Reconstitution of the central and peripheral nervous system during salamander tail regeneration

We show that after tail amputation in Ambystoma mexicanum (Axolotl) the correct number and spacing of dorsal root ganglia are regenerated. By transplantation of spinal cord tissue and nonclonal neurospheres, we show that the central spinal cord represents a source of peripheral nervous system cells. Interestingly, melanophores migrate from preexisting precursors in the skin. Finally, we demonstrate that implantation of a clonally derived spinal cord neurosphere can result in reconstitution of all examined cell types in the regenerating central spinal cord, suggesting derivation of a cell with spinal cord stem cell properties.     

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

Regulatory T cells (Tregs) exert their immunosuppressive activity through several immunoregulatory mechanisms, including the production of anti-inflammatory cytokines such as IL-10. Although several studies suggest a role for Tregs in modulating crescentic GN, the underlying mechanisms are not well understood. Here, using IL-10 reporter mice, we detected IL-10–producing Foxp3⁺ T cells in the kidney, blood, and secondary lymphoid tissue in a mouse model of crescentic GN. Specific inactivation of Il10 in Foxp3⁺ Tregs eliminated the ability of these cells to suppress renal and systemic production of IFNγ and IL-17; these IL-10–deficient Tregs lost their capacity to attenuate renal tissue injury. These data highlight the suppressive functions of Tregs in crescentic GN and suggest the importance of Treg-derived IL-10 in ameliorating disease severity and in modulating both the Th1 and most notably Th17 immune response.The discovery of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) in the 1990s and their indispensable role in (self) tolerance and autoimmunity marked the beginning of a new era in immunology.¹ Since then, different suppressive mechanisms mediated by various Treg cell subsets were identified,^2,3 particularly in well studied models of autoimmune diseases such as Crohn''s disease,⁴ multiple sclerosis,⁵ or rheumatoid arthritis.^6,7 Until now, only limited numbers of studies have assessed the function of regulatory T cells in crescentic GN. Adoptive cell transfer experiments in mice showed the beneficial role of exogenous wild-type (wt) CD4⁺CD25⁺ Tregs in attenuation of crescentic GN,⁸ whereas CCR6- and CCR7-deficient CD4⁺CD25⁺ Tregs failed to protect mice against GN.^9,10 Recently, our own published data revealed the importance of endogenous Foxp3⁺ Tregs in suppressing the Th1 immune response and consequently ameliorating the disease severity in the T cell–dependent GN model of nephrotoxic nephritis (NTN).¹¹ Concurrently, Ooi and coworkers confirmed the relevance of endogenous Foxp3⁺ Tregs in an accelerated model of experimental crescentic GN.¹² However, the mechanisms of Treg cell-mediated suppression in crescentic GN are still unclear. One important player might be the anti-inflammatory cytokine IL-10, which is known to be released by Tregs in order to suppress immune responses and therefore might protect against autoimmunity.¹³ Indeed, endogenous IL-10 regulates the Th1 immune response in an accelerated model of experimental crescentic GN, as kidney damage is aggravated in IL-10–deficient mice.¹⁴ However, the source of protective IL-10 still needs to be clarified. Because IL-10 detection and tracking in vivo is difficult, most findings are based on studies with IL-10^−/− mice.Therefore, to study the cell-specific function of IL-10, we used a double-knockin reporter mouse model (Foxp3-IRES-mRFP (FIR) x IL-10 ires gfp-enhanced reporter [tiger]), which enables detection of the well-defined and simultaneous expression of IL-10 (green fluorescent protein [GFP]) and Foxp3 (monomeric red fluorescent protein [mRFP]). Indeed, we detected a distinct population of renal mRFP⁺(Foxp3⁺) Tregs expressing GFP (IL-10) upon induction of NTN. Thus, to investigate the role of Treg cell-derived IL-10 in NTN, we first adoptively transferred CD4⁺CD25⁺ Tregs from wt or IL-10^−/− mice into wt mice subsequently challenged with nephrotoxic sheep serum. Adoptively transferred wt Tregs attenuated the course of NTN, whereas IL-10^−/− Tregs did not. Furthermore, to analyze the role of endogenous IL-10 produced by Tregs, we generated Foxp3^YFP-Cre x Il10^flox/flox mice, in which IL-10 is selectively inactivated in Foxp3⁺ Tregs.¹⁵ Indeed, lack of Treg-derived IL-10 resulted in an aggravated course of NTN. In summary, we demonstrated a crucial role of Treg cell-derived IL-10 in regulating the Th1 and most notably the Th17 immune response in NTN. Hence, this study contributes to the understanding of the suppressive mechanisms of Tregs in crescentic GN and will have biologic implications for designing therapeutic approaches.     

Standard of Care for Neuropsychological Monitoring in Pediatric Neuro‐Oncology: Lessons From the Children's Oncology Group (COG)

As the mortality of pediatric cancers has decreased, focus on neuropsychological morbidities of treatment sequelae have increased. Neuropsychological evaluations are essential diagnostic tools that assess cognitive functioning and neurobiological integrity. These tests provide vital information to support ongoing medical care, documenting cognitive morbidity and response to interventions. We frame standards for neuropsychological monitoring of pediatric patients with CNS malignancy or who received cancer‐directed therapies involving the CNS and discuss billing for these services in the United States in the context of clinical research. We describe a cost‐effective, efficient model of neuropsychological monitoring that may increases access to neuropsychological care. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.     

Gender differences in the activation of inferior frontal cortex during emotional speech perception

We investigated the brain regions that mediate the processing of emotional speech in men and women by presenting positive and negative words that were spoken with happy or angry prosody. Hence, emotional prosody and word valence were either congruous or incongruous. We assumed that an fRMI contrast between congruous and incongruous presentations would reveal the structures that mediate the interaction of emotional prosody and word valence. The left inferior frontal gyrus (IFG) was more strongly activated in incongruous as compared to congruous trials. This difference in IFG activity was significantly larger in women than in men. Moreover, the congruence effect was significant in women whereas it only appeared as a tendency in men. As the left IFG has been repeatedly implicated in semantic processing, these findings are taken as evidence that semantic processing in women is more susceptible to influences from emotional prosody than is semantic processing in men. Moreover, the present data suggest that the left IFG mediates increased semantic processing demands imposed by an incongruence between emotional prosody and word valence.     

Structural basis for membrane binding and catalytic activation of the peripheral membrane enzyme pyruvate oxidase from Escherichia coli

The thiamin- and flavin-dependent peripheral membrane enzyme pyruvate oxidase from E. coli catalyzes the oxidative decarboxylation of the central metabolite pyruvate to CO₂ and acetate. Concomitant reduction of the enzyme-bound flavin triggers membrane binding of the C terminus and shuttling of 2 electrons to ubiquinone 8, a membrane-bound mobile carrier of the electron transport chain. Binding to the membrane in vivo or limited proteolysis in vitro stimulate the catalytic proficiency by 2 orders of magnitude. The molecular mechanisms by which membrane binding and activation are governed have remained enigmatic. Here, we present the X-ray crystal structures of the full-length enzyme and a proteolytically activated truncation variant lacking the last 23 C-terminal residues inferred as important in membrane binding. In conjunction with spectroscopic results, the structural data pinpoint a conformational rearrangement upon activation that exposes the autoinhibitory C terminus, thereby freeing the active site. In the activated enzyme, Phe-465 swings into the active site and wires both cofactors for efficient electron transfer. The isolated C terminus, which has no intrinsic helix propensity, folds into a helical structure in the presence of micelles.