Association Between Objectively Measured Physical Activity and Cognitive Function in Older Adults—The Reasons for Geographic and Racial Differences in Stroke Study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116310/1/jgs13829_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/116310/2/jgs13829.pd

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

microRNA regulation of mammalian target of rapamycin expression and activity controls estrogen receptor function and RAD001 sensitivity

Background: The AKT/mammalian target of rapamycin (mTOR) signaling pathway is regulated by 17 α -estradiol (E2) signaling and mediates E2-induced proliferation and progesterone receptor (PgR) expression in breast cancer. Methods and results: Here we use deep sequencing analysis of previously published data from The Cancer Genome Atlas to demonstrate that expression of a key component of mTOR signaling, rapamycin-insensitive companion of mTOR (Rictor), positively correlated with an estrogen receptor- α positive (ER α + ) breast tumor signature. Through increased microRNA-155 (miR-155) expression in the ER α + breast cancer cells we demonstrate repression of Rictor enhanced activation of mTOR complex 1 (mTORC1) signaling with both qPCR and western blot. miR-155-mediated mTOR signaling resulted in deregulated ER α signalingbothinculturedcells in vitro and in xenografts in vivo in addition to repressed PgR expression and act ivity.FurthermoreweobservedthatmiR-155 enhanced mTORC1 signaling (observed through western blot for increased phosphorylation on mTOR S2448) and induced inhibition of mTORC2 signaling (evident through repressed Rictor and tuberous sclerosis 1 (TSC1) gene expression). mTORC1 induced deregulation of E2 signaling was confirmed using qPCR and the mTORC1-specific inhibitor RAD001. Co-treatment of MCF7 breast cancer cells stably overexpressing miR-155 with RAD001 and E2 restored E2-induced PgR gene expression. RAD001 treatment of SCID/CB17 mice inhibited E2-induced tumorigenesis of the MCF7 miR-155 overexpressing cell line. Finally we demonstrated a strong positive correlation between Rictor and PgR expression and a negative correlation with Raptor expression in Luminal B breast cancer samples, a breast cancer histological subtype known for having an altered ER α -signaling pathway. Conclusions: miRNA mediated alterations in mTOR and ER α signaling establishes a new mechanism for altered estrogen responses independent of growth factor stimulation

Relationships between seasonal changes in diet of multimammate rat (Mastomys natalensis) and its breeding patterns in semi-arid areas in Tanzania

The diet and breeding patterns of Mastomys natalensis in semi-arid areas of Isimani division, Iringa region, Tanzania were investigated in maize fields and fallow land. The aim was to investigate the influence of diet on breeding patterns of M. natalensis. Removal trapping was used to capture rodents and analyse diet categories while Capture-mark-release trapping was used to investigate breeding patterns of female M. natalensis. Mastomys natalensis comprised 94%of the total capture, and the remaining 6% comprised of six other species. Statistical analysis of food preferences indicated that both vegetative materials and seeds were significantly higher in the overall diet of M. natalensis compared with other food materials. Significant differences in the proportions of vegetativematerials and seeds were found between seasons (dry, wet), but not between habitats (fallow, maize). There was a clear seasonal pattern in the proportion of reproductively active females with peaks in April and troughs in October. The proportion of vegetative materialswas highest during thewet season and correlated positively with reproductive activity, suggesting that vegetative materials contain certain compounds (e.g. 6-MBOA) that trigger reproductive activity in M. natalensis. The breeding activity of M. natalensis in semi-arid areas might, thus, be reduced by limiting access to fresh vegetative food (e.g. young sprouting grass)

Representation of Time-Varying Stimuli by a Network Exhibiting Oscillations on a Faster Time Scale

Sensory processing is associated with gamma frequency oscillations (30–80 Hz) in sensory cortices. This raises the question whether gamma oscillations can be directly involved in the representation of time-varying stimuli, including stimuli whose time scale is longer than a gamma cycle. We are interested in the ability of the system to reliably distinguish different stimuli while being robust to stimulus variations such as uniform time-warp. We address this issue with a dynamical model of spiking neurons and study the response to an asymmetric sawtooth input current over a range of shape parameters. These parameters describe how fast the input current rises and falls in time. Our network consists of inhibitory and excitatory populations that are sufficient for generating oscillations in the gamma range. The oscillations period is about one-third of the stimulus duration. Embedded in this network is a subpopulation of excitatory cells that respond to the sawtooth stimulus and a subpopulation of cells that respond to an onset cue. The intrinsic gamma oscillations generate a temporally sparse code for the external stimuli. In this code, an excitatory cell may fire a single spike during a gamma cycle, depending on its tuning properties and on the temporal structure of the specific input; the identity of the stimulus is coded by the list of excitatory cells that fire during each cycle. We quantify the properties of this representation in a series of simulations and show that the sparseness of the code makes it robust to uniform warping of the time scale. We find that resetting of the oscillation phase at stimulus onset is important for a reliable representation of the stimulus and that there is a tradeoff between the resolution of the neural representation of the stimulus and robustness to time-warp. Author Summary Sensory processing of time-varying stimuli, such as speech, is associated with high-frequency oscillatory cortical activity, the functional significance of which is still unknown. One possibility is that the oscillations are part of a stimulus-encoding mechanism. Here, we investigate a computational model of such a mechanism, a spiking neuronal network whose intrinsic oscillations interact with external input (waveforms simulating short speech segments in a single acoustic frequency band) to encode stimuli that extend over a time interval longer than the oscillation's period. The network implements a temporally sparse encoding, whose robustness to time warping and neuronal noise we quantify. To our knowledge, this study is the first to demonstrate that a biophysically plausible model of oscillations occurring in the processing of auditory input may generate a representation of signals that span multiple oscillation cycles.National Science Foundation (DMS-0211505); Burroughs Wellcome Fund; U.S. Air Force Office of Scientific Researc

A molecular basis for neurofibroma-associated skeletal manifestations in NF1

Purpose: Plexiform neurofibromas (pNF) develop in children with neurofibromatosis type 1 (NF1) and can be associated with several skeletal comorbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown. Methods: We used mouse models of NF1 neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used dual-energy X-ray absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib. Results: We detected increased nonmineralized bone surfaces adjacent to tumors in mouse models of NF1 neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib. Conclusion: Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease

Comparison study of microarray meta-analysis methods

<p>Abstract</p> <p>Background</p> <p>Meta-analysis methods exist for combining multiple microarray datasets. However, there are a wide range of issues associated with microarray meta-analysis and a limited ability to compare the performance of different meta-analysis methods.</p> <p>Results</p> <p>We compare eight meta-analysis methods, five existing methods, two naive methods and a novel approach (mDEDS). Comparisons are performed using simulated data and two biological case studies with varying degrees of meta-analysis complexity. The performance of meta-analysis methods is assessed via ROC curves and prediction accuracy where applicable.</p> <p>Conclusions</p> <p>Existing meta-analysis methods vary in their ability to perform successful meta-analysis. This success is very dependent on the complexity of the data and type of analysis. Our proposed method, mDEDS, performs competitively as a meta-analysis tool even as complexity increases. Because of the varying abilities of compared meta-analysis methods, care should be taken when considering the meta-analysis method used for particular research.</p

Unveiling Cosmic Dawn: the synergetic role of space and ground-based telescopes

Large scale structure and cosmolog

Depth refuge and the impacts of SCUBA spearfishing on coral reef fishes

In recent decades, spearfishing with SCUBA has emerged as an efficient method for targeting reef fish in deeper waters. However, deeper waters are increasingly recognised as a potential source of refuge that may help sustain fishery resources. We used a combination of historical catch data over a 20-year time period and fishery-independent surveys to investigate the effects of SCUBA spearfishing on coral reef fish populations in the southern Mariana Islands. Two jurisdictions were studied; Guam, where SCUBA spearfishing is practiced, and the nearby Commonwealth of Northern Mariana Islands (CNMI), where SCUBA spearfishing has been banned since 2003. Fishery-independent data were collected using baited remote underwater stereo-video systems (stereo-BRUVs) stratified by depth, marine protected area status and jurisdiction. Herbivores (primary consumers) dominated spearfishing catches, with parrotfish (scarines) and surgeonfish/unicornfish (acanthurids) the main groups harvested. However, the large, endangered humphead wrasse (Cheilinus undulatus) was the main species by weight landed by SCUBA spearfishers. SCUBA spearfishing was associated with declining size of scarines over time and catches shifting from a dominance of large parrotfishes to a mixed assemblage with increasing proportions of acanthurids. Comparisons between Guam and the nearby CNMI revealed differences in the assemblage of fished species and also greater size of scarines and acanthurids in deep water where SCUBA fishing is banned. These results suggest that SCUBA spearfishing impacts reef fish populations and that the restriction of this fishing method will ensure refuge for fish populations in deeper waters. We recommend a ban on SCUBA spearfishing to preserve or aid the recovery of large, functionally important coral reef species and to improve the sustainability of coral reef fisheries

ZEB2 regulates endocrine therapy sensitivity and metastasis in luminal a breast cancer cells through a non-canonical mechanism

PURPOSE: The transcription factors ZEB1 and ZEB2 mediate epithelial-to-mesenchymal transition (EMT) and metastatic progression in numerous malignancies including breast cancer. ZEB1 and ZEB2 drive EMT through transcriptional repression of cell-cell junction proteins and members of the tumor suppressive miR200 family. However, in estrogen receptor positive (ER +) breast cancer, the role of ZEB2 as an independent driver of metastasis has not been fully investigated. METHODS: In the current study, we induced exogenous expression of ZEB2 in ER + MCF-7 and ZR-75-1 breast cancer cell lines and examined EMT gene expression and metastasis using dose-response qRT-PCR, transwell migration assays, proliferation assays with immunofluorescence of Ki-67 staining. We used RNA sequencing to identify pathways and genes affected by ZEB2 overexpression. Finally, we treated ZEB2-overexpressing cells with 17β-estradiol (E2) or ICI 182,780 to evaluate how ZEB2 affects estrogen response. RESULTS: Contrary to expectation, we found that ZEB2 did not increase canonical epithelial nor decrease mesenchymal gene expressions. Furthermore, ZEB2 overexpression did not promote a mesenchymal cell morphology. However, ZEB1 and ZEB2 protein expression induced significant migration of MCF-7 and ZR-75-1 breast cancer cells in vitro and MCF-7 xenograft metastasis in vivo. Transcriptomic (RNA sequencing) pathway analysis revealed alterations in estrogen signaling regulators and pathways, suggesting a role for ZEB2 in endocrine sensitivity in luminal A breast cancer. Expression of ZEB2 was negatively correlated with estrogen receptor complex genes in luminal A patient tumors. Furthermore, treatment with 17β-estradiol (E2) or the estrogen receptor antagonist ICI 182,780 had no effect on growth of ZEB2-overexpressing cells. CONCLUSION: ZEB2 is a multi-functional regulator of drug sensitivity, cell migration, and metastasis in ER + breast cancer and functions through non-canonical mechanisms