Neurotrophin-Induced Transport of a β-Actin mRNP Complex Increases β-Actin Levels and Stimulates Growth Cone Motility

AbstractNeurotrophin regulation of actin-dependent changes in growth cone motility may depend on the signaling of β-actin mRNA transport. Formation of an RNP complex between the β-actin mRNA zipcode sequence and Zipcode Binding Protein 1 (ZBP1) was required for its localization to growth cones. Antisense oligonucleotides to the zipcode inhibited formation of this RNP complex in vitro and the neurotrophin-induced localization of β-actin mRNA and ZBP1 granules. Live cell imaging of neurons transfected with EGFP-ZBP1 revealed fast, bidirectional movements of granules in neurites that were inhibited by antisense treatment, as visualized by FRAP analysis. NT-3 stimulation of β-actin protein localization was dependent on the 3′UTR and inhibited by antisense treatment. Growth cones exhibited impaired motility in the presense of antisense. These results suggest a novel mechanism to influence growth cone dynamics involving the regulated transport of mRNA

Nuclear accessibility of β-actin mRNA is measured by 3D single-molecule real-time tracking

Imaging single proteins or RNAs allows direct visualization of the inner workings of the cell. Typically, three-dimensional (3D) images are acquired by sequentially capturing a series of 2D sections. The time required to step through the sample often impedes imaging of large numbers of rapidly moving molecules. Here we applied multifocus microscopy (MFM) to instantaneously capture 3D single-molecule real-time images in live cells, visualizing cell nuclei at 10 volumes per second. We developed image analysis techniques to analyze messenger RNA (mRNA) diffusion in the entire volume of the nucleus. Combining MFM with precise registration between fluorescently labeled mRNA, nuclear pore complexes, and chromatin, we obtained globally optimal image alignment within 80-nm precision using transformation models. We show that {beta}-actin mRNAs freely access the entire nucleus and fewer than 60% of mRNAs are more than 0.5 {my}m away from a nuclear pore, and we do so for the first time accounting for spatial inhomogeneity of nuclear organization

Global analysis of contact-dependent human-to-mouse intercellular mRNA and lncRNA transfer in cell culture

Full-length mRNAs transfer between adjacent mammalian cells via direct cell-to-cell connections called tunneling nanotubes (TNTs). However, the extent of mRNA transfer at the transcriptome-wide level (the 'transferome') is unknown. Here, we analyzed the transferome in an human-mouse cell co-culture model using RNA-sequencing. We found that mRNA transfer is non-selective, prevalent across the human transcriptome, and that the amount of transfer to mouse embryonic fibroblasts (MEFs) strongly correlates with the endogenous level of gene expression in donor human breast cancer cells. Typically, <1% of endogenous mRNAs undergo transfer. Non-selective, expression-dependent RNA transfer was further validated using synthetic reporters. RNA transfer appears contact-dependent via TNTs, as exemplified for several mRNAs. Notably, significant differential changes in the native MEF transcriptome were observed in response to co-culture, including the upregulation of multiple cancer and cancer-associated fibroblast-related genes and pathways. Together, these results lead us to suggest that TNT-mediated RNA transfer could be a phenomenon of physiological importance under both normal and pathogenic conditions

Tidal torques. A critical review of some techniques

We point out that the MacDonald formula for body-tide torques is valid only in the zeroth order of e/Q, while its time-average is valid in the first order. So the formula cannot be used for analysis in higher orders of e/Q. This necessitates corrections in the theory of tidal despinning and libration damping. We prove that when the inclination is low and phase lags are linear in frequency, the Kaula series is equivalent to a corrected version of the MacDonald method. The correction to MacDonald's approach would be to set the phase lag of the integral bulge proportional to the instantaneous frequency. The equivalence of descriptions gets violated by a nonlinear frequency-dependence of the lag. We explain that both the MacDonald- and Darwin-torque-based derivations of the popular formula for the tidal despinning rate are limited to low inclinations and to the phase lags being linear in frequency. The Darwin-torque-based derivation, though, is general enough to accommodate both a finite inclination and the actual rheology. Although rheologies with Q scaling as the frequency to a positive power make the torque diverge at a zero frequency, this reveals not the impossible nature of the rheology, but a flaw in mathematics, i.e., a common misassumption that damping merely provides lags to the terms of the Fourier series for the tidal potential. A hydrodynamical treatment (Darwin 1879) had demonstrated that the magnitudes of the terms, too, get changed. Reinstating of this detail tames the infinities and rehabilitates the "impossible" scaling law (which happens to be the actual law the terrestrial planets obey at low frequencies).Comment: arXiv admin note: sections 4 and 9 of this paper contain substantial text overlap with arXiv:0712.105

Actors and networks or agents and structures: towards a realist view of information systems

Actor-network theory (ANT) has achieved a measure of popularity in the analysis of information systems. This paper looks at ANT from the perspective of the social realism of Margaret Archer. It argues that the main issue with ANT from a realist perspective is its adoption of a `flat' ontology, particularly with regard to human beings. It explores the value of incorporating concepts from ANT into a social realist approach, but argues that the latter offers a more productive way of approaching information systems

The 3-3-1 model with S_4 flavor symmetry

We construct a 3-3-1 model based on family symmetry S_4 responsible for the neutrino and quark masses. The tribimaximal neutrino mixing and the diagonal quark mixing have been obtained. The new lepton charge \mathcal{L} related to the ordinary lepton charge L and a SU(3) charge by L=2/\sqrt{3} T_8+\mathcal{L} and the lepton parity P_l=(-)^L known as a residual symmetry of L have been introduced which provide insights in this kind of model. The expected vacuum alignments resulting in potential minimization can origin from appropriate violation terms of S_4 and \mathcal{L}. The smallness of seesaw contributions can be explained from the existence of such terms too. If P_l is not broken by the vacuum values of the scalar fields, there is no mixing between the exotic and the ordinary quarks at the tree level.Comment: 20 pages, revised versio

Occupational Exposures and Metabolic Syndrome among Hispanics/Latinos

Objective: We assessed the cross-sectional relationships of self-reported current occupational exposures to solvents, metals, and pesticides with metabolic syndrome and its components among 7127 participants in the Hispanic Community Health Study/Study of Latinos. Methods: Metabolic syndrome was defined as a clustering of abdominal obesity, high triglycerides, low high-density lipoprotein cholesterol, high blood pressure, and/or high fasting glucose. Regression models that incorporated inverse probability of exposure weighting were used to estimate prevalence ratios. Results: Solvent exposure was associated with a 32% higher prevalence of high blood pressure (95% confidence interval: 1.09 to 1.60) than participants not reporting exposure. No associations were observed for occupational exposures with abdominal obesity, high triglycerides, low high-density lipoprotein, or metabolic syndrome. Conclusion: Our findings suggest that solvent exposure may be an important occupational risk factor for high blood pressure among Hispanics/Latinos in the United States

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Bodily tides near spin-orbit resonances

Spin-orbit coupling can be described in two approaches. The method known as "the MacDonald torque" is often combined with an assumption that the quality factor Q is frequency-independent. This makes the method inconsistent, because the MacDonald theory tacitly fixes the rheology by making Q scale as the inverse tidal frequency. Spin-orbit coupling can be treated also in an approach called "the Darwin torque". While this theory is general enough to accommodate an arbitrary frequency-dependence of Q, this advantage has not yet been exploited in the literature, where Q is assumed constant or is set to scale as inverse tidal frequency, the latter assertion making the Darwin torque equivalent to a corrected version of the MacDonald torque. However neither a constant nor an inverse-frequency Q reflect the properties of realistic mantles and crusts, because the actual frequency-dependence is more complex. Hence the necessity to enrich the theory of spin-orbit interaction with the right frequency-dependence. We accomplish this programme for the Darwin-torque-based model near resonances. We derive the frequency-dependence of the tidal torque from the first principles, i.e., from the expression for the mantle's compliance in the time domain. We also explain that the tidal torque includes not only the secular part, but also an oscillating part. We demonstrate that the lmpq term of the Darwin-Kaula expansion for the tidal torque smoothly goes through zero, when the secondary traverses the lmpq resonance (e.g., the principal tidal torque smoothly goes through nil as the secondary crosses the synchronous orbit). We also offer a possible explanation for the unexpected frequency-dependence of the tidal dissipation rate in the Moon, discovered by LLR