The public health burden of type 2 diabetes has risen unabated over the past decades, fueled by obesity and lifestyle influences, including diet quality. Epidemiological evidence is accumulating for an inverse association between dairy product intake and type 2 diabetes risk; this is somewhat counterintuitive to the saturated fat and cardiometabolic disease paradigm. The present report reviews the contribution that the findings of the European Prospective Investigation into Cancer (EPIC) study have made to this debate, noting that types of dairy products, particularly fermented dairy products including yogurt, may be more relevant than overall dairy intake for the prevention of type 2 diabetes. The EPIC study has contributed evidence through complementary approaches of a large prospective study across 8 European countries with heterogeneous dietary intakes assessed using food-frequency questionnaires (EPIC-InterAct study) and through a more detailed examination of diet assessed using a 7-day food diary (EPIC-Norfolk study). The implications of these findings are placed in the wider context, including the use of individual fatty acid blood biomarkers in the EPIC-InterAct study and an appraisal of current research gaps and suggestions for future research directions. The global burden of diabetes mellitus is high, and increasing, with the latest estimates from the International Diabetes Federation suggesting that 382 million people had diabetes in 2013; that number is projected to increase to 592 million by 2035.There is increasing interest in the potential role that dairy products might play in diabetes etiology, though research evidence has been mixed as to whether different types of dairy products have a beneficial, detrimental, or null association with type 2 diabetes.,Contrary to expectations and based on the strong focus on saturated fat as a risk factor for cardiometabolic disease, recent appraisal of the evidence has not been convincing for the effects of saturated fatty acids on such outcomes.In particular, EPIC investigators addressed 2 interlinked objectives in order to advance this field of inquiry. The first objective was to investigate the association between consumption of different amounts and types of dairy products and the development of incident type 2 diabetes; this was done using the heterogeneity of dietary exposures measured with food-frequency questionnaires (FFQs) across 8 European countries in the EPIC-InterAct study.At the time the InterAct project was conducted,,Described in detail previously,P trend, 0.02) in adjusted analyses comparing extreme intake quintiles. In separate analyses for yogurt and thick fermented milk intake, there was an inverse association with diabetes incidence in model 1, which was rendered nonsignificant after further adjustment. For cheese intake, there was a significant inverse association with type 2 diabetes in model 1 , but this was attenuated and became nonsignificant upon further adjustment for confounders, though an inverse trend remained across increasing quintiles of cheese intake . These findings were robust to a range of sensitivity analyses, and there were no interactions between dairy product intake and each of sex, BMI, physical activity, or smoking habit and the risk of type 2 diabetes.Analyses found no significant association between diabetes and total dairy product intake or milk intake, but a higher combined intake of fermented dairy products  was inversely associated with diabetes . For yogurt intake, the corresponding HR was 0.72 . Other subtypes of dairy and total dairy, whether high fat or low fat, were not significantly associated with type 2 diabetes risk.The higher consumption of low-fat fermented dairy products was associated with a lower risk of new-onset diabetes over 11 years compared with nonconsumption. Low-fat fermented dairy products consisted largely (87%) of yogurt but also included low-fat, unripened cheeses, e.g., fromage frais. In adjusted analyses, the HR for the association of low-fat, fermented dairy (highest compared with lowest tertile of intake) with incident diabetes was 0.76  in the EPIC-Norfolk study. However, without repeat dietary assessment, both studies could not account for change in dietary habits over time. The issue of potential residual confounding is a possibility in both studies as the confounding factors may be measured with error or unknown confounders may remain unaccounted for.,A cause-and-effect relationship, for which a randomized trial would provide the highest form of evidence, cannot be established. However, in reality, such a trial is unlikely to be feasible for a dietary intervention for a “hard” endpoint such as type 2 diabetes, which would require participants to adhere to particular diets for several years in order to allow enough time for onset of the disease. Alternatively, criteria such as those proposed by Hill,,,,Fatty acids are the building blocks of fat, and reducing the consumption of saturated fatty acids (SFAs) to below 10% or even below 7% of total energy intake has been deeply embedded in dietary guidelines.In identifying the reasons for some of the observed discrepancies, it is important to acknowledge that previous research on SFA and diabetes focused on total SFA intake, without distinguishing between SFAs of different carbon chain lengths, which can have important differences in biological action. This, in turn, has been the result of past nutritional research that relied on dietary assessment based on self-report from questionnaires, which did not readily permit the examination of SFA of different carbon chain lengths. In contrast, the objective measurement of SFAs of different carbon chain lengths in blood factions enables the assessment of individual SFAs.Thus, the aim was to investigate the prospective association between objectively measured individual SFAs in the plasma phospholipid fraction and incident type 2 diabetes using the advantages of the EPIC-InterAct study, including variation in SFA levels across 8 European countries.,,P trend, < 0.0001) and for 17:0 it was 0.24 . Conversely, for the even-chain SFAs, the corresponding HRs were 1.64  for 14:0, 1.75  for 16:0, and 1.75  for 18:0 . Interpretation of the findings for even-chain SFAs is complex because these circulating SFAs are mainly derived from hepatic endogenous synthesis (de novo lipogenesis), stimulated by intakes of carbohydrates and alcohol.,,,Described in detail previously,With the EPIC-InterAct study across 8 European countries and the EPIC-Norfolk study in the United Kingdom, large-scale and robust evidence has been generated among European populations on the association between the consumption of dairy products and the incidence of type 2 diabetes. There was a remarkable consistency of findings for fermented dairy products being inversely associated with diabetes across the 2 dietary instruments (FFQ in the EPIC-InterAct study and the 7-day food diary in the EPIC-Norfolk study). The EPIC-Norfolk study allowed greater differentiation by fat content status, i.e., low-fat fermented dairy products  were inversely associated with diabetes risk. Moreover, the measurement of individual circulating SFAs in the InterAct study enabled the world’s largest appraisal of the association of SFAs of different carbon chain lengths with the risk of type 2 diabetes. This is an important step toward recognizing that SFAs are not a single homogenous group and that differences exist between the differential health effects of subtypes of blood SFAs. The question of whether 15:0 and 17:0, presumed derived from dairy fat, have direct physiological effects on the development of diabetes or whether they are markers of other components in dairy is currently unclear and should be the subject of further research, together with gaining a better understanding of the extent to which the content of these odd-chain SFAs varies by type of dairy product. The implication, however, of the EPIC-InterAct study’s blood fatty acid biomarker findings is that it informs the recognition that it is not enough to provide public health messages about overall saturated fat intake, but that more nuanced messages acknowledging the food sources of different types of SFAs are required.,Taken together, the findings from the EPIC study (EPIC-InterAct and EPIC-Norfolk) indicate that a public health focus solely on nutrients  may be misplaced, and what is required is consideration of the food sources associated with those nutrients. For instance, both meat and dairy products are rich in total fat and SFAs, but their association with type 2 diabetes is in opposite directions: a positive association has been observed between red and processed meat intake and diabetes risk,Considerable progress has been made through the EPIC study and other studies that have advanced understanding of the relationship between dairy consumption and development of type 2 diabetes. However, it is important to note that dairy products should be consumed within an overall healthy diet. Moreover, healthy diets should be complemented with other healthy lifestyle factors, such as taking part in regular physical activity, maintaining a healthy weight, and not smoking, to provide greater potential for the prevention of type 2 diabetes and other chronic diseases.More research on dairy products and health is warranted because there are still unanswered questions. A nonexhaustive list of currently unresolved issues is outlined in Box 1 Sample of unanswered research questions regarding dairy products and health.If there is a cause–effect relationship between dairy product consumption and type 2 diabetes, does dairy intake exert direct effects on insulin sensitivity or are the effects on diabetes risk exerted through changes in weight or obesity?Which components of dairy products exert the health effects, including specific fatty acids, protein, minerals, vitamins, and constituents associated with fermentation? What are the roles of milk sugars in dairy products? What are the mechanisms by which the components of dairy products exert health effects?To what extent are there differences in composition  and health effects by the type of dairy product, such as full-fat, low-fat or reduced-fat or fermented/nonfermented dairy, and are these dependent on cattle-feed? More specifically, how do different types of dairy products vary in their content of 15:0 and 17:0?What is the net effect on cardiometabolic risk of consuming reduced-fat dairy products that have added sugars?As sources of animal-derived protein and fat, how do dairy and meat products compare in their relative effects on cardiometabolic health, and is there a difference in meat products from ruminants vs other animals?Do the odd-chain SFAs such as 15:0 and 17:0 have direct physiological benefits or are they merely correlates of other beneficial substances in dairy products?What is the effect of fatty acids in dairy products (other than SFAs) on cardiometabolic risk?Are there healthy and less healthy dairy options? Should butter be included within the definition of “dairy” or kept separate?To what extent is the consumption of dairy products a marker of overall  diets and  lifestyles?What are the facilitators and barriers to dairy product consumption?Efforts to understand the mechanisms of association and to investigate potential cause–effect relationships between dairy consumption and health outcomes are ongoing, but the collective epidemiological findings thus far suggest that specific types of dairy products, particularly fermented dairy products including yogurt, may help prevent type 2 diabetes within overall healthy lifestyles. Such findings highlight the importance of considering food group subtypes , rather than overall food group categories , when examining the role of diet in the prevention of chronic diseases.


A preliminary speculative framework is outlined, based on the evidence of what appears to be a cohesive set of interactions at molecular, biophysical and electrostatic level between the various components contributing to chromatin conformation and dynamics. It proposes that within plant nuclei, general and localized ionic homeostasis plays an important role in maintaining chromatin conformation, whilst maintaining complex genomic regulation that involves specific patterns of epigenetic marks. More generally, reversible changes in DNA methylation appear to be consistent with the ability of nuclear chromatin to manage variation in external ionic and temperature environment. Whilst tentative, this framework provides scope to develop experimental approaches to understand in greater detail the internal environment of plant nuclei. It is hoped that this will generate a deeper understanding of the molecular mechanisms underlying genotype × environment interactions that may be beneficial for long-term improvement of crop performance in less predictable climates.Crop plants encounter thermal environments which fluctuate on a diurnal and seasonal basis. Future climate resilient cultivars will need to respond to thermal profiles reflecting more variable conditions, and harness plasticity that involves regulation of epigenetic processes and complex genomic regulatory networks. Compartmentalization within plant cells insulates the genomic central processing unit within the interphase nucleus. This review addresses the properties of the chromatin hardware in which the genome is embedded, focusing on the biophysical and thermodynamic properties of DNA, histones and nucleosomes. It explores the consequences of thermal and ionic variation on the biophysical behavior of epigenetic marks such as DNA cytosine methylation (5mC), and histone variants such as H2A.Z, and how these contribute to maintenance of chromatin integrity in the nucleus, while enabling specific subsets of genes to be regulated. Information is drawn from theoretical molecular  Crop plants are sessile autotrophs, represented by relatively few monocotyledon and dicotyledon angiosperm species which lack the internal thermoregulation of hot blooded animals. Modern breeding programs have contributed to increases in yield, with major advances made during a period of relative climate stability. However, the planet has entered a period of climate variability, in which higher global temperatures also increase amplitude and temporal variance of climate parameters, and temperature accounts for over 30% of global crop yield variability . These eSuch issues require a deeper understanding of the molecular mechanisms underlying plant responses to the environment . Crop peThe detection of temperature by plants is required for appropriate responses on multiplexed timescales covering periods from seconds to years , with suAlthough many crop traits and developmental phase changes are dependent upon thermal and ionic signals, conventional genetic models have not provided a complete understanding of the relevant signal transduction pathways and behavior . More reEnvironment is detected in a number of ways, including via effector proteins, small RNAs  and direPlant growth and development progress within biophysical and thermodynamic constraints imposed by the molecular composition of cells . In eukaThe performance potential of crop plants relies on maximizing harvest index, the ratio of harvestable to total biomass . This isin vitro and molecular modeling studies is placed where possible in the context of in vivo observations for model species and crop plants. The contribution of ions to mediating electrostatic interactions of chromatin and epigenetic marks is placed in the context of ionic variation at whole plant level. Recent advances in understanding how specific epigenetic marks mediate plant thermosensory signaling and other responses to abiotic environment are placed in the context of chromatin dynamics and biophysics.This review describes the macromolecular components of the chromatin hardware in which plant genomes are embedded. It explores their biophysical behavior in the context of the ionic and thermal environment of the nucleus, and how this is affected by the local distribution of DNA and histone epigenetic marks. Evidence from A preliminary speculative framework is outlined, based on the evidence of what appears a cohesive set of interactions at molecular, biophysical and electrostatic level between the various components contributing to chromatin conformation and dynamics Figure . It propArabidopsis (125 Mbp), crop genome sizes vary over 60-fold, from around 265 Mbp  to the larger cereal genomes  and other interacting proteins, as well as having greater sensitivity to DNase I , which provide an accurate experimental indication of where the DNA is exposed and accessible . For exaith DHSs , indicatbidopsis . In ricebidopsis . This isbidopsis . Rice DHbidopsis . For probidopsis , while fbidopsis .cis-regulatory and gene body sequences  occurring in all context in plants compared with solely CG in animals, the presence of hydroxymethylated cytosine (5 hmC) in animals, the distinct plant methyltransferases CMT3, DRM1/2, and MET  and defiequences . In addiequences , and tigequences  comparedequences .Various experimental approaches have shown that DNA cytosine methylation contributes to regulating higher order chromatin structure in plants , primariin vitro by 3 bp  in regulation of gene expression makes a significant contribution to definition of cellular identity and coordination of ontogeny . The speleosomes , and a sThe processes underlying hypomethylation that are associated with reprogramming, particularly in establishing pluripotency and imprinting effects in plant and animal systems, are now starting to be uncovered . DynamicThe RNA-directed DNA methylation (RdDM) epigenetic pathway is the primary mechanism by which plants mediate responses involving small RNAs, and is dependent upon the RNA polymerases Pol IV and Pol V, which are specific to plants, along with various accessory proteins currently being characterized . There ide novo methylation of cytosines in each of the CG, CHG, CHH contexts, and although Pol V-mediated RdDM operates over many genomic regions, there appears to be a preference toward euchromatin, more recently acquired intergenic TEs, and genes containing TEs or other repeat sequences in their promoters and introns  affects a wide range of DNA biophysical properties, with variation in the localized patterns of steric and conformational energy, as well as hydrophobic modifications to polarity . TogetheIn addition to DNA flexibility, stacking energies also contribute to the cooperative melting associated with the DNA helical-coil transition that is observed both in naked form  as well These contributions of 5mC to increased DNA duplex stability and reduced flexibility also appear to affect some aspects of nucleosome positioning, as well as the ability of nucleotide sequences to wrap around the histone complex . A pictuArabidopsis, H3.1 is enriched in silent areas of the genome, including those with the H3K27me3 and H3K9me3 modifications that contribute to transcriptional repression, as well as with DNA methylation tetramer . These dtetramer , and cantetramer .Sequence analysis of human H2A.Z and H2A-containing nucleosomes has also indicated a prominent association with DNA flexibility at nucleosome boundaries , with H2By adding a negative charge, phosphorylation of H1 generally has the effect of weakening the electrostatic interaction between H1 and DNA, thus increasing H1 mobility . Althoug+ to sustain nuclear function  had the effect of increasing meiotic chiasmata frequency at 30°C, although with little effect at 20°C  is the most abundant inorganic cation in plants, representing up to 10% of dry weight  analysis suggesting a significant role for variation in K+ transporters  present in soil solution, allowing about 2% to be transported in the xylem to shoots . Na+ sev+ ratios . Thus, w+ ratios . Na+ toxribution . Rice apribution , and so nd 80 mM .Medicago callus cultures indicated that while short term exposure to NaCl in had no effect on histone variant composition, it did lead to major increases in acetylation of H3.1, H3.3, and H4  hypermethylated in shoots  provides a useful demonstration of the consequences of temperature variation at different phases of development, with each phase transition typically sensitive to a genotype-specific optimal temperature range , the mobile integrator gene of the floral pathway.The autonomous flowering pathway was conventionally regarded as being independent of environmental signals such as photoperiod. However, mutant analysis has demonstrated that genes of this pathway are also directly involved in mediating the effects of ambient temperature , with coFT locus mediates the thermosensory flowering pathway , where candidate genes at such loci appear to account for differences between over-wintering and summer crop types  has been repressed by transposon insertion, with high levels of 5mC in both B. napus and the ancestral B. oleracea. Meanwhile the FT-A7/C6 homologs are specifically silenced in winter type B. napus, but abundantly expressed in spring type cultivars under vernalization-free conditions.Detection of accumulated thermal units or growing day degrees above or below a threshold has been resolved to major QTLs , even inop types . NaturalFT locus . In B. nbidopsis  with probidopsis  indicatiArabidopsis, dissection of the molecular mechanisms underlying vernalization has uncovered the role of epigenetic marks, particularly the polycomb-mediated additive effect of histone modifications, which under cold conditions regulate silencing of the flowering repressor FLOWERING LOCUS C  albeit transitory effect of hypomethylation in mature leaves compared with untreated controls at the same stage of development. These phenomena appeared to be reversible, as after 7 days growth at 22°C DNA methylation in seedlings developed from the vernalized controls was comparable to those of control seedlings. Cold stress has since been found to lead to genome-wide demethylation in maize seedlings (Antirrhinum majus in low-temperature conditions results in hypomethylation of the transposon Tam3 (An early study by eedlings , while gson Tam3 . A relatson Tam3 .Arabidopsis cold-responsive genes COR15A and ATGOLS3 (Histone methylation at H3K27me3 has also been shown to decrease gradually during cold exposure in two  ATGOLS3 . It appeOur current understanding of the direct involvement of ionic and temperature variation on chromatin structure and transcription is fragmentary. However, it is clear that some key biophysical properties of chromatin components and epigenetic marks are affected by electrostatic and thermal interactions, and these more fundamental observations are starting to align with observations at cellular and whole organism level. In order to unravel these relationships, experimental approaches need to distinguish between direct effects and those mediated by signal transduction pathways that sense variation in external ionic or temperature environment and are then apparent at the level of epigenetic modifications.Few studies have systematically evaluated the ensemble of interactions that place the ionic and thermal environment, the biophysical attributes of 5mC, H2A.Z and other epigenetic marks in the context of chromatin dynamics and genomic regulation . Thus, aTaken together, the various lines of evidence outlined here appear to be internally consistent in describing contributions to accessible versus inaccessible chromatin. The framework that emerges is based on what appears to be a cohesive set of interactions at molecular, biophysical and electrostatic level between the various components that affect chromatin conformation and dynamics. This is represented in a simple schematic Figure  that outThe contributions of 5mC to local DNA stability and reduced flexibility appear to be consistent with the association of 5mC with stable, more ordered nucleosomes and localized transcription, with denser methylation leading to tighter chromatin and gene repression. The complementary contributions of 5mC and H2A.Z to less accessible chromatin is consistent with their observed relative mutual exclusivity in chromatin , and H2A+ and K+ in chromatin condensation (+ and K+ gradients are observed within some eukaryote nuclei (Complex electrostatic interactions within the nucleus contribute to the condensation state of chromatin, with the localized net charge state of the interaction between DNA and histone affecting position and stability of nucleosomes. Post-translational histone modifications play a major role, although it is currently unclear how these may be affected by the proposed differential roles played by Naensation . The late nuclei . Given te nuclei  and concWhilst tentative, this framework provides scope to develop experimental approaches to understanding in greater detail the internal environment of plant nuclei. It is hoped that this will generate a deeper understanding of the molecular mechanisms underlying genotype × environment interactions that may be beneficial for long-term improvement of crop performance in less predictable climates.Arabidopsis (Arabidopsis, spontaneous transgenerational epiallelic variation can occur at a rate 103 times higher than the genetic mutation rate (A high proportion of crop traits exhibit quantitative inheritance, many with relatively low penetrance. For example, in rapeseed hundreds of significant environment-specific QTL have been identified for yield and other traits in a “fixed” segregating population of homozygous lines grown in 10 environments, with relatively few coinciding in multiple environments . In manybidopsis . It is wion rate , with hyion rate . This stion rate . For croAt present we have only a partial understanding of how the various epigenetic components confer dynamic functional information content in the context of the ionic and thermal environment of the nucleus. It is becoming clear that most regions of complex eukaryotic genomes play some role in gene regulation . HoweverThe ability of plants to accommodate fluctuations in thermal and ionic environment is an essential fitness attribute and a key determinant for crop performance, and requires a deeper understanding of the interactions at intra-cellular and intra-nuclear level, including those with epigenetic marks and processes. The availability of comprehensive tissue-specific epi-genome, nucleosome and snRNA datasets will contribute to more comprehensive models of interactions between genome organization, chromatin dynamics, and epigenetic signaling systems. These can help provide new tools and approaches for breeding selection and agronomic management of crops able to perform in changeable environments.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Inflammatory choroidal neovascularization is a severe but uncommon complication of uveitis, more frequent in posterior uveitis such as punctate inner choroidopathy, multifocal choroiditis, serpiginous choroiditis, and Vogt-Koyanagi-Harada syndrome. Its pathogenesis is supposed to be similar to the wet age related macular degeneration: hypoxia, release of vascular endothelial growth factor, stromal cell derived factor 1-alpha, and other mediators seem to be involved in the uveitis-related choroidal neovascularization. A review on the factors implicated so far in the pathogenesis of inflammatory choroidal neovascularization was performed. Also we reported the success rate of single studies concerning the therapies of choroidal neovascularization secondary to uveitis during the last decade: photodynamic therapy, intravitreal bevacizumab, and intravitreal ranibizumab, besides steroidal and immunosuppressive therapy. Hereby a standardization of the therapeutic approach is proposed. Beside the well-known choroidal neovascularization (CNV) in the age related macular degeneration (ARMD) in myopic eyes or in angioid streaks, neovascular membranes can develop even as a complication of uveitis with an incidence of 2% , accountThe prevalence of CNV secondary to uveitis varies among different entities, commonly occurring in presumed ocular histoplasmosis (POHS) 3.8%), toxoplasmosis, punctate inner choroidopathy (PIC) 17–40%), idiopathic multifocal choroiditis (MC) (33%), and serpiginous choroiditis (SC) . Yet, CN7–40%, id.8%, toxoInflammatory CNV can develop close to chorioretinal scar or choroidal granuloma and is classified topographically as foveal, juxtafoveal, or extrafoveal. The first is often early recognized by the patient himself complaining of metamorphopsia or central scotoma and can lead to the diagnosis of a subclinical posterior or intermediate uveitis. Otherwise, an extrafoveal membrane may be asymptomatic and can be found only at a follow-up examination or in case of posterior pole acute hemorrhage. As in ARMD, the microscopical features define type 1 or type 2 membrane, if it invades or not the subretinal space. In uveitis the classic membrane strongly shows the main type; it has a grayish appearance with an evidence of exudative or hemorrhagic foci surrounding the lesion. However, opthalmoscopically subretinal membrane could be missed because of very few levels of exudation; the only indirect sign could be a small intraretinal hemorrhagic lesion. Atrophic CNVs are yellow-white plaques. Often a bigger CNV can have a mixed pattern, bearing active foci in a globally fibrous plaque. A membrane can manifest only with macular edema or serous retinal detachment; however, macular edema and serous retinal detachment also can represent signs of inflammation found in course of intermediate/posterior uveitis, leading sometimes to a misdiagnosis or imprecise evaluation of the activity of the underlying disease.In this case the role of the diagnostic imaging is crucial. Fluorescein angiography (FA) has been for long time the principal way to assess the presence and the activity of a CNV in uveitic patients, showing early hyperfluorescence in the choroidal phase and late leakage, associated sometimes with screen effect in presence of blood or pigment. Indocyanine green angiography (ICG) is useful for highlighting the feeder vessel or occult membranes; the new Heidelberg SLO video ICG enhances the diagnostic potentialities of this procedure. Nowadays a growing role is played by optical coherence tomography (OCT), a fast, noninvasive instrument able to assess the presence and the activity of the disease. Kotsolis et al.  showed tGiven the low incidence of inflammatory CNV and the difficulty in obtaining a reliable experimental model, most of our knowledge about this disease is mutated from the histopathological studies on ARMD-related CNV, supposing that similar clinical features correspond to common biological pathways.In CNV a key role of vascular endothelial growth factor (VEGF) in the new blood vessels development has been widely demonstrated , 6.VEGF is produced by endothelial cells, pericytes, Müller cells, Ganglion cells, photoreceptors, and RPE cells that can produce the growth factor in a polarized way towards Brüch's membrane and choriocapillaris , 8. The The endothelial progenitor cells (EPCs) are attracted by the stromal cell derived factor 1-alpha (SDF1) that is known to be secreted by hypoxic or damaged retinal pigment epithelium (RPE) or retina , 13. TheGuerin et al.  performeP values of the comparisons are reported. The study is underpowered for most of the comparisons but, interestingly, a low P value was found for the CXCR4 staining of the vascular meshwork of uveitis-related CNV versus ARMD-related CNV, suggesting that capillaries have a different role in the membrane development. Further studies on this distinctive aspect should be necessary.Furthermore we performed an adjunctive statistical analysis on the dataset reported by Guerin: using Mann-Whitney test (in R environment ) we testα (TNFα) and IL-1 [CNV has also an extravascular component consisting in fibroblasts and leucocytes that express the CXCR4 themselves; furthermore RPE cells showed an increased production of tumor necrosis factor and IL-1  recruitiand IL-1 .β (TGF-β) is responsible for the process of recruiting choroidal fibroblasts, but on the other hand, at the same time, it induces the production of VEGF leading to the formation of new active foci [Other mediators play a role in the membrane development: nitric oxide that induces the membrane formation, besides angiostatin, endostatin, CCR3, and the pigment epithelium derived growth factor (PEDF) contrasting the neovascularization. Focally the membrane can become fibrous and it is thought that the transforming growth factor ive foci .Understanding the uveitis as better as possible and identifying underlying infectious diseases are mandatory in order to keep the inflammation under control using the correct medical therapy. The use of steroids and immunosuppressors  has showIn the literature most of clinical studies on inflammatory CNV therapy are case series with few underpowered retrospective studies often uncontrolled. Commonly patient selection was done in many different ways , making any attempt of rigorous meta-analysis impossible. We focused on the three main therapies available in the last decade: (i) photodynamic therapy (PDT), (ii) intravitreal bevacizumab (IVB), and (iii) intravitreal ranibizumab (IVR). We selected most important published articles in the last ten years with more than 2 subjects and, where possible, we extracted the data of patients. In The first articles report the case series on the PDT; overall success rate is quite high (78.4%) compared to previously reported significative vision loss in untreated patients (77% VA below 20/100) . In mostAlthough more than 30 articles were published about the argument, a decision about the treatment of inflammatory CNV cannot be assessed on evidence based medicine, as case series and uncontrolled studies are in the lower half of the scale of scientific evidences. Thus, well-designed randomized clinical trials should be necessary, but a correct comparison between the three main therapeutic strategies would need studies with a large number of people, which is not feasible for a rare complication of a rare disease such as posterior uveitis with strict inclusion and exclusion criteria.thorough control of the underlying inflammation using steroids, immunosuppressors, or specific treatment where appropriate;use of PDT for early extrafoveal lesions not causing a decrease in the VA, a less invasive procedure is always preferable in a uveitic eye in order to keep the possibility of flogosis reactivation low;use of IVR for foveal or juxtafoveal membranes or as second line therapy after PDT, the paper of Battaglia-Parodi demonstrated a higher VA for the IVB, but this drug is currently off-label for intravitreal use, and we could expect similar efficacy. Furthermore the literature showed that inflammatory CNV needs much less intravitreal injection than ARMD-related CNV to achieve the complete regression of the membrane.Every year there is the announcement of new therapeutic approaches for wet ARMD, aflibercept, and stereotactic radiotherapy as examples, and the treatment of inflammatory CNV will benefit from these news although again it will be difficult to obtain a specific randomized controlled trial, so necessarily we will have to rely on indirect data.A wise therapeutic approach we may suggest is the following:


The (PhTe)2-evoked signal is transduced downstream of voltage-dependent Ca2+ channels (VDCC), N-methyl-D-aspartate receptors (NMDA), or metabotropic glutamate receptors activation via different kinase pathways , and Akt signaling pathway). Among the most relevant cues of misregulated signaling mechanisms evoked by (PhTe)2 is the cytoskeleton of neural cells. The in vivo and in vitro exposure to (PhTe)2 induce hyperphosphorylation/hypophosphorylation of neuronal and glial intermediate filament (IF) proteins  in different brain structures of young rats. Phosphorylation of IFs at specific sites modulates their association/disassociation and interferes with important physiological roles, such as axonal transport. Disrupted cytoskeleton is a crucial marker of neurodegeneration and is associated with reactive astrogliosis and apoptotic cell death. This review focuses the current knowledge and important results on the mechanisms of (PhTe)2 neurotoxicity with special emphasis on the cytoskeletal proteins and their differential regulation by kinases/phosphatases and Ca2+-mediated mechanisms in developmental rat brain. We propose that the disrupted cytoskeletal homeostasis could support brain damage provoked by this neurotoxicant.Evidence from our group supports that diphenyl ditelluride (PhTe) Tellurium (Te) is an element sharing the same group of sulfur and selenium in the periodic table; that is, it is the heaviest of the stable chalcogens group 16) and is classified as a metalloid. In contrast to oxygen, sulfur, and selenium, tellurium has no essential physiological role in cell biology 6 and is –6). In a2, has been described to possess very contrasting and interesting biological activities glutamate uptake, emphasizing a critical role of altered Ca2+ levels in this process, since IP3 and ryanodine receptors may be important sensors of disturbed intracellular Ca2+ homeostasis [2 produced alterations in Ca2+ homeostasis and glutamatergic neurotransmission which lead to excitotoxicity and neurodegeneration in the developing rat brain.Neurodegeneration in (PhTe)eostasis . On the 2-injected rats, it is feasible that this neurotoxicant is not able to provoke demyelination in the CNS, in contrast with peripheral demyelination described in rats [ in vivo actions of (PhTe)2 in the brain of young rats is depicted in Taking into account the great deal of evidence of NF hyperphosphorylation evoked in cerebral cortex, cerebellum, and striatum of (PhTe) in rats , 21, 232 in rats , 233. A 2 causes gestational and lactational toxicity [2 together with the high vulnerability during a period of intense brain development define the high vulnerability of perinatal rat brain as important targets of intoxication with Te.There are experimental points of evidence that (PhTe)toxicity , 90. Contoxicity . Thus, tThe immature brain is a much more dynamically active tissue than the mature brain. Its high degree of plasticity and a broad range of potential developmental directions underlie developmental toxicity studies, indicating that maternal toxicity during the pregnancy and/or lactation has been shown to produce adverse effects in offspring . Althoug2 could be detected in their offspring has been previously reported. High doses of (PhTe)2 (0.12 mg/kg of body weight) can be teratogenic to rat and mice fetuses, causing malformations in fore- and hind-limbs, absent or short tail, subcutaneous blood clots, exophthalmia, hydrocephalus, and presence of exposed brain. However, the mice are less susceptible to toxic effects induced by (PhTe)2 than the rats, suggesting a different developmental toxicity induced by (PhTe)2 among species [Evidence that the toxic effects of maternal exposure to (PhTe) species , 90.2 (0.03 mg/kg of body weight), via maternal milk, caused oxidative stress in brain structures of young rats. The exposure to (PhTe)2 increased lipid peroxidation and inhibited δ-aminolevulinate dehydratase (δ-ALA-D), catalase, and superoxide dismutase (SOD) activities in hippocampus and striatum of young rats. Moreover, dam exposure to the same concentration of (PhTe)2 induced changes in the levels of nonenzymatic defenses in cerebral cortex and striatum of the lactating rats. Supporting the relevance of maternal milk as an important via of toxicity with the (PhTe)2, exposure of dams to low levels of (PhTe)2 during the first 14 days of lactation causes neurobehavioral changes of their offspring, which emphasizes the potential neurotoxicity of organic tellurium compounds [2 (0.01 mg/kg of body weight) evoked aberrantly phosphorylated astrocyte and neuron IFs observed on PND 15 and 21 in striatum and cerebellum of rats. On the other hand, exposure to (PhTe)2 via maternal milk provoked hyperphosphorylation of IF protein in the hippocampus only on PND 21 and 30 (unpublished results), evidencing a latter effect in this brain structure. This is in line with ex vivo and in vivo studies reporting disrupted phosphorylation level of hippocampal IFs in 21-day-old rats [Stangherlin et al.  demonstrompounds . Disruptold rats , 183. Thold rats .2 was spatiotemporally regulated, and the posttraductional mechanisms regulating the cytoskeleton from striatum and cerebellum in younger pups are more susceptible to the action of the neurotoxicant than in older ones. In fact, suckling rats can be considered extremely susceptible to (PhTe)2-induced neurotoxicity, since the dose of (PhTe)2 given to dams was extremely low. As a corollary, the offspring of (PhTe)2-treated dams is expected to be exposed to telluride levels much lower than those given to their mothers.The effect of (PhTe)2 via maternal milk comes from the previously reported inhibition of glutamate uptake and Na+/K+ATPase activity in the brain of pups from exposed dams [+/K+ATPase activity as well as disrupted cytoskeleton could be involved in the neurobehavioral changes of the offspring.Further evidence of the great susceptibility of pups to the toxic effects of (PhTe)sed dams . Moreovesed dams . This co2 reaches the brain of their offspring via systemic circulation, we are tempted to propose that results from the animal model could mimic the risk of a potential (PhTe)2 exposure of pregnant or lactating women to their babies. However, little information about human intoxication with (PhTe)2 during pregnancy and lactation is available in the literature and further efforts will be necessary to understand the pathology of this compound.Taking into account the whole evidence that, following maternal exposure, (PhTe)2 toxicity that remain posed relate to the mechanisms that underlie their actions in the CNS. To address this question, we have focused our efforts on the actions of this neurotoxicant targeting the endogenous phosphorylating system associated with the cytoskeleton of neural cells of young rats. It is always expected that the deleterious effects of a toxin are preferentially expressed during development, since the intense plasticity underlying the developmental events [The major questions concerning the (PhTe)l events , 216 is 2 in neural cells of rats. Central to its function is its dynamic phosphorylation and defects in the capacity to maintain the homeostasis of IF phosphorylation would probably have detrimental effects on cell function. These actions are complex, and integrated processes carefully and precisely orchestrated by the cell through membrane receptors and channels are able to activate diverse signal transduction pathways misregulating the homeostasis of the cytoskeleton. It is remarkable that Ca2+-mediated mechanisms were shown to play a central role in these membrane-initiated mechanisms. It is presumed that aberrantly phosphorylated/dephosphorylated IF proteins may interfere with neural cell structure and function which is associated with neurodegeneration in young animals. Further studies on membrane receptors and their downstream events might provide us with new insights into the molecular basis of the mechanisms triggered by the toxicant in brain. Although cell signaling transduction of (PhTe)2 does not have necessarily the same mechanisms in different brain regions, the Ca2+-initiated events highlight a role for this neurotoxicant as a disruptor of the cytoskeleton.Compelling evidence from our group supports that IF proteins could be crucial in mediating spatiotemporal responses to (PhTe)2 on the developing brain, a fact that might explain at least in part the neurotoxicity of this compound; however, these consequences need further investigation. One aspect that needs further investigation is the effect of inorganic tellurium on IF phosphorylation. This is particularly relevant in view of the increased industrial use of tellurium in electronic devices.Taking into account the relevance of the signaling mechanisms targeting the cytoskeleton during early postnatal brain development, we presume that the spatiotemporal misregulation of the homeostasis of the cytoskeleton we evidenced can probably contribute to the deleterious action of (PhTe)2-mediated injury. These studies provide the opportunity to examine cellular, molecular, and morphological changes after exposure to the neurotoxicant. However, extrapolation of conclusions from animal data to human beings must be done with caution. Of particular experimental importance, the study of (PhTe)2 neurotoxicity can be instrumental to understand not only the basis of tellurium toxicity but also the role of pathways involved in the neuropathology of different types of brain diseases associated with neurodegeneration and aging.We think that our studies in injected rats or in acute brain slices have made important contributions to our understanding of (PhTe)


Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome . In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes.The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in  DNA methylation was the first described epigenetic mark of eukaryotic genomes shown to affect gene expression, and perturbations to this process were rapidly suspected to cause aberrant transcription in physiopathological situations like aging and cancer .DNA methylation within mammalian genomes is found mainly within the context of CpG dinucleotides. Recent advances in high throughput sequencing have enabled the generation of base pair resolution maps of DNA methylation in an array of different cell types and developmental stages. These maps have unveiled the uneven distribution of DNA methylation, in particular with respect to CpG density ,3. They de novo methyltransferases DNMT3A and DNMT3B, which are highly expressed in embryonic stem cells and are subsequently down-regulated during development in most tissues. These enzymes, in concert with their catalytically inactive cofactor DNMT3L, or alone, depending on the developmental context [de novo methyltransferases in the maintenance of methylation patterns at loci such as germ line genes and repetitive elements, suggesting that these enzymes participate in the silencing of these regions in many cellular and developmental contexts [DNA methylation is established and maintained by three enzymes with DNA methyltransferase activity, all of which are essential for life ,15. Semi context ,19, ensu context . In addicontexts ,22,23.DNMT3B shares structural organization with DNMT3A. Both proteins possess a variable N-terminal domain, which is followed by a moderately conserved PWWP (Pro-Trp-Trp-Pro) domain . This doDNMT3B human gene has 23 exons. The full length DNMT3B1 isoform is strongly expressed during early development and is barely detectable in differentiated cells. Many isoforms have been described for DNMT3B, which result from alternative splicing as mentioned above and/or alternative promoter usage [de novo DNMTs and regulate their activity; DNMT3B3 stimulates the basal activity of DNMT3 enzymes, but partially inhibits the stimulatory effect of DNMT3L, whereas DNMT3B4 significantly impairs de novo methylation [The er usage . Notablyer usage ,34,35. Der usage ,30. Theshylation .de novo DNA methyltransferases being implicated in establishment of methylation profiles, one can assume that the enzymes themselves are not randomly recruited to the genome. The identification of genomic regions preferentially methylated by DNMT3B has been largely inferred from studies involving the targeted disruption of the gene in mice and from the analysis of molecular defects observed in human diseases. The first genomic regions shown to be affected by loss of Dnmt3b function were not protein-coding regions, but non-coding repetitive elements found around centromeres [With DNA methylation being non-randomly distributed, and with two tromeres ,36.per se, that serves as the point of assembly for the kinetochore, and flanking heterochromatin domains, thought to protect the centromere and ensure sister chromatid cohesion [In most higher eukaryotes, these regions are assembled on large arrays of tandemly repeated DNA sequences, which can be divided into two distinct functional domains ; the cencohesion . In the cohesion . The concohesion . In humacohesion .Molecular analysis of mutant mouse embryos lacking Dnmt3b and those lacking Dnmt3a have suggested that Dnmt3b is specifically required for the methylation of centromeric minor satellites whereas Dnmt3a preferentially methylates pericentromeric heterochromatin . The parThe discovery of additional loci affected by the loss or reduced function of DNMT3B awaited the detailed transcriptional analysis of mouse embryos deficient or partially deficient in Dnmt3b, which revealed the aberrant activation of many genes, of which the most deregulated are normally mainly expressed in the germ line ,50. Promde novo methylation of repetitive sequences located in pericentromeric constitutive heterochromatin. The non-satellite repeats NBL2 and D4Z4, which are aberrantly methylated in particular pathological contexts [In humans, DNMT3B appears to be the major enzyme involved in the contexts ,55, are contexts . Likewiscontexts . Perhapscontexts . Howevercontexts .Thus, in humans, DNMT3B loss of function appears to mainly affect methylation at DNA repeats within or proximal to large heterochromatin domains, consistent with DNA methylation being a hallmark of heterochromatin and DNMT3B playing the principal role in its establishment and maintenance. In the mouse, Dnmt3b cytologically accumulates on constitutive heterochromatin nuclear domains formed by pericentromeric repeats and Dnmt3b loss of function is linked to its delocalization from these domains ,61. In tDNA methylation is highly dynamic during development and patterns of DNA methylation are reprogrammed genome-wide at two different stages: once in pre-implantation embryos and again at a later time point in developing germ cells .de novo methylation is required for the differentiation of the epiblast, as shown by the lethality at gastrulation of embryos deficient of both de novo methyltransferases Dnmt3a and Dnmt3b [In the mouse, a wave of methylation erasure occurs in the early embryo . Enzymesd Dnmt3b ,67. Howed Dnmt3b . This cod Dnmt3b .de novo methyltransferases Dnmt3a and Dnmt3b, a bias towards methylation of high CpG island promoters in EpiSC was recently described [in vitro and “in embryo” cells show a strikingly different promoter methylation profile [in vitro. Along the same lines, when cultured in serum conditions, mouse ESCs fluctuate between a naive ICM-like state and a primed epiblast-like state. However, recent reports have shown that ESCs cultured with inhibitors of the mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 pathways (2i), that more faithfully recapitulate the naive state of ICM cells, are significantly more hypomethylated than their serum-cultured counterparts, consistent with low methylation levels found in pre-implantation blastocysts [In murine embryonic pluripotent cells captured in culture, ESC derived from the inner cell mass (ICM) or the late epiblast of post-implantation embryos (EpiSC) do not display quantitative differences in DNA methylation . Howeverescribed . However profile . Not surstocysts ,73.de novo methylation during early embryogenesis, and the absence of DNA methylation leads to ectopic gene activation in the embryo. Methylation at centromeric sequences in ES cells has been more difficult to dissect. In serum-cultured ESCs, many repetitive DNA elements, including centromeric repeats, are highly methylated as they are in somatic cells [de novo Dnmts described for the ICM in vivo. Therefore, repetitive elements, in particular centromeric sequences, are probably hypomethylated in the ICM of pre-implantation embryos.These systems have been widely used to decipher when and where on the genome DNA methylation is established early in development. Major changes occur at the transition from the blastocyst to the post-implantation epiblast, where DNA methylation is primarily targeted to repress the germ line expression program and lineage-affiliated genes such as haematopoietic genes . Dnmt3b ic cells , althougic cells . In “2i”ic cells ,76, recade novo methylation in the germ line [DNA methylation is reprogrammed a second time in developing germ cells . The majerm line . Thus, iAs mentioned above, most CpGs outside CpG islands and regulatory elements are methylated in somatic cells in contrast to the majority of CpG islands that remain unmethylated throughout development. However, CpG methylation is highly dynamic. Although variation may occur stochastically during development and lineage specification, certain CpG islands become selectively methylated, raising the question of how this selectivity is achieved ,3,82.et al. used an approach in which various promoter fragments were targeted to the same genomic insertion site in ESCs to show that DNA methylation is primarily dictated by cis-acting sequences and they identified autonomous methylation determining regions (MDRs) that reside within promoter elements [Classic studies established that the unmethylated state of promoter CpG islands is strongly influenced by transcription factor binding. For instance, CpG islands can acquire methylation following deletion or mutation of promoter Sp1 binding sites ,84. Lienelements . DNMT enelements . Hervoueelements . Among telements  or otherelements .de novo methylation to these regions. Indeed, DNMT3B interacts with the centromeric-specific protein CENP-C, which appears to be important for its recruitment to centromeric regions [Given the lack of sequence conservation of centromeric repeats amongst species, it is highly likely that other mechanisms besides DNA sequence are involved in the targeting of  regions . In addi regions ,4. The i regions , thus ex−/−Lsh and −/−Dnmt3b cells should have similar molecular defects. Indeed, DNA methylation defects in these mutants are strikingly similar [−/−Lsh cells than in −/−Dnmt3b cells, suggesting that Lsh participates in DNA methylation at particular sequences independently of Dnmt3b [The lymphoid-specific helicase LSH (HELLS) is also emerging as a key factor that may be involved in crosstalk between chromatin environment and the establishment of DNA methylation. LSH is a member of the SNF2 family of helicases that are involved in chromatin remodeling . Althoug similar , notablyf Dnmt3b .de novo methylation of rRNA genes [de novo methylation to these regions in mammals.In the developing germ line, small non-coding RNAs are important for the establishment of DNA methylation at transposable elements . Non-codNA genes . Grummt NA genes . AlthougNA genes ,47,48. TDNMT3B lead to perturbed methylation patterns [Given the pivotal role that DNA methylation plays during development to regulate gene expression, it comes as no surprise that aberrant patterns of methylation are associated with many human diseases . These mpatterns . Both diOne of the first reports to establish a clear connection between DNA methylation and cancer came from Feinberg and Vogelstein in 1983, who found hypomethylation in primary tumor samples . Such reDnmt3b in the context of Myc-driven lymphomagenesis resulted in a dramatic increase in the incidence of lymphoma, coincident with alterations in DNA methylation profiles. This suggests that Dnmt3b can act as a haplo-insufficient tumor suppressor gene in the context of myeloid malignancies. Another possible source of altered patterns of DNA methylation in cancer cells is the expression of splice variants. Godley and colleagues documented over 20 DNMT3B transcripts from various cancer cell lines and primary acute leukemia cells that were alternatively spliced at the 5' end of the gene. These variants encode truncated proteins lacking all or part of the C-terminal catalytic domain that may act as dominant-negative isoforms [in vitro [MAEL, SYCE1, and SYCP1, are aberrantly expressed in human cancers and are listed as cancer testes genes [DNMTs are frequently deregulated in cancers. The general trend appears to be towards the over-expression of these enzymes, which may explain the hypermethylation of TSGs . Nonetheisoforms . Indeed,in vitro . Ectopicin vitro ,89. A diin vitro ,50, incles genes .DNMT3B are responsible for the autosomal recessive disease named Immunodeficiency with Centromeric instability and Facial anomalies (ICF syndrome) [et al. [Germ line gene mutations in yndrome) ,36,113. yndrome) ,115. ICFyndrome) , suggest [et al. . Facial The characteristic chromosomal instabilities that are observed in mitogen-stimulated peripheral blood cultures are used for diagnostic purposes. Decondensation of juxtacentromeric heterochromatin of chromosomes 1, and 16, and to a lesser extent chromosome 9, leads to a wide variety of chromosomal anomalies including chromosome breaks and rearrangements, whole-arm deletions, and often multi-branched chromosomes containing three or more arms of chromosome 1 and 16 joined in the vicinity of the centromere ,119,120.DNMT3B, referred to as ICF1 patients. All affected individuals are homozygotes or compound heterozygotes, mostly for mutations in the C-terminal portion of the protein that contains the catalytic domain [ICF is a genetically heterogeneous disease ,124. Fifc domain . This suc domain . ICF mutc domain .zinc-finger and BTB domain-containing 24 (ZBTB24) gene [DNMT3B or ZBTB24, which have been referred to as ICFX [DNMT3B would be caused by mutations in genes that are functionally related to DNMT3B, for example factors that are important for the recruitment of DNMT3B to its target sites. However, molecular and clinical differences between ICF1, ICF2, and ICFX patients are emerging, which is consistent with the involvement of several pathways. In addition to the characteristic Sat II and Sat III sequences, patients without mutations in DNMT3B also show hypomethylation of centromeric α-satellite DNA [MAEL and SYCE1, which we had identified previously as targets of Dnmt3b in the mouse [Zbtb24 mutations on the methylation of these repeats has not been determined. We also identified two ICFX patients with molecular characteristics somewhere in between an ICF1 type and an ICFX type [A proportion of ICF patients possess mutations in the 24) gene , referre24) gene ), howeve as ICFX . It was lite DNA . We havehe mouse , are hyphe mouse . Howeverhe mouse ,131. YetCFX type . Indeed,Clinical heterogeneity has recently been documented amongst ICF1, ICF2, and ICFX patients, with ICF1 patients displaying a pronounced impairment in humoral immunity and ICF2 patients showing a high incidence of intellectual disability . The ideThe hypomethylation of germ line genes and centromeric repeats constitute molecular signatures of the ICF syndrome and cancer  but it iDrosophilamelanogaster [The hypomethylation and off context expression of germ line genes in somatic cells during carcinogenesis is thought to confer phenotypic traits, including immortality, invasiveness, and immune evasion that are essential for the survival and function of gametes but are hijacked in somatic cells to drive malignancy . In partnogaster . In ICF nogaster , raises During early development in the mouse, satellite sequences are transcribed in the testis and brain , in undiper se is not sufficient to promote their transcription, at least in cultured cells. Overall, there is a clear correlation between DNA hypomethylation of satellite repeats and their strong transcription in certain cellular contexts, although the relationship between methylation and transcription at these regions appears complex. However, this raises the interesting possibility that tissue-specific or developmental stage-specific factors are required, and may explain why all tissues of the ICF patients or mice are not similarly affected.How perturbations to the methylation status of these regions directly affect cellular phenotypes is not known. In addition to the alteration of gene expression programs, the hypomethylation of satellite repeats is believed to contribute to chromosomal instability that is typical of cancer cells and ICF patient cells. An emerging possibility is that hypomethylation leads to the aberrant transcription of underlying repeat sequences, as illustrated by treatment of cultured cells with the DNA demethylating agent 5’azacytidine that promotes the accumulation of pericentromeric transcripts in human cells  or centr−/−Dnmt3b−/−Dnmt3a ES cells is lower than in wild-type ES cells, and this is associated with a higher rate of centromere mitotic recombination in −/−Dnmt3b−/−Dnmt3a ES cells [It is also possible that DNA methylation at centromeric repeats plays additional roles besides transcriptional regulation. The number of centromeric repeats in mouse ES cells . Thus, DThe hypomethylation of telomeric and sub-telomeric repeats in ICF patient cells is also associated with abnormally short telomeres in both the telomerase-positive and -negative cells, suggesting that DNA methylation may protect cells from telomere shortening . FurtherRepetitive sequences play an essential role in the three-dimensional organization of the nucleus through the formation of repressive compartments ,150. Thutrans and contribute to the developmental defects of ICF patients and to the phenotypic characteristics of cancer cells. The nuclear volume occupied by the juxtacentromeric compartments of chromosomes 1 and 16, along with their positioning relative to the nuclear periphery, differs between cells from ICF patients and those from healthy individuals [Alterations to juxtacentromeric heterochromatin resulting from DNA hypomethylation leads to perturbed nuclear heterochromatin and mis-localization of associated proteins . These pividuals . The autividuals . Three ode novo DNMTs is crucial for our understanding of normal and pathological development, and animal models have been indispensable for the elucidation of methylation patterning.The establishment of correct patterns of DNA methylation is essential for normal development, and the loss of or deviation from these patterns is a critical event in many human diseases. Thus, the identification of the targets of No clear mechanistic link between genomic hypomethylation and chromosomal instability has been yet established, and cells from ICF patients and ICF mouse models constitute powerful tools to study the complex relationship between DNA hypomethylation and pathological phenotypes, although there are some limitations regarding the sequence conservation between human and mouse centromeric/pericentromeric satellite repeats. They also provide a unique opportunity to study the targets and function of DNMT3B in a human or murine context free from experimental manipulation. Indeed, these systems may be used to examine the role of DNA methylation at satellite repeats, the complex relationship between hypomethylation and transcription of these regions, and the relevance for perturbed molecular and nuclear phenotypes. Many questions still remain about the identity of factors that are important for the establishment of DNA methylation at germ line genes and centromeric repeats and the study of the ICF syndrome is likely to provide some clues to this conundrum. Indeed, human genetic studies of the ICF syndrome have identified a new player in DNA methylation at DNA repeats in centromeric regions, ZBTB24, and functional studies will soon dissect the role of this factor in the establishment or maintenance of methylation. The identification of more factors from the study of ICFX patients seems probable and will contribute to our understanding of how DNA methylation is established and maintained at centromeric and pericentromeric DNA repeats. Finally, further studies of the significance of the off-context expression of DNMT3B targets, in particular centromeric RNA and germ line genes, will help to elucidate the specific contribution of these factors to pathological phenotypes and may even firmly establish them as viable therapeutic targets or powerful biomarkers.


The central nervous system (CNS) is a highly complex network comprising long-lived neurons and glial cells. Accordingly, numerous mechanisms have evolved to tightly regulate the initiation of inflammatory responses within the brain. Under neuroinflammatory conditions, as in the case of viral encephalitides, the infiltration of leukocytes is often required for efficient viral clearance and recovery. The orchestration of leukocyte migration into the inflamed CNS is largely coordinated by a large family of chemotactic cytokines and their receptors. In this review, we will summarize our current understanding of how chemokines promote protection or pathogenesis during arbovirus induced encephalitis, focusing on neurotropic flaviviruses and alphaviruses. Furthermore, we will highlight the latest developments in chemokine and chemokine receptor based drugs that could have potential as therapeutics and have been shown to play a pivotal role in shaping the outcome of disease. Arboviruses (arthropod-borne viruses) are a significant cause of human morbidity and mortality and have worldwide distribution. In recent years, these viruses have become an increasing public health concern due to climate change, increased globalization, and other environmental factors, that have caused their unexpected geographic expansion and increased the frequency of outbreaks . The WorFlavivirus (Flaviviridae family) and Alphavirus (Togaviridae family) genera. The main perpetrators of arboviral infections in humans include JEV, with 30,000–50,000 cases reported annually, WNV, and TBEV . Recently, a novel role for CCR2 in regulating monocyte egress from the bone marrow under homeostatic and inflammatory conditions has been identified . In a third study that utilized a lethal intranasal model and a non-neurotropic strain of WNV, depletion of peripheral monocytes, after treatment with clodronate, resulted in a reduction of CD11b+ cells in the WNV-infected brain during WNV encephalitis , suggesting that inflammatory monocytes may function pathogenically during WNV encephalitis in this model .Monocytes appear to have a critical role during WNV infection, although whether these cells function to protect or promote pathogenesis is unclear. Several studies have evaluated the role of monocytes using clodronate-loaded liposomes. In the first study, mice were infected intraperitoneally using a non-neuroinvasive strain of WNV, and monocyte depletion resulted in increased viremia, enhanced viral entry into the CNS, and increased mortality . Anotherphalitis . The autCcr2-deficient mice, which are monocytopenic, we observed higher mortality and enhanced viral titers in the CNS during WNV infection compared to wild type mice, supporting a protective role of CCR2  remained unchanged compared to wild type controls, correlating the specific loss of inflammatory monocyte accumulation in the CNS with increased mortality. Adoptive transfer of monocytes into WNV-infected -/-Ccr2 mice showed that both CCR2-expressing and CCR2-deficient monocytes were capable of entering the CNS, suggesting monocyte migration into the CNS is CCR2-independent.Using  of CCR2 . Detailein vitro . We also evaluated the therapeutic potential of CCR2 blockade during SFV infection using a CCR2-specific antagonist, RS504393, which is a highly selective small molecule inhibitor , suggesting that monocytes may not contribute to viral clearance in the CNS , including monocytes, DCs, and microglia .Pathogenesis studies in mice have revealed a critical role for CCR5 during flavivirus infection. In the context of WNV infection, significant differences were observed only within the CNS, with rophages . The los-/-Ccr5 mice infected with JEV exhibit increased mortality (64%) compared to wild type mice (28%), correlating with higher viral titers in the CNS. Peripheral control of virus and the induction of the humoral immune response were similar between wild type and -/-Ccr5 mice. However, NK and CD8+ T-cell effector functions were blunted in the absence of CCR5 compared to wild type mice . Rather than a loss of leukocyte infiltration, as observed in WNV infection, a transient delay in the recruitment of NK cells, CD4+ and CD8+ T-cells, and monocytes into the infected CNS was observed. Together, these data suggest that the functions of CCR5 are critical for controlling both leukocyte trafficking as well as effector functions, which is required for efficient clearance of virus from the CNS.Similar results, showing a critical role for CCR5 in host defense, have been obtained in a mouse model of JEV infection . Larena -/-Ccr5 mice have not been tested, we evaluated the efficacy of a small molecule CCR5 receptor antagonist, named DAPTA, in a mouse model of SFV. DAPTA is a synthetic peptide comprising eight amino acids (185–192) of the gp120 V2 region of HIV-1 that binds competitively to the ligand-binding site of CCR5 (Table 1). However, the number of CCR5 expressing cells in the brains of treated mice was significantly reduced compared to untreated mice, confirming the efficacy of DAPTA in blocking CCR5. Our data suggest that other chemokine receptors may be involved in attracting leukocytes into the virally infected brain during SFV infection.During SFV infection in mice, evaluation of chemokine transcript numbers in the CNS revealed high induction of CCL3, CCL4, and CCL5 expression, suggesting a possible role for CCR5 in pathogenesis of SFV . Althoug of CCR5 . Mice weCCR5Δ32. This phenotype is commonly found at 10% allele frequency in the US  is a mosquito-transmitted neurotropic flavivirus, endemic to parts of Australia and Papua New Guinea. Using a mouse model of MVEV infection, one study showed that the leukocytic infiltrate in the CNS predominantly comprised neutrophils, which appeared to colocalize with neurons and was preceded by the induction of CXCL1 expression . DepletiIn the context of SFV infection, we showed that neutrophil-associated chemokines CXCL1 and CXCL2 were not expressed in the brain of mice infected with the avirulent strain. Consistent with this, no neutrophils were observed in the CNS as assessed by flow cytometric analysis and immunohistochemistry . In contBecause of the dominant role of CXCL8 in the activation and recruitment of neutrophils in humans, several antagonists for its receptors CXCR1 and CXCR2 have been developed for a wide range of diseases, including COPD, cystic fibrosis, and pancreatic islet transplantation . ReparixFigure 3). CXCL10 is the most highly induced chemokine in the CNS in mouse models of WNV, JEV, TBEV, and SFV encephalitis . These results were phenocopied using -/-Cxcr3 mice . Additionally, the effect of CXCL10 on the pathogenesis of WNV infection appears to be CNS-specific since clearance of WNV in peripheral tissues were identical compared to wild type infected mice . These data exemplify the complexity of chemokines during CNS inflammation and suggest that the use of CXCR3-specific antagonists may be beneficial or detrimental, depending on cell-type specific effects and timing.In addition to the role of the CXCL10:CXCR3 axis in regulating CD8+ T-cells were positive for CXCR3. These data suggest that the CXCL10:CXCR3 axis may also be critical for T-cell migration into the CNS. Although CXCL10 expression is highly upregulated in the CNS during TBEV infection in mice, the specific role of these cells in directing T-cell migration into the CNS has not been studied . Surprisingly, blockade of CXCR3 during lethal SFV infection did not result in a change in survival (Table 1). However, the combined blockade of CXCR3 and CCR2, did result in significantly enhanced survival compared to untreated mice (Table 1). Thus, the dual blockade of CXCR3 and CCR2 is necessary to achieve a survival benefit during lethal SFV-induced encephalitis. It is likely that these antagonists are inhibiting both T-cells and monocytes, implying that lethality in this model is immune-mediated. Furthermore, our data suggest that dual blockade of chemokine receptors may be more effective for treating diseases, a paradigm known as polypharmacology . Interrupting this interaction through the continuous administration of AMD3100 from the initial time of WNV infection in mice, resulted in the release of CD8+ T-cells in the perivascular space, allowing subsequent migration of these cells into the brain parenchyma, and is leading to enhanced viral clearance and survival . Importantly, the authors showed the same pattern of perivascular retention of T-cells through CXCL12 and CXCR4 expression patterns in WNV-infected patients with neuroinvasive disease , the use of this antagonist for the treatment of WNV-infected individuals is possible. In fact, The emergence and spread of arboviral infections in the past few decades has highlighted the unpredictable nature of human outbreaks and emphasizes the need for novel treatment and prevention measures. The recent outbreak of WNV disease in the United States, and its continued emergence in several regions within Europe are just a few examples . Althougin vivo, and it is apparent that the chemokine network plays an integral role in the generation of an effective host immune response in the CNS. It is clear that both innate and adaptive immune responses are required for responding to and counteracting viral replication and spread, and since naturally acquired arboviral infections are initiated in the periphery, the timing and magnitude of both innate, as well as T- and B-cell responses, are critical for efficient viral control once the virus has accessed the CNS (Leukocyte migration is critically important during all phases of viral replication  the CNS . Howeverin vitro have found that these cells respond to virus through the TLR-3 pathway (in vivo is currently unknown. Since these cells exclusively express CX3CR1 in the healthy CNS, and its ligand CX3CL1 is constitutively expressed by neurons, this receptor:ligand interaction is likely to function during infection (3CL1:CX3CR1 is hypothesized to suppress certain aspects of microglial activity (3CR1-deficiency, results in microglia displaying an increased propensity for activation and function (3CR1 expression on microglia alters the outcome of WNV and other arboviral infections of the CNS will provide critical insights into their role in neuropathogenesis.There are many areas of research that have remained relatively unexplored with regards to arboviral encephalitides: What are the key chemokine-mediated events that take place in local draining lymph node? What receptors coordinate optimal B- and T-cell activation within lymphoid tissues? How do neutrophils mobilize and migrate into the CNS? Still many questions remain, and there are many cell types that have not been studied in the context of arboviral encephalitis, most notably microglia. Several studies have shown that microglia are highly activated and proliferate during WNV encephalitis, and studies  pathway . Howevernfection . In a heactivity . Based ofunction . How the+ T-cell migration into the CNS and promotes viral clearance and survival. However, it has also been shown that neuronally expressed CXCR3, and its interaction with CXCL10 on WNV-infected neurons, promotes neuronal apoptosis. Thus, CXCR3 antagonism would have both a protective and pathogenic effect on disease outcome; the diametric consequences of CXCR3 blockade could result in unanticipated effects. Additionally, due to the positive and negative pressures that contribute to the evolution of chemokine receptors over time, the role of any given receptor could be beneficial in one setting and detrimental in another. This complexity is best illustrated with CCR5, which functions in promoting infection in the context of HIV-1 infection but has the reciprocal effect during WNV infection (The use of chemokine receptor antagonists is an active area for drug development but is complicated by their pleiotropic functions that may have opposing effects. One such example is the dual role of CXCR3 during WNV pathogenesis. It has been shown that CXCR3 is critical for CD8nfection . Thus, CIt is pivotal to understand the underlying immunological mechanism of encephalitis in order to develop effective treatment of acute viral encephalitis. New insights into the role of chemokines and their receptors in these contexts are also informative for studies of brain inflammation caused by multiple sclerosis, Alzheimer’s or Parkinson’s disease. The successful development of CCR5 and CXCR4 antagonists in humans demonstrates that chemokine receptors are feasible and effective targets that have the capacity to modulate disease. In fact, studies in mice and humans predict that these two antagonists would have opposite effects in human WNV disease, with Maraviroc promoting symptomatic disease and CXCR4 blockers promoting survival during infection. Because most chemokine receptor antagonists currently being developed will likely be administered chronically, it is critical to understand how these therapies may affect the individual in the context of their specific infection. This is an important goal that has been and should continue to be tested in the laboratory setting. Moreover, it is important to note that data obtained in inbred mouse models may not be applicable to humans. Thus, treatment of infected individuals with chemokine receptor antagonists may not function as anticipated based on mouse studies and should be approached with caution. Despite the success of Maraviroc and Mozobil/Plerixafor, there have been many receptor antagonists that have failed in clinical trials. Due to the redundancy of the chemokine system, antagonists that inhibit more than one receptor or the use of several compounds in conjunction may prove beneficial.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 mammalian cerebellum is located in the posterior cranial fossa and is critical for motor coordination and non-motor functions including cognitive and emotional processes. The anatomical structure of cerebellum is distinct with a three-layered cortex. During development, neurogenesis and fate decisions of cerebellar primordium cells are orchestrated through tightly controlled molecular events involving multiple genetic pathways. In this review, we will highlight the anatomical structure of human and mouse cerebellum, the cellular composition of developing cerebellum, and the underlying gene expression programs involved in cell fate commitments in the cerebellum. A critical evaluation of the cell death literature suggests that apoptosis occurs in ~5% of cerebellar cells, most shortly after mitosis. Apoptosis and cellular autophagy likely play significant roles in cerebellar development, we provide a comprehensive discussion of their role in cerebellar development and organization. We also address the possible function of unfolded protein response in regulation of cerebellar neurogenesis. We discuss recent advancements in understanding the epigenetic signature of cerebellar compartments and possible connections between DNA methylation, microRNAs and cerebellar neurodegeneration. Finally, we discuss genetic diseases associated with cerebellar dysfunction and their role in the aging cerebellum. Microscopic anatomy of the cerebellum was described in detail at the end of the 19th century by Ramon y Cajal and has attracted the attention of many researchers over the last century, and yet many questions remain unanswered. The role of cerebellum in motor coordination is well studied Ito, . IncreasThe mammalian cerebellum is characterized by a midline vermis flanked by hemispheres on each side. Folds and fissures divide the cerebellum into lobes, lobules, and folia. Mammalian and avian cerebellum is conventionally divided into 3 lobes that are further subdivided into 10 lobules (I–X) Larsell, . The cerCerebellar neurons can be classified into inhibitory gamma-butyric acid (GABAergic) and excitatory glutamatergic neurons Hoshino, . PurkinjGlutamatergic neurons include the granule cells, unipolar brush cells, and excitatory projection neurons (large neurons in the cerebellar nuclei)  the medial , which is subdivided further into caudomedial, middle, and dorsolateral  nuclei; (B) anterior and posterior interposed nuclei; and (C) lateral (dentate) nuclei , the central zone (CZ: lobules VI–VII), which can be further subdivided into anterior (CZa) and posterior (CZp) components  the cerebellar plate begins as a bulge on the dorsal aspect of the rhombencephalon , dorsolateral to the sulcus limitans on the floor of the fourth ventricle  part of the brain is >5% of the total weight from 14 to 17 weeks, about 5% from 18 to 29 weeks, and exceeds 6.5% by 40 weeks  in the EGZ, molecular layer, and granular layer  and lampreys and are called cerebellum-like (cerebelloid) structures Larsell, . The cerCerebellum-like structures arise from the alar plate of the neural tube  , Sonic Hedgehog (SHH), and transforming growth factor (TGF)-β family member expression  have anterior cerebellar anomalies  7–8 as a neuroepithelial swelling of the rostral lip of the fourth ventricle, which is part of the alar plate of the metencephalon (rhombomere-1/r1)  are summarized in Table 0–E12 areThe cerebellar primordium contains two germinal zones: the neuroepithelium of the fourth ventricle wall (ventricular zone—VZ) and the rhombic lip  and direct contact with the Lmx1a- and Gdf7-positive non-neural cells of the roof plate  is expressed in the interior face of the rhombic lip, complementary to and independent of Math1, which is localized to the exterior face of the rhombic lip  and fetuses at 17, 22, and 24 weeks of gestation. Barhl1 was restricted to the central nervous system, with strong expression in the rhombic lip at stage 17 and continued expression in the EGZ and granular layer to 24 weeks  is a temporary population of proliferating cerebellar cells located at the subpial surface of the developing cerebellum. The vast majority of cells from the EGZ produce granule cells during the postnatal period in rodents. In rats, the EGZ volume peaks at 15 days postnatal and disappears by 24 days Heinsen, . A subseThe EGZ can be divided into an outer layer (proliferating zone) and an inner layer (post-mitotic granule cells). The post-mitotic granule cells develop axons that extend among the parallel fibers in the developing molecular layer while the somata migrate inward to the granular layer. The molecular signals involved in granule cell migration and differentiation have been reviewed recently  receptors appear to be important for cerebellar development in rodents. Basille et al.  showed tZic (zinc finger of the cerebellum) gene is expressed in the dorsal cranial neural tube and somites of E9.5 mouse. Granule cells and their precursors all express ZIC family members, even in adult stages in cerebellum  pathway signals in the EGZ  within the granule cell layer. This exuberant proliferative activity is accompanied by apoptosis, with dying cells scattered throughout the developing cerebellar cortex  leads to severe abnormalities in anterior cerebellum  are associated with defects in the posterior cerebellum  end of cerebellar primordium. In midway, the cerebellar nuclei neurons precursors change direction to reach the nuclei transitory zone Figure .Math1 expression and directing the precursor processes away from the rhombic lip  signaling.Other molecules reported to be involved in granule cells migration include neurotrophin-3, stromal-cell-derived factor 1α (SDF-1α), ephrin-B2, tissue plasminogen activator, platelet-activating factor, cyclin-dependent kinase 5, and 9-O-acetyl GD3  is a vital process present in different cell types, including neurons  were TUNEL labeled  and were much less frequent than mitotic cells that had incorporated bromodeoxyuridine (~1200 cells/mm2 tissue area)  and animals  indicate that cell death occurs in the developing cerebellum to a limited extent, particularly in the EGZ among recently postmitotic cells and to a lesser extent in the granular layer. The reported extent to which this occurs varies widely, but overall it seems reasonable to estimate that a maximum 5% of granule cells and a smaller proportion of Purkinje cells are lost, although it must be noted that studies in the very early developmental stages are lacking. Even the so-called “specific” methods of TUNEL and activated caspase 3 detection have limitations and must be interpreted cautiously. Nevertheless, the fact is that some of the cells do die and therefore the molecular mechanisms are worth considering.in vitro models have been used. Cerebellar granule cells undergo apoptosis when they are deprived of extracellular potassium  mice phenotype. The deficiency in ULK1, an autophagic protein being involved in autophagosome initiation, causes abnormal growth cone and axon formation in the cerebellar granule neurons  deficiency in mice is associated with severe neuronal loss from the cerebellar cortices . Selective ablation of Atg5 or Atg7 genes in neurons leads to behavioral deficits associated with neuronal loss in the cerebellar cortices  is responsible for the synthesis and folding of proteins entering the secretary pathway  gene mutations. MECP2 gene encodes for a key epigenetic regulator in brain that binds to methylated DNA , are imprinted in a reciprocal manner by methylation of specific alleles within the Igf2/H19 imprinting control region (ICR). The Igf2/H19 ICR contains four CTCF binding sites, which are methylation sensitive and capable of regulating the interaction between the promoter of Igf2 and enhancers located downstream of the H19 gene , mostly in the context of CpG dinucleotides  , a neurodegenerative disorder associated with expansion of multiple CGG repeats (premutations) located within the gene  are selectively reduced compared to other brain regions such as amygdala and hippocampus   and mesenchymal-epithelial transition (MET) receptor tyrosine kinase , EGZ, caudomedial germinal zone (rhombic lip) and RGZ . VZ is the source of Purkinje cells as well as all GABAergic interneurons in addition to a subset of non-neuronal cells. The EGZ is the source of all granular cells and some interneurons (such as Golgi) and non-neuronal cells. Granular cell are generated in the postnatal period of both humans and rodents. Many genes and signaling pathways are involved in the development, cell fate commitment, and migration of these cells in the cerebellum. Cell death occurs among a limited number of EGZ and granular cells. Recent studies have shown a critical role for epigenetic factors in cerebellum development. This includes DNA methylation and specific miRNAs in controlling various neural processes. The necessity of miRNAs for the survival of cerebellar neurons underscores its importance in cerebellar development. Furthermore, the various forms of DNA methylation are being recognized for their multifaceted role in regulating the precise expression levels of transcription factors essential for normal cerebellar function. The significance of these regulatory mechanisms has been further elucidated by studies that have linked several neurological disorders to alterations in epigenetic control of cerebellar gene expression.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches—from basic neurobiological approaches to human studies—might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5's important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC's arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems. Glutamate is the primary excitatory neurotransmitter in the brain, and numerous researchers have suggested that it plays a significant role in various mental health and medical conditions. Indeed, researchers often mention the potential of developing ionotropic or metabotropic glutamate-based pharmacological treatment for numerous psychiatric disorders, in the form of either agonists or antagonists. Knowledge about the glutamatergic system has greatly advanced in the last decade, which has resulted from technological advances in receptor and transmitter imaging in humans. Even though there are a large number of experimental studies on glutamate intervention in various psychiatric disorders, there is a lack of systematic reviews that focus on combining the results of preclinical animal research studies with other neuroscience methods, such as human Positron Emission Tomography (PET). Thus, compared to previous reviews  need to be developed. The scanner device detects gamma rays emitted by the tracer, which is introduced into the body. An mGluR5 PET tracer suitable for human studies was successfully developed at the Paul Scherrer Institute (PSI) in Villigen, Switzerland, and the Swiss Federal Institute of Technology (ETH) in Zurich, Switzerland. ABP688 is a non-competitive and highly selective antagonist, which binds to an allosteric site of the mGluR5. 11C-ABP688 showed high selectivity for mGluR5 and high uptake in receptor-rich brain regions. The first description of these characteristics of 11C-ABP688 in animals is previously published  receptors modify neuronal activity through G-protein coupled signaling. Groups of mGluRs are distinguished by their pharmacological and intracellular signaling properties. mGluR5, which was first cloned in animals in 1992 and a few years later in humans, belongs to group I metabotropic receptors Olive, . Its actPre-synaptic mGluR5 receptors were found to participate in the regulation of synaptic plasticity and changes in neuronal excitability to maintain homeostasis Schoepp, . ImportaBecause of its functions in different neuronal processes, gross abnormalities in the glutamate system lead to severe neurological impairment , whereas smaller changes can contribute to various psychiatric conditions . The mGluR5 theory of FXS posits that the lack of fragile X mental retardation protein (FMRP) results in excessive glutamatergic signaling via mGluR5  , and OCD. In one study, we researched mGluR5 Distribution Volume Ratio (DVR) in 10 patients with OCD and 10 healthy controls using [11C]ABP688 PET . This initiative was the results of restructuring rigid DSM categories, most of which were also developed before neuroscience research  has initiated a novel, state-of-the art project: The Research Domain Criteria (RDoC). This reflects the implementation of NIMH Strategy 1.4 “Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measure.” . mGluR5 overactivity has also been reported in FXS, which is characterized by important social deficits. As a result, mGluR5 activity may not just normalize activity in the negative valence systems and arousal systems, but also attenuate impairments in the systems for social processes (RDoC). This is of high clinical importance because poor social functioning is an important outcome of prevalent psychiatric conditions such as OCD, depression and addiction, leading to enormous personal suffering and important indirect costs for the society. And finally, mGluR5 was also shown to have a significant involvement in drug addiction, suggested to be mainly caused by increasing the reward value of the drug. mGluR5 antagonistic intervention would thus be most effective for the treatment of pathological anxiety and addiction, and to improve social stress resiliency and social functioning.Dr Terbeck, Dr Chesterman, and Dr Akkus have no conflict of interest. Dr Hasler has received grant funding from Novartis, which is producing and testing drugs targeting mGluR5.


Four criteria are generally used to prioritize agricultural lands for placing conservation buffers. The criteria include soil erodibility, hydrological sensitivity, wildlife habitat, and impervious surface rate that capture conservation buffers’ benefits in reducing soil erosion, controlling runoff generation, enhancing wildlife habitat, and mitigating stormwater impacts, respectively. This article describes the data used to derive the values of those attributes and a scheme to classify the values in multi-criteria analysis of conservation buffer placement in “Choosing between alternative placement strategies for conservation buffers using borda count”  The wildlife habitat value is the sum of the habitat rank for potential presence of species of concern (rank 1–5) and the presence of bald eagle, falcon or wood turtle in forested wetlands and emergent wetlands (1). The final wildlife habitat values ranged from zero to eight and their spatial distribution is presented in 2.4Impervious surfaces are built-up surfaces  covered by impenetrable materials, such as asphalt, concrete, brick, and stone. Impervious surface rate was extracted from the NJDEP 2002 land use/cover data for the basin. The land use/cover data estimate the impervious surface rate for each land use/cover polygon using aerial photography and reported it in 5% increments between 0% and 100%. The spatial distribution of the impervious surface rate in the basin is presented in