Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

TGF‐β1‐activated type 2 dendritic cells promote wound healing and induce fibroblasts to express tenascin c following corneal full‐thickness hydrogel transplantation

We showed previously that 1‐ethyl‐3‐(3‐dimethylamino‐propyl)‐carbodiimide hydrochloride (EDC) cross‐linked recombinant human collagen III hydrogels promoted stable regeneration of the human cornea (continued nerve and stromal cell repopulation) for over 4 years. However, as EDC cross linking kinetics were difficult to control, we additionally tested a sterically bulky carbodiimide. Here, we compared the effects of two carbodiimide cross linkers—bulky, aromatic N‐cyclohexyl‐N0‐(2‐morpholinoethyl)‐carbodiimide (CMC), and nonbulky EDC—in a mouse corneal graft model. Murine corneas undergoing full‐thickness implantation with these gels became opaque due to dense retro‐corneal membranes (RCM). Corneal epithelial cytokeratin 12 and alpha smooth muscle actin indicative of functional tissue regeneration and wound contraction were observed in RCM surrounding both hydrogel types. However, quantitatively different levels of infiltrating CD11c⁺ dendritic cells (DC) were found, suggesting a hydrogel‐specific innate immune response. More DC infiltrated the stroma surrounding EDC‐N‐hydroxysuccinimide (NHS) hydrogels concurrently with higher fibrosis‐associated tenascin c expression. The opposite was true for CMC‐NHS gels that had previously been shown to be more tolerising to DC. In vitro studies showed that DC cultured with transforming growth factor β1 (TGF‐β1) induced fibroblasts to secrete more tenascin c than those cultured with lipopolysaccharide and this effect was blocked by TGF‐β1 neutralisation. Furthermore, tenascin c staining was found in 40‐ to 50μm long membrane nanotubes formed in fibroblast/DC cocultures. We suggest that TGF‐β1 alternatively activated (tolerising) DC regulate fibroblast‐mediated tenascin c secretion, possibly via local production of TGF‐β1 in early wound contraction, and that this is indirectly modulated by different hydrogel chemistries.     

Evaluation of Family Skills Training Programs to Prevent Alcohol and Drug Use: A Critical Review of the Field in Latin America

International Journal of Mental Health and Addiction - Family skills training programs (FSTPs) are the interventions of choice for the prevention of alcohol and drug use worldwide. However, the...     

A Rare Case of Carcinoma Cuniculatum Involving the Larynx in Association with a Saccular Cyst

Carcinoma cuniculatum (CC), a rare, well-differentiated variant of squamous cell carcinoma, is uncommon in head and neck sites but when it does occur is most common in the oral cavity. Here we report a rare case of CC involving the larynx. A 49-year-old man presented with 10 months of worsening hoarseness and, despite multiple biopsies, no diagnosis of malignancy could be established. Eventual partial excision of the lesion and histologic review of prior specimens confirmed the diagnosis of CC. Focally, a transition to respiratory epithelium indicated the presence of an associated saccular cyst. Total laryngectomy was performed and 6 months later the patient is free of disease. Only two prior cases of CC have been reported in the larynx. Diagnosis of CC is challenging given the low grade histologic features and awareness of this entity for both treating physicians and the pathologist is important to reach a diagnosis of malignancy. This case highlights the challenges in diagnosis of CC, especially in unusual locations and when associated with other lesions such as a saccular cyst. Awareness of this rare tumor type combined with close communication between treating clinicians, radiologists and pathologists should allow earlier diagnosis and treatment.