table Advancement in the field of cellular therapy for osteoarthritis is an exciting and quickly evolving area of research and medicine. Current cellular therapies are summarized in Table Recent development in stem cell tissue engineering has created a lot of excitement in the field of cartilage regeneration biology. Stem cells are progenitor cells which differentiate into various cell types including osteoblasts, osteocytes, adipocytes, and cartilage –40. BecaTwo types of stem cells being investigated are embryonic stem cells  and induced pluripotent stem cells (iPSCs). Both cells possess the pluripotent ability to differentiate into chondrocytes or any type of cell; ESCs have been found to improve cartilage repair in animal models, and Wei et al. have generated iPSCs from human OA chondrocytes and subsequently induced the cells into chondrocytic differentiation , 25. WhiThe other type of stem cell currently being investigated for its ability to treat OA is the mesenchymal stem cell (MSC). MSCs are a heterogeneous group of stromal cells that can come from a variety of sources including adipose tissue, bone marrow, and synovium; numerous studies have proven MSCs’ abilities to differentiate into chondrocytes and regeneratively treat OA . While MAdipose-derived mesenchymal stem cells (ADSCs) can be harvested from the patient’s own adipose tissue most commonly via surgical resection or liposuction; specifically, infrapatellar fat pads (IFPs) provide cells with higher chondrogenic potential in comparison to other sources . ADSC thSeveral clinical studies also prove ADSCs’ efficacy in treating OA in human patients. Koh et al. treated patients with knee OA undergoing arthroscopic debridement with injected autologous ADSCs derived from IFPs and prepared in platelet rich plasma (PRP). Treated patients demonstrated improved mobility and function in the affected knees, reduced pain levels, and better clinical prognoses in a 1 year follow up . In a 2 Another source of MSCs for the treatment of OA is bone marrow-derived MSCs (BM-MSCs). BM-MSCs have a higher chondrogenic capability than ADSCs , and theIn a human trial, Orozco et al. used autologous BM-MSCs to treat OA knee patients who were unresponsive to conservative treatments. BM-MSCs were intra-articularly injected, and their results indicated strong clinical efficacies such as improved cartilage quality in T2 mapping in 11 of the 12 patients and pain relief without hospitalization or surgery . These fSeveral human studies have been conducted on ADSCs and BM-MSC treatments for OA, but less has been done in recent times with synovial-derived MSCs (S-MSCs). In a rat knee OA model, S-MSCs injected weekly, rather than at a single time, were found to have migrated into the synovium and retained their undifferentiated S-MSC properties. The S-MSCs increased genetic expression of chondroprotective proteins such as BMP-2 and an anti-inflammatory gene, TSG-6 . This suAlthough MSCs have demonstrated the unique ability and promise to combat degenerative diseases such as OA, they possess another mechanism of regenerative abilities not previously discussed: their exosomal products. Exosomes are packaged microvesicles that can contain proteins, lipids, factors, and/or genetic material that can be released in times of cellular stress , 64. FurCurrent treatment strategies for OA are inadequate and costly. Due to the increasing incidence and prevalence of OA, more innovative and effective therapeutic modalities need to be investigated, including MSCs. More randomized clinical trials need to be completed in order to demonstrate the efficacy, safety, and benefits of MSCs in treating patients with OA. Most of MSC research on humans only involves knee OA, and additional analysis should include clinical trials for ankle OA, shoulder OA, hip OA, and elbow OA. MSC-based cellular therapy has the potential and opportunity to effectively combat OA, but more extensive clinical trial and animal studies are required to understand the basic molecular mechanisms of MSC dependent cartilage regeneration. Further research is also necessary to better understand the potential of MSC-derived exosomes in the treatment of OA.