let-7 microRNAs regulate microglial function and suppress glioma growth through Toll-like receptor 7

Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 UUGU motif. In human and murine glioblastoma/glioma, let-7 miRNAs are differentially expressed and reduce murine GL261 glioma growth in the same sequence-specific fashion through microglial TLR7. Taken together, these data establish let-7 miRNAs as key TLR7 signaling activators that serve to regulate the diverse functions of microglia in health and glioma

Real-time dynamics of clusters. III. I_2Ne_n (n=2–4), picosecond fragmentation, and evaporation

In this paper (III) we report real-time studies of the picosecond dynamics of iodine in Ne clusters I*2Nen(n = 2–4) --> I*2 + nNe. The results are discussed in relation to vibrational predissociation (VP), basic to the I2X systems, and to the onset of intramolecular vibrational-energy redistribution (IVR). The latter process, which is a precursor for the evaporation of the host atoms or for further fragmentation, is found to be increasingly effective as the cluster size increases; low-energy van der Waals modes act as the accepting (bath) modes. The reaction dynamics for I2Ne2 are examined and quantitatively compared to a simple model which describes the dynamics as consecutive bond breaking. On this basis, it is concluded that the onset of energy redistribution is observed in I2Ne2. Comparison of I2Ne and I2Ne2 to larger clusters (n=3,4) is accomplished by introducing an overall effective reaction rate. From measurements of the rates and their dependence on v[script ']i, the initial quantum number of the I2 stretch, we are able to examine the dynamics of direct fragmentation and evaporation, and compare with theory

Real-time dynamics of clusters. II. I_2X_n (n=1; X=He, Ne, and H_2), picosecond fragmentation

In this second paper (II) of a series, we report our picosecond time-resolved studies of the state-to-state rates of vibrational predissociation in iodine–rare gas (van der Waals) clusters. Particular focus is on the simplest system, I2He, which serves as a benchmark for theoretical modeling. Comparisons with I2Ne and I2H2 are also presented. The results from measurements made in real time are compared with those deduced from linewidth measurements, representing a rare example of a system studied by both methods under identical conditions and excited to the same quantum (v[script ']i) states. The discrepancies are discussed in relation to the origin of the broadening and preparation of the state. The rates as a function of v[script ']i display a nonlinear behavior which is examined in relation to the energy-gap law. The measured absolute rates and their dependence on v[script ']i are compared with numerous calculations invoking classical, quantum, and semiclassical theories. In the following paper (III in this series), the cluster size of the same system, I2Xn, is increased (n=2–4) and the dynamics are studied

Reproducibility of cognitive endpoints in clinical trials: Lessons from neurofibromatosis type 1

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design

Children with 5′-end NF1 gene mutations are more likely to have glioma

Objective:To ascertain the relationship between the germline NF1 gene mutation and glioma development in patients with neurofibromatosis type 1 (NF1).Methods:The relationship between the type and location of the germline NF1 mutation and the presence of a glioma was analyzed in 37 participants with NF1 from one institution (Washington University School of Medicine [WUSM]) with a clinical diagnosis of NF1. Odds ratios (ORs) were calculated using both unadjusted and weighted analyses of this data set in combination with 4 previously published data sets.Results:While no statistical significance was observed between the location and type of the NF1 mutation and glioma in the WUSM cohort, power calculations revealed that a sample size of 307 participants would be required to determine the predictive value of the position or type of the NF1 gene mutation. Combining our data set with 4 previously published data sets (n = 310), children with glioma were found to be more likely to harbor 5′-end gene mutations (OR = 2; p = 0.006). Moreover, while not clinically predictive due to insufficient sensitivity and specificity, this association with glioma was stronger for participants with 5′-end truncating (OR = 2.32; p = 0.005) or 5′-end nonsense (OR = 3.93; p = 0.005) mutations relative to those without glioma.Conclusions:Individuals with NF1 and glioma are more likely to harbor nonsense mutations in the 5′ end of the NF1 gene, suggesting that the NF1 mutation may be one predictive factor for glioma in this at-risk population.</jats:sec