83 research outputs found

    Presynaptic Translation: Stepping Out of the Postsynaptic Shadow

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    The ability of the nervous system to convert transient experiences into long-lasting structural changes at the synapse relies upon protein synthesis. It has become increasingly clear that a critical subset of this synthesis occurs within the synaptic compartment. While this process has been extensively characterized in the postsynaptic compartment, the contribution of local translation to presynaptic function remains largely unexplored. However, recent evidence highlights the potential importance of translation within the presynaptic compartment. Work in cultured neurons has shown that presynaptic translation occurs specifically at synapses undergoing long-term plasticity and may contribute to the maintenance of nascent synapses. Studies from our laboratory have demonstrated that Fragile X proteins, which regulate mRNA localization and translation, are expressed at the presynaptic apparatus. Further, mRNAs encoding presynaptic proteins traffic into axons. Here we discuss recent advances in the study of presynaptic translation as well as the challenges confronting the field. Understanding the regulation of presynaptic function by local protein synthesis promises to shed new light on activity-dependent modification of synaptic architecture

    UTILIZATION OF THE LINE-INTERCEPT METHOD TO ESTIMATE THE COVERAGE, DENSITY, AND AVERAGE LENGTH OF ROW SKIPS IN COTTON AND OTHER ROW CROPS

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    In row crops, a skip is a length of row within the drill where the crop has failed to establish. If the number of skips and their mean length per acre becomes too high, then considerable losses in crop yield occur. Frequently, farmers are faced with the decision to replant a crop which has row skips. To make the best decision, reliable estimates of the stand loss due to skips must be available. In making this decision, three parameters are useful: the percent of the area per acre that is skipped, the number of individual skips (that is, density) per acre, and the mean row length per skip. The line-intercept method for the sampling of two-dimensional objects (particles) can be used to obtain estimates of these parameters. The method is illustrated with an example from a cotton field

    EGFP insertional mutagenesis reveals multiple FXR2P fibrillar states with differing ribosome association in neurons

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    RNA-binding proteins (RBPs) function in higher-order assemblages such as RNA granules to regulate RNA localization and translation. The Fragile X homolog FXR2P is an RBP essential for formation of neuronal Fragile X granules that associate with axonal mRNA and ribosomes in the intact brain. However, the FXR2P domains important for assemblage formation in a cellular system are unknown. Here we used an EGFP insertional mutagenesis approach to probe for FXR2P intrinsic features that influence its structural states. We tested 18 different in-frame FXR2P(EGFP) fusions in neurons and found that the majority did not impact assemblage formation. However, EGFP insertion within a 23 amino acid region of the low complexity (LC) domain induced FXR2P(EGFP) assembly into two distinct fibril states that were observed in isolation or in highly-ordered bundles. FXR2P(EGFP) fibrils exhibited different developmental timelines, ultrastructures and ribosome associations. Formation of both fibril types was dependent on an intact RNA-binding domain. These results suggest that restricted regions of the LC domain, together with the RNA-binding domain, may be important for FXR2P structural state organization in neurons

    TRANSFORM (Multicenter Experience With Rapid Deployment Edwards INTUITY Valve System for Aortic Valve Replacement) US clinical trial: Performance of a rapid deployment aortic valve

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    Background: The TRANSFORM (Multicenter Experience With Rapid Deployment Edwards INTUITY Valve System for Aortic Valve Replacement) trial (NCT01700439) evaluated the performance of the INTUITY rapid deployment aortic valve replacement (RDAVR) system in patients with severe aortic stenosis. Methods: TRANSFORM was a prospective, nonrandomized, multicenter (n 1�4 29), single-arm trial. INTUITY is comprised of a cloth-covered balloon- expandable frame attached to a Carpentier-Edwards PERIMOUNT Magna Ease aortic valve. Primary and effectiveness endpoints were evaluated at 1 year. Results: Between 2012 and 2015, 839 patients underwent RDAVR. Mean age was 73.5 8.3 years. Full sternotomy (FS) was used in 59% and minimally invasive surgical incisions in 41%. Technical success rate was 95%. For isolated RDAVR, mean crossclamp and cardiopulmonary bypass times for FS were 49.3 26.9 minutes and 69.2 34.7 minutes, respectively, and for minimally invasive surgical 63.1 25.4 minutes and 84.6 33.5 minutes, respectively. These times were favorable compared with Society of Thoracic Surgeons data- base comparators for FS: 76.3 minutes and 104.2 minutes, respectively, and for minimally invasive surgical, 82.9 minutes and 111.4 minutes, respectively (P<.001). At 30 days, all-cause mortality was 0.8%; valve explant, 0.1%; throm- boembolism, 3.5%; and major bleeding, 1.3%. In patients with isolated aortic valve replacement, the rate of permanent pacemaker implantation was 11.9%. At 1 year, mean effective orifice area was 1.7 cm2; mean gradient, 10.3 mm Hg; and moderate and severe paravalvular leak, 1.2% and 0.4%, respectively

    COSMOS-Web: Intrinsically Luminous z\gtrsim10 Galaxy Candidates Test Early Stellar Mass Assembly

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    We report the discovery of 15 exceptionally luminous 10z1410\lesssim z\lesssim14 candidate galaxies discovered in the first 0.28 deg2^2 of JWST/NIRCam imaging from the COSMOS-Web Survey. These sources span rest-frame UV magnitudes of 20.5>MUV>22-20.5>M_{\rm UV}>-22, and thus constitute the most intrinsically luminous z10z\gtrsim10 candidates identified by JWST to-date. Selected via NIRCam imaging with Hubble ACS/F814W, deep ground-based observations corroborate their detection and help significantly constrain their photometric redshifts. We analyze their spectral energy distributions using multiple open-source codes and evaluate the probability of low-redshift solutions; we conclude that 12/15 (80%) are likely genuine z10z\gtrsim10 sources and 3/15 (20%) likely low-redshift contaminants. Three of our z12z\sim12 candidates push the limits of early stellar mass assembly: they have estimated stellar masses 5×109M\sim5\times10^{9}\,M_\odot, implying an effective stellar baryon fraction of ϵ0.20.5\epsilon_{\star}\sim0.2-0.5, where ϵM/(fbMhalo)\epsilon_{\star}\equiv M_{\star}/(f_{b}M_{halo}). The assembly of such stellar reservoirs is made possible due to rapid, burst-driven star formation on timescales <<100\,Myr where the star-formation rate may far outpace the growth of the underlying dark matter halos. This is supported by the similar volume densities inferred for M1010MM_\star\sim10^{10}\,M_\odot galaxies relative to M109MM_\star\sim10^{9}\,M_\odot -- both about 10610^{-6} Mpc3^{-3} -- implying they live in halos of comparable mass. At such high redshifts, the duty cycle for starbursts would be of order unity, which could cause the observed change in the shape of the UVLF from a double powerlaw to Schechter at z8z\approx8. Spectroscopic redshift confirmation and ensuing constraints of their masses will be critical to understanding how, and if, such early massive galaxies push the limits of galaxy formation in Λ\LambdaCDM.Comment: 30 pages, 9 figures; ApJ submitte

    The Web Epoch of Reionization Lyman-α\alpha Survey (WERLS) I. MOSFIRE Spectroscopy of z78\mathbf{z \sim 7-8} Lyman-α\alpha Emitters

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    We present the first results from the Web Epoch of Reionization Lyman-α\alpha Survey (WERLS), a spectroscopic survey of Lyman-α\alpha emission using Keck I/MOSFIRE and LRIS. WERLS targets bright (J<26J<26) galaxy candidates with photometric redshifts of 5.5z85.5\lesssim z \lesssim 8 selected from pre-JWST imaging embedded in the Epoch of Reionization (EoR) within three JWST deep fields: CEERS, PRIMER, and COSMOS-Web. Here, we report 11 z78z\sim7-8 Lyman-α\alpha emitters (LAEs; 3 secure and 8 tentative candidates) detected in the first five nights of WERLS MOSFIRE data. We estimate our observed LAE yield is 13\sim13%, broadly consistent with expectations assuming some loss from redshift uncertainty, contamination from sky OH lines, and that the Universe is approximately half-ionized at this epoch, whereby observable Lyman-α\alpha emission is unlikely for galaxies embedded in a neutral intergalactic medium. Our targets are selected to be UV-bright, and span a range of absolute UV magnitudes with 23.1<MUV<19.8-23.1 < M_{\text{UV}} < -19.8. With two LAEs detected at z=7.68z=7.68, we also consider the possibility of an ionized bubble at this redshift. Future synergistic Keck+JWST efforts will provide a powerful tool for pinpointing beacons of reionization and mapping the large scale distribution of mass relative to the ionization state of the Universe.Comment: 27 pages, 8 figures; ApJ submitte

    Adult Cardiac Progenitor Cell Aggregates Exhibit Survival Benefit Both In Vitro and In Vivo

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    Background: A major hurdle in the use of exogenous stems cells for therapeutic regeneration of injured myocardium remains the poor survival of implanted cells. To date, the delivery of stem cells into myocardium has largely focused on implantation of cell suspensions. Methodology and Principal Findings: We hypothesize that delivering progenitor cells in an aggregate form would serve to mimic the endogenous state with proper cell-cell contact, and may aid the survival of implanted cells. Microwell methodologies allow for the culture of homogenous 3D cell aggregates, thereby allowing cell-cell contact. In this study, we find that the culture of cardiac progenitor cells in a 3D cell aggregate augments cell survival and protects against cellular toxins and stressors, including hydrogen peroxide and anoxia/reoxygenation induced cell death. Moreover, using a murine model of cardiac ischemia-reperfusion injury, we find that delivery of cardiac progenitor cells in the form of 3D aggregates improved in vivo survival of implanted cells. Conclusion: Collectively, our data support the notion that growth in 3D cellular systems and maintenance of cell-cell contact improves exogenous cell survival following delivery into myocardium. These approaches may serve as a strategy to improve cardiovascular cell-based therapies

    Unveiling the distant Universe: Characterizing z9z\ge9 Galaxies in the first epoch of COSMOS-Web

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    We report the identification of 15 galaxy candidates at z9z\ge9 using the initial COSMOS-Web JWST observations over 77 arcmin2^2 through four NIRCam filters (F115W, F150W, F277W, F444W) with an overlap with MIRI (F770W) of 8.7 arcmin2^2. We fit the sample using several publicly-available SED fitting and photometric redshift codes and determine their redshifts between z=9.3z=9.3 and z=10.9z=10.9 (z=10.0\langle z\rangle=10.0), UV-magnitudes between MUV_{\rm UV} = -21.2 and -19.5 (with \langle MUV=20.2_{\rm UV}\rangle=-20.2) and rest-frame UV slopes (β=2.4\langle \beta\rangle=-2.4). These galaxies are, on average, more luminous than most z9z\ge9 candidates discovered by JWST so far in the literature, while exhibiting similar blue colors in their rest-frame UV. The rest-frame UV slopes derived from SED-fitting are blue (β\beta\sim[-2.0, -2.7]) without reaching extremely blue values as reported in other recent studies at these redshifts. The blue color is consistent with models that suggest the underlying stellar population is not yet fully enriched in metals like similarly luminous galaxies in the lower redshift Universe. The derived stellar masses with log10(\langle \log_{\rm 10} (M/_\star/M)89_\odot)\rangle\approx8-9 are not in tension with the standard Λ\LambdaCDM model and our measurement of the volume density of such UV luminous galaxies aligns well with previously measured values presented in the literature at z910z\sim9-10. Our sample of galaxies, although compact, are significantly resolved.Comment: Submitted to Ap

    Cyclic di-GMP is Essential for the Survival of the Lyme Disease Spirochete in Ticks

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    Cyclic dimeric GMP (c-di-GMP) is a bacterial second messenger that modulates many biological processes. Although its role in bacterial pathogenesis during mammalian infection has been documented, the role of c-di-GMP in a pathogen's life cycle within a vector host is less understood. The enzootic cycle of the Lyme disease pathogen Borrelia burgdorferi involves both a mammalian host and an Ixodes tick vector. The B. burgdorferi genome encodes a single copy of the diguanylate cyclase gene (rrp1), which is responsible for c-di-GMP synthesis. To determine the role of c-di-GMP in the life cycle of B. burgdorferi, an Rrp1-deficient B. burgdorferi strain was generated. The rrp1 mutant remains infectious in the mammalian host but cannot survive in the tick vector. Microarray analyses revealed that expression of a four-gene operon involved in glycerol transport and metabolism, bb0240-bb0243, was significantly downregulated by abrogation of Rrp1. In vitro, the rrp1 mutant is impaired in growth in the media containing glycerol as the carbon source (BSK-glycerol). To determine the contribution of the glycerol metabolic pathway to the rrp1 mutant phenotype, a glp mutant, in which the entire bb0240-bb0243 operon is not expressed, was generated. Similar to the rrp1 mutant, the glp mutant has a growth defect in BSK-glycerol medium. In vivo, the glp mutant is also infectious in mice but has reduced survival in ticks. Constitutive expression of the bb0240-bb0243 operon in the rrp1 mutant fully rescues the growth defect in BSK-glycerol medium and partially restores survival of the rrp1 mutant in ticks. Thus, c-di-GMP appears to govern a catabolic switch in B. burgdorferi and plays a vital role in the tick part of the spirochetal enzootic cycle. This work provides the first evidence that c-di-GMP is essential for a pathogen's survival in its vector host
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