Antigen Complexed with a TLR9 Agonist Bolsters c-Myc and mTORC1 Activity in Germinal Center B Lymphocytes.

The germinal center (GC) is the anatomical site where humoral immunity evolves. B cells undergo cycles of proliferation and selection to produce high-affinity Abs against Ag. Direct linkage of a TLR9 agonist (CpG) to a T-dependent Ag increases the number of GC B cells. We used a T-dependent Ag complexed with CpG and a genetic model for ablating the TLR9 signaling adaptor molecule MyD88 specifically in B cells (B-MyD88- mice) together with transcriptomics to determine how this innate pathway positively regulates the GC. GC B cells from complex Ag-immunized B-MyD88- mice were defective in inducing gene expression signatures downstream of c-Myc and mTORC1. In agreement with the latter gene signature, ribosomal protein S6 phosphorylation was increased in GC B cells from wild-type mice compared with B-MyD88- mice. However, GC B cell expression of a c-Myc protein reporter was enhanced by CpG attached to Ag in both wild-type and B-MyD88- mice, indicating a B cell-extrinsic effect on c-Myc protein expression combined with a B cell-intrinsic enhancement of gene expression downstream of c-Myc. Both mTORC1 activity and c-Myc are directly induced by T cell help, indicating that TLR9 signaling in GC B cells either enhances their access to T cell help or directly influences these pathways to further enhance the effect of T cell help. Taken together, these findings indicate that TLR9 signaling in the GC could provide a surrogate prosurvival stimulus, "TLR help," thus lowering the threshold for selection and increasing the magnitude of the GC response

Benefits from synergies and advanced technologies for an advanced-technology space station

A configuration for a second-generation advanced technology space station has been defined in a series of NASA-sponsored studies. Definitions of subsystems specifically addressed opportunities for beneficial synergistic interactions and those potential synergies and their benefits are identified. One of the more significant synergistic benefits involves the multi-function utilization of water within a large system that generates artificial gravity by rotation. In such a system, water not only provides the necessary crew life support, but also serves as counterrotator mass, as moveable ballast, and as a source for propellant gases. Additionally, the synergistic effects between advanced technology materials, operation at reduced artificial gravity, and lower cabin atmospheric pressure levels show beneficial interactions that can be quantified in terms of reduced mass to orbit

Quantitative systematic review of the effects of non‐pharmacological interventions on reducing apathy in persons with dementia

AimTo review the quantitative evidence concerning the effects of non‐pharmacological interventions on reducing apathy in persons with dementia.BackgroundApathy, a prevalent behavioural symptom among persons with Alzheimer Disease, is defined as a disorder of motivation with deficits in behavioural, emotional and cognitive domains and is associated with serious social and physical obstacles. Non‐pharmacological interventions show promise as symptom control modalities among persons with dementia.DesignQuantitative systematic review.Data sourcesCINAHL, PubMed, PSYCHinfo and Cochrane Trials databases were searched for published English language research inclusive through December 2014, with no early year limiters set.Review methodsComprehensive searches yielded 16 international randomized controlled trials or quasi‐experimental studies based on inclusion criteria and a rigorous quality appraisal process.ResultsA narrative summary analysis revealed that non‐pharmacological interventions for apathy varied substantially and lacked specificity, conceptual clarity and were methodologically heterogeneous. Select interventions demonstrated effectiveness, but lacked systematic long‐term follow‐up. Limitations include publication bias and lack of a meta‐analytic approach due to the methodological heterogeneity of included studies.ConclusionStudy results demonstrate promise for the use of non‐pharmacological interventions, particularly music‐based interventions, in reducing apathy levels in individuals with dementia. Intervening to reduce apathy may have a positive clinical impact and healthcare providers should be encouraged to incorporate positive sources of interest and intellectual stimulation into care. However, future research is needed to examine the aetiologic mechanism and predictors of apathy, to improve evidence‐based interventions and specificity and to optimize dosage and timing of non‐pharmacological interventions across the disease trajectory.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134246/1/jan13026_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134246/2/jan13026.pd

Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility

We were supported by the Biotechnology and Biological Sciences Research Council grant BB/H001123/1 (P.W.), the Medical Research Council grants G0601498 and G1100546/2 (P.W.), Tenovus Scotland Grant G09/17 (A.J.M.) and the University of Aberdeen (P.W.). We thank O. Tüscher for discussion, P. Teismann and the microscopy core facility at the University of Aberdeen for the use of microscopy equipment, L. Strachan, A. Plano, S. Deiana for help with behavioral testing.Peer reviewedPublisher PD