Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis of pancreatic ductal adenocarcinoma ...(PDAC), one of the most lethal human cancers. We found that KDM2B (also known as Ndy1, FBXL10, and JHDM1B), an H3K36 histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogated tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperated with KrasG12D to promote PDAC formation in mouse models. Gain- and loss-of-function experiments coupled to genome-wide gene expression and ChIP studies revealed that KDM2B drives tumorigenicity through 2 different transcriptional mechanisms. KDM2B repressed developmental genes through cobinding with Polycomb group (PcG) proteins at transcriptional start sites, whereas it activated a module of metabolic genes, including mediators of protein synthesis and mitochondrial function, cobound by the MYC oncogene and the histone demethylase KDM5A. These results defined epigenetic programs through which KDM2B subverts cellular differentiation and drives the pathogenesis of an aggressive subset of PDAC.
Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of ...early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to determine whether a gain-of-function nonsynonymous OXTR SNP interacted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavioral differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.
Parental reading to young children is well-established as being positively associated with child cognitive development, particularly their language development. Research indicates that a particular, ..."intersubjective," form of using books with children, "Dialogic Book-sharing" (DBS), is especially beneficial to infants and pre-school aged children, particularly when using picture books. The work on DBS to date has paid little attention to the theoretical and empirical underpinnings of the approach. Here, we address the question of what processes taking place during DBS confer benefits to child development, and why these processes are beneficial. In a novel integration of evidence, ranging from non-human primate communication through iconic gestures and pointing, archaeological data on Pre-hominid and early human art, to experimental and naturalistic studies of infant attention, cognitive processing, and language, we argue that DBS entails core characteristics that make it a privileged intersubjective space for the promotion of child cognitive and language development. This analysis, together with the findings of DBS intervention studies, provides a powerful intellectual basis for the wide-scale promotion of DBS, especially in disadvantaged populations.
The aim of this paper is to promote the use of mine clay washing residues for the preparation of alkali activated materials (AAMs). In particular, the influence of the calcination temperature of the ...clayey by-product on the geopolymerization process was investigated in terms of chemical stability and durability in water. The halloysitic clay, a mining by-product, has been used after calcination and mixed with an alkaline solution to form alkali activated binders. Attention was focused on the influence of the clay's calcination treatment (450-500-600 °C) on the geopolymers' microstructure of samples, remaining in the lower limit indicated by the literature for kaolinite or illite calcination. The mixtures of clay and alkali activators (NaOH 8M and Na-silicate) were cured at room temperature for 28 days. The influence of solid to liquid ratio in the mix formulation was also tested in terms of chemical stability measuring the pH and the ionic conductivity of the eluate after 24-h immersion time in water. The results reported values of ionic conductivity higher for samples made with untreated clay or with low temperature of calcination (≥756 mS/m) compared with values of samples made with calcined clay (292 mS/m). This result suggests that without a proper calcination of the as-received clay it was not possible to obtain 25 °C-consolidated AAMs with good chemical stability and dense microstructure. The measures of integrity test, pH, and ionic conductivity in water confirmed that the best sample is made with calcined clay at 600 °C, being similar (53% higher ionic conductivity of the eluate) or equal (integrity test and pH) to values recorded for the metakaolin-based geopolymer considered the reference material. These results were reflected in term of reticulation and morphology of samples through the analysis with scanning electron microscope (SEM) and X-ray diffraction (XRD), which show a dense and homogeneous microstructure predominantly amorphous with minor amounts of quartz, halloysite, and illite crystalline phases. Special attention was dedicated to this by-product to promote its use, given that kaolinite (and metakaolin), as primary mineral product, has a strong impact on the environment. The results obtained led us to consider this halloysite clay very interesting as an aluminosilicate precursor, and extensively deepening its properties and reactivity for the alkaline activation. In fact, the heart of this work is to study the possibility of reusing this by-product of an industrial process to obtain more sustainable high-performance binders.
The generation of induced pluripotent stem cells (iPSCs) often results in aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster, compromising the ability to generate entirely ...iPSC-derived adult mice ('all-iPSC mice'). Here, we show that reprogramming in the presence of ascorbic acid attenuates hypermethylation of Dlk1-Dio3 by enabling a chromatin configuration that interferes with binding of the de novo DNA methyltransferase Dnmt3a. This approach allowed us to generate all-iPSC mice from mature B cells, which have until now failed to support the development of exclusively iPSC-derived postnatal animals. Our data show that transcription factor-mediated reprogramming can endow a defined, terminally differentiated cell type with a developmental potential equivalent to that of embryonic stem cells. More generally, these findings indicate that culture conditions during cellular reprogramming can strongly influence the epigenetic and biological properties of the resultant iPSCs.
Introduction An association between hemorrhoidal disease and matrix metalloproteinases (MMPs) has been described previously. MMPs regulate extracellular structural proteins and tissue remodeling. ...Neutrophil gelatinase-associated lipocalin (NGAL) is involved in the regulation of MMP activity. The aim of this work was to study the relationship between tissue immunoreactive levels of MMPs and NGAL and different stages of hemorrhoids. Methods In a multicenter, open-label, prospective study, the population under investigation consisted of 2 groups: group I (with symptomatic hemorrhoids; Goligher grade I–IV) and group II (healthy volunteers). Results We enrolled 97 patients with hemorrhoids: 21 with grade I hemorrhoids, 37 with grade II, 14 with grade III, and 25 with grade IV. Finally, 90 healthy volunteers (53 males and 37 females; age range, 19–70 years; median, 56) were enrolled in group II. Enzyme-linked immunosorbent assay and Western blot analysis revealed greater levels of immunoreactive MMPs and NGAL in all patients with hemorrhoids. We recorded significantly greater levels of MMP-1 and MMP-3 in grade I and II patients compared with control, and greater levels of MMP-3, MMP-7, MMP-8, and MMP-9 in grade III compared with grade II. MMP-9 and NGAL were particularly increased in patients with grade IV especially in case of thrombosed hemorrhoids. Conclusion These results provide potentially important insights into the understanding of the natural history of hemorrhoids. MMPs and NGAL play a role in development of disease and may represent molecular markers for the complications such as hemorrhoidal thrombosis.
For many genes, RNA polymerase II stably pauses before transitioning to productive elongation. Although polymerase II pausing has been shown to be a mechanism for regulating transcriptional ...activation, the extent to which it is involved in control of mammalian gene expression and its relationship to chromatin structure remain poorly understood.
Here, we analyze 85 RNA polymerase II chromatin immunoprecipitation (ChIP)-sequencing experiments from 35 different murine and human samples, as well as related genome-wide datasets, to gain new insights into the relationship between polymerase II pausing and gene regulation. Across cell and tissue types, paused genes (pausing index > 2) comprise approximately 60 % of expressed genes and are repeatedly associated with specific biological functions. Paused genes also have lower cell-to-cell expression variability. Increased pausing has a non-linear effect on gene expression levels, with moderately paused genes being expressed more highly than other paused genes. The highest gene expression levels are often achieved through a novel pause-release mechanism driven by high polymerase II initiation. In three datasets examining the impact of extracellular signals, genes responsive to stimulus have slightly lower pausing index on average than non-responsive genes, and rapid gene activation is linked to conditional pause-release. Both chromatin structure and local sequence composition near the transcription start site influence pausing, with divergent features between mammals and Drosophila. Most notably, in mammals pausing is positively correlated with histone H2A.Z occupancy at promoters.
Our results provide new insights into the contribution of RNA polymerase II pausing in mammalian gene regulation and chromatin structure.
The chromatin state of pluripotency genes has been studied extensively in embryonic stem cells (ESCs) and differentiated cells, but their potential interactions with other parts of the genome remain ...largely unexplored. Here, we identified a genome-wide, pluripotency-specific interaction network around the Nanog promoter by adapting circular chromosome conformation capture sequencing. This network was rearranged during differentiation and restored in induced pluripotent stem cells. A large fraction of Nanog-interacting loci were bound by Mediator or cohesin in pluripotent cells. Depletion of these proteins from ESCs resulted in a disruption of contacts and the acquisition of a differentiation-specific interaction pattern prior to obvious transcriptional and phenotypic changes. Similarly, the establishment of Nanog interactions during reprogramming often preceded transcriptional upregulation of associated genes, suggesting a causative link. Our results document a complex, pluripotency-specific chromatin “interactome” for Nanog and suggest a functional role for long-range genomic interactions in the maintenance and induction of pluripotency.
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•The Nanog promoter forms a pluripotency-specific, genome-wide chromatin interactome•Nanog interactions in ESCs are enriched for active marks and pluripotency factors•Mediator and cohesin are essential for the maintenance of the Nanog interactome•Many Nanog interactions form before increased gene expression during reprogramming
The Nanog promoter interacts with the rest of the genome in an unexpectedly complex pluripotency-specific chromatin interaction network that depends on Mediator and cohesin.
This study compared the postoperative analgesic efficacy of intraperitoneal and incisional lidocaine versus ropivacaine in dogs undergoing major abdominal surgeries. Dogs randomly received ...intraperitoneal lidocaine irrigation (4 mg kg-1, diluted to 5 ml kg-1, L group), ropivacaine (4 mg kg-1, diluted to 5 ml kg-1, R group) or 0.9% saline (5 ml kg-1, C group). Prior to skin closure, dogs received incisional lidocaine 2 mg kg-1 (group L), incisional ropivacaine 2 mg kg-1 (group R) or incisional saline 0.2 ml kg-1 (group C). Pain was assessed at different time points up to 24 hours after extubation, using the Short Form-Glasgow Composite Measure Pain Scale and VAS Scale. In group C, postoperative pain scores were significantly higher than in groups L and R from T0.5 to T6 (p < 0.05). In R group, postoperative pain scores were significantly lower than in groups L and C from T12 to T24 (p < 0.05). Rescue analgesia was administered to 5/11 dogs in L group, 1/10 dogs in R group and 8/10 dogs in C group. Groups L and R experienced a significantly lower postoperative pain during the first 6 hours after extubation, compared with group C. Ropivacaine provided lower postoperative pain scores than lidocaine and saline up to 24 hours after extubation. According to the obtained results, ropivacaine seemed to provide better and longer lasting postoperative analgesia compared with lidocaine. Therefore, intraperitoneal and incisional administration of ropivacaine in dogs undergoing major abdominal surgeries is recommended.
The primate play-face is homologous to the human facial display accompanying laughter. Through facial mimicry, the play-face evokes in the perceiver a similar positive emotional state. This ...sensorimotor and emotional sharing can be adaptive, as it allows individuals to fine-tune their own motor sequences accordingly thus increasing cooperation in play. It has been recently demonstrated that, not only humans and apes, but also geladas are able to mimic others' facial expressions. Here, we describe two forms of facial mimicry in Theropithecus gelada: rapid (RFM, within 1.0 s) and delayed (DFM, within 5.0 s). Play interactions characterized by the presence of RFM were longer than those with DFM thus suggesting that RFM is a good indicator of the quality of communicative exchanges and behavioral coordination. These findings agree with the proposal of a mirror mechanism operating during perception and imitation of facial expressions. In an evolutionary perspective, our findings suggest that RFM not only was already present in the common ancestor of cercopitecoids and hominoids, but also that there is a relationship between RFM and length and quality of playful interactions.
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