RNA Docking and Local Translation Regulate Site-Specific Axon Remodeling In Vivo

Nascent proteins can be positioned rapidly at precise subcellular locations by local protein synthesis (LPS) to facilitate localized growth responses. Axon arbor architecture, a major determinant of synaptic connectivity, is shaped by localized growth responses, but it is unknown whether LPS influences these responses in vivo. Using high-resolution live imaging, we examined the spatiotemporal dynamics of RNA and LPS in retinal axons during arborization in vivo. Endogenous RNA tracking reveals that RNA granules dock at sites of branch emergence and invade stabilized branches. Live translation reporter analysis reveals that de novo ß-actin hotspots colocalize with docked RNA granules at the bases and tips of new branches. Inhibition of axonal ß-actin mRNA translation disrupts arbor dynamics primarily by reducing new branch emergence and leads to impoverished terminal arbors. The results demonstrate a requirement for LPS in building arbor complexity and suggest a key role for pre-synaptic LPS in assembling neural circuits.This work was supported by Cambridge Trust, Croucher Foundation, Sir Edward Youde Memorial Fund (H.H.-W.W.), Gates Cambridge (J.Q.L.), Fundac¸ a˜ o para a Cieˆ ncia e Tecnologia (C.M.R.), Wellcome Trust Senior Investigator Award (100329/Z/ 12/Z) (W.A.H.), EPSRC Grant (EP/H018301/1), MRC Grant (MR/K015850/1 and MR/K02292X/1), Wellcome Trust (089703/Z/09/Z) (C.F.K.), Wellcome Trust Programme Grant (085314/Z/08/Z), and ERC Advanced Grant (322817) (C.E.H.)

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression

Neurospora from natural populations: Population genomics insights into the Life history of a model microbial Eukaryote

The ascomycete filamentous fungus Neurospora crassa played a historic role in experimental biology and became a model system for genetic research. Stimulated by a systematic effort to collect wild strains initiated by Stanford geneticist David Perkins, the genus Neurospora has also become a basic model for the study of evolutionary processes, speciation, and population biology. In this chapter, we will first trace the history that brought Neurospora into the era of population genomics. We will then cover the major contributions of population genomic investigations using Neurospora to our understanding of microbial biogeography and speciation, and review recent work using population genomics and genome-wide association mapping that illustrates the unique potential of Neurospora as a model for identifying the genetic basis of (potentially adaptive) phenotypes in filamentous fungi. The advent of population genomics has contributed to firmly establish Neurospora as a complete model system and we hope our review will entice biologists to include Neurospora in their research

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres

Export of functional Streptomyces coelicolor alditol oxidase to the periplasm or cell surface of Escherichia coli and its application in whole-cell biocatalysis

Streptomyces coelicolor A3(2) alditol oxidase (AldO) is a soluble monomeric flavoprotein in which the flavin cofactor is covalently linked to the polypeptide chain. AldO displays high reactivity towards different polyols such as xylitol and sorbitol. These characteristics make AldO industrially relevant, but full biotechnological exploitation of this enzyme is at present restricted by laborious and costly purification steps. To eliminate the need for enzyme purification, this study describes a whole-cell AldO biocatalyst system. To this end, we have directed AldO to the periplasm or cell surface of Escherichia coli. For periplasmic export, AldO was fused to endogenous E. coli signal sequences known to direct their passenger proteins into the SecB, signal recognition particle (SRP), or Twin-arginine translocation (Tat) pathway. In addition, AldO was fused to an ice nucleation protein (INP)-based anchoring motif for surface display. The results show that Tat-exported AldO and INP-surface-displayed AldO are active. The Tat-based system was successfully employed in converting xylitol by whole cells, whereas the use of the INP-based system was most likely restricted by lipopolysaccharide LPS in wild-type cells. It is anticipated that these whole-cell systems will be a valuable tool for further biological and industrial exploitation of AldO and other cofactor-containing enzymes.

Dark Force Detection in Low Energy e-p Collisions

We study the prospects for detecting a light boson X with mass m_X < 100 MeV at a low energy electron-proton collider. We focus on the case where X dominantly decays to e+ e- as motivated by recent "dark force" models. In order to evade direct and indirect constraints, X must have small couplings to the standard model (alpha_X 10 MeV). By comparing the signal and background cross sections for the e- p e+ e- final state, we conclude that dark force detection requires an integrated luminosity of around 1 inverse attobarn, achievable with a forthcoming JLab proposal.Comment: 38 pages, 19 figures; v2, references adde

The genetic profile of elite youth soccer players and its association with power and speed depends on maturity status

We investigated the association of multiple single nucleotide polymorphisms (SNPs) with athlete status and power/speed performance in elite male youth soccer players (ESP) and control participants (CON) at different stages of maturity. ESP (n = 535; aged 8–23 years) and CON (n = 151; aged 9–26 years) were genotyped for 10 SNPs and grouped according to years from predicted peak-height-velocity (PHV), i.e. pre- or post-PHV, to determine maturity status. Participants performed bilateral vertical countermovement jumps, bilateral horizontal-forward countermovement jumps, 20m sprints and modified 505-agility tests. Compared to CON, pre-PHV ESP demonstrated a higher ACTN3 (rs1815739) XX (‘endurance’) genotype frequency distribution, while post-PHV ESP revealed a higher frequency distribution of the PPARA (rs4253778) C-allele, AGT (rs699) GG genotype and NOS3 (rs2070744) T-allele (‘power’ genotypes/alleles). BDNF (rs6265) CC, COL5A1 (rs12722) CC and NOS3 TT homozygotes sprinted quicker than A-allele carriers, CT heterozygotes and CC homozygotes, respectively. COL2A1 (rs2070739) CC and AMPD1 (rs17602729) GG homozygotes sprinted faster than their respective minor allele carrier counterparts in CON and pre-PHV ESP, respectively. BDNF CC homozygotes jumped further than T-allele carriers, while ESP COL5A1 CC homozygotes jumped higher than TT homozygotes. To conclude, we have shown for the first time that pre- and post-PHV ESP have distinct genetic profiles, with pre-PHV ESP more suited for endurance, and post-PHV ESP for power and speed (the latter phenotypes being crucial attributes for post-PHV ESP). We have also demonstrated that power, acceleration and sprint performance were associated with five SNPs, both individually and in combination, possibly by influencing muscle size and neuromuscular activation

Inorganic speciation of dissolved elements in seawater: the influence of pH on concentration ratios

Assessments of inorganic elemental speciation in seawater span the past four decades. Experimentation, compilation and critical review of equilibrium data over the past forty years have, in particular, considerably improved our understanding of cation hydrolysis and the complexation of cations by carbonate ions in solution. Through experimental investigations and critical evaluation it is now known that more than forty elements have seawater speciation schemes that are strongly influenced by pH. In the present work, the speciation of the elements in seawater is summarized in a manner that highlights the significance of pH variations. For elements that have pH-dependent species concentration ratios, this work summarizes equilibrium data (S = 35, t = 25°C) that can be used to assess regions of dominance and relative species concentrations. Concentration ratios of complex species are expressed in the form log[A]/[B] = pH - C where brackets denote species concentrations in solution, A and B are species important at higher (A) and lower (B) solution pH, and C is a constant dependent on salinity, temperature and pressure. In the case of equilibria involving complex oxy-anions (MO(x)(OH)(y)) or hydroxy complexes (M(OH)(n)), C is written as pK(n )= -log K(n )or pK(n)* = -log K(n)* respectively, where K(n )and K(n)* are equilibrium constants. For equilibria involving carbonate complexation, the constant C is written as pQ = -log(K(2)(l)K(n )[HCO(3)(-)]) where K(2)(l )is the HCO(3 )(- )dissociation constant, K(n )is a cation complexation constant and [HCO(3)(-)] is approximated as 1.9 × 10(-3 )molar. Equilibrium data expressed in this manner clearly show dominant species transitions, ranges of dominance, and relative concentrations at any pH