Preferential binding of a stable G3BP ribonucleoprotein complex to intron-retaining transcripts in mouse brain and modulation of their expression in the cerebellum.

Neuronal granules play an important role in the localization and transport of translationally silenced messenger ribonucleoproteins (mRNPs) in neurons. Among the factors associated with these granules, the RNA-binding protein G3BP1 (stress-granules assembly factor) is involved in neuronal plasticity and is induced in Alzheimer's disease. We immunopurified a stable complex containing G3BP1 from mouse brain and performed High-Throughput Sequencing and CrossLinking Immunoprecipitation (HITS-CLIP) to identify the associated RNAs. The G3BP-complex contained the deubiquitinating protease USP10, CtBP1 and the RNA binding proteins Caprin-1, G3BP2a and SFPQ (Splicing Factor Proline and Glutamine rich, or PSF). The G3BP-complex binds preferentially to transcripts that retain introns, and to non-coding sequences like 3'UTR and long non-coding RNAs. Specific transcripts with retained introns appear to be enriched in the cerebellum compared to the rest of the brain and G3BP1 depletion decreased this intron retention in the cerebellum of G3BP1 knockout mice. Among the enriched transcripts, we found an overrepresentation of genes involved in synaptic transmission, especially glutamate-related neuronal transmission. Notably, G3BP1 seems to repress the expression of the mature Grm5 (metabotropic glutamate receptor 5) transcript, by promoting the retention of an intron in the immature transcript in the cerebellum. Our results suggest that G3BP is involved in a new functional mechanism to regulate non-coding RNAs including intron-retaining transcripts, and thus have broad implications for neuronal gene regulation, where intron retention is widespread. This article is protected by copyright. All rights reserved

Entorhinal cortex volume is associated with episodic memory related brain activation in normal aging and amnesic mild cognitive impairment

The present study examined the relationship between entorhinal cortex and hippocampal volume with fMRI activation during episodic memory function in elderly controls with no cognitive impairment and individuals with amnesic mild cognitive impairment (aMCI). Both groups displayed limited evidence for a relationship between hippocampal volume and fMRI activation. Smaller right entorhinal cortex volume was correlated with reduced activation in left and right medial frontal cortex (BA 8) during incidental encoding for both aMCI and elderly controls. However, during recognition, smaller left entorhinal cortex volume correlated with reduced activation in right BA 8 for the control group, but greater activation for the aMCI group. There was no significant relationship between entorhinal cortex volume and activation during intentional encoding in either group. The recognition-related dissociation in structure/function relationships in aMCI paralleled our behavioral findings, where individuals with aMCI displayed poorer performance relative to controls during recognition, but not encoding. Taken together, these results suggest that the relationship between entorhinal cortex volume and fMRI activation during episodic memory function is altered in individuals with aMCI.Illinois. Department of Public HealthNational Institute on Aging (Grant P01 AG09466)National Institute on Aging (Grant P30 AG10161)National Institute on Aging (Grant R01 AG017917)National Institute on Aging (Grant T32 AG000257

Atrophy in the parahippocampal gyrus as an early biomarker of Alzheimer’s disease

The main aim of the present study was to compare volume differences in the hippocampus and parahippocampal gyrus as biomarkers of Alzheimer’s disease (AD). Based on the previous findings, we hypothesized that there would be significant volume differences between cases of healthy aging, amnestic mild cognitive impairment (aMCI), and mild AD. Furthermore, we hypothesized that there would be larger volume differences in the parahippocampal gyrus than in the hippocampus. In addition, we investigated differences between the anterior, middle, and posterior parts of both structures. We studied three groups of participants: 18 healthy participants without memory decline, 18 patients with aMCI, and 18 patients with mild AD. 3 T T1-weighted MRI scans were acquired and gray matter volumes of the anterior, middle, and posterior parts of both the hippocampus and parahippocampal gyrus were measured using a manual tracing approach. Volumes of both the hippocampus and parahippocampal gyrus were significantly different between the groups in the following order: healthy > aMCI > AD. Volume differences between the groups were relatively larger in the parahippocampal gyrus than in the hippocampus, in particular, when we compared healthy with aMCI. No substantial differences were found between the anterior, middle, and posterior parts of both structures. Our results suggest that parahippocampal volume discriminates better than hippocampal volume between cases of healthy aging, aMCI, and mild AD, in particular, in the early phase of the disease. The present results stress the importance of parahippocampal atrophy as an early biomarker of AD

Hadronic resonance production in dd+Au collisions at sNN\sqrt{s_{_{NN}}} = 200 GeV at RHIC

We present the first measurements of the $\rho(770)^0$, $K^*$(892), $\Delta$(1232)$^{++}$, $\Sigma$(1385), and $\Lambda$(1520) resonances in $d$+Au collisions at $\sqrt{s_{_{NN}}}$ = 200 GeV, reconstructed via their hadronic decay channels using the STAR detector at RHIC. The masses and widths of these resonances are studied as a function of transverse momentum ($p_T$). We observe that the resonance spectra follow a generalized scaling law with the transverse mass ($m_T$). The $$of resonances in minimum bias collisions is compared to the$$ of $\pi$, $K$, and $\bar{p}$. The $\rho^0/\pi^-$, $K^*/K^-$, $\Delta^{++}/p$, $\Sigma(1385)/\Lambda$, and $\Lambda(1520)/\Lambda$ ratios in $d$+Au collisions are compared to the measurements in minimum bias $p+p$ interactions, where we observe that both measurements are comparable. The nuclear modification factors ($R_{dAu}$) of the $\rho^0$, $K^*$, and $\Sigma^*$ scale with the number of binary collisions ($N_{bin}$) for $p_T >$ 1.2 GeV/$c$.Comment: STAR Collaboration. Submitted to PR

Reorganization of Functional Networks in Mild Cognitive Impairment

Whether the balance between integration and segregation of information in the brain is damaged in Mild Cognitive Impairment (MCI) subjects is still a matter of debate. Here we characterize the functional network architecture of MCI subjects by means of complex networks analysis. Magnetoencephalograms (MEG) time series obtained during a memory task were evaluated by synchronization likelihood (SL), to quantify the statistical dependence between MEG signals and to obtain the functional networks. Graphs from MCI subjects show an enhancement of the strength of connections, together with an increase in the outreach parameter, suggesting that memory processing in MCI subjects is associated with higher energy expenditure and a tendency toward random structure, which breaks the balance between integration and segregation. All features are reproduced by an evolutionary network model that simulates the degenerative process of a healthy functional network to that associated with MCI. Due to the high rate of conversion from MCI to Alzheimer Disease (AD), these results show that the analysis of functional networks could be an appropriate tool for the early detection of both MCI and AD

Expression of NES-hTERT in Cancer Cells Delays Cell Cycle Progression and Increases Sensitivity to Genotoxic Stress

Telomerase is a reverse transcriptase associated with cellular immortality through telomere maintenance. This enzyme is activated in 90% of human cancers, and inhibitors of telomerase are currently in clinical trials to counteract tumor growth. Many aspects of telomerase biology have been investigated for therapy, particularly inhibition of the enzyme, but little was done regarding its subcellular shuttling. We have recently shown that mutations in the nuclear export signal of hTERT, the catalytic component of telomerase, led to a mutant (NES-hTERT) that failed to immortalize cells despite nuclear localization and catalytic activity. Expression of NES-hTERT in primary fibroblast resulted in telomere-based premature senescence and mitochondrial dysfunction. Here we show that expression of NES-hTERT in LNCaP, SQ20B and HeLa cells rapidly and significantly decreases their proliferation rate and ability to form colonies in soft agar while not interfering with endogenous telomerase activity. The cancer cells showed increased DNA damage at telomeric and extra-telomeric sites, and became sensitive to ionizing radiation and hydrogen peroxide exposures. Our data show that expression of NES-hTERT efficiently counteracts cancer cell growth in vitro in at least two different ways, and suggest manipulation with the NES of hTERT or its subcellular shuttling as a new strategy for cancer treatment

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Babies with brain damage who can not swallow: surgical management

BACKGROUND: Neonates with severe neurological impairment are often unable to swallow, necessitating gastrostomy for feeding. Because of the risk of developing severe reflux, this procedure is often associated with fundoplication. OBJECTIVE: To assess the safety and efficacy of gastrostomy and Nissen fundoplication in 22 neonates with swallowing difficulties due to serious neurological impairment. METHOD: All children underwent an initial period of nasogastric feeding and after informed consent underwent gastrostomy and Nissen fundoplication. RESULTS: There were no significant intraoperative complications. There were two cases of postoperative periostomy leakage. Of the 22 neonates 16 were alive four months after surgery. Six neonates died of complications due to underlying disease. CONCLUSION: We concluded that gastrostomy and Nissen fundoplication are safe procedures and help parents give a better care to these children.INTRODUÇÃO: Neonatos com dano neurológico são freqüentemente incapazes de deglutir necessitando de gastrostomia para alimentação. Devido ao risco de refluxo grave, esse procedimento é associado à fundoplicatura. OBJETIVO: Avaliar a segurança e eficácia da gastrostomia com fundoplicatura Nissen em 22 neonatos com dificuldades de deglutição devido à lesão neurológica grave. MÉTODO: Todos os neonatos foram submetidos a um período inicial de alimentação por sonda nasogástrica e, após consentimento informado, foram submetidos a gastrostomia com fundoplicatura Nissen. RESULTADOS: Não houve complicações intra-operatórias significativas. Houve dois casos de vazamento pós-operatório da ostomia. Dos 22 neonatos, 16 estavam vivos 4 meses após a cirurgia. Seis neonatos morreram por complicações devido à doença de base. CONCLUSÃO: A gastrostomia com fundoplicatura Nissen é procedimento seguro e ajuda os pais a darem melhor cuidado a crianças com lesão neurológica