Ribosome recycling, diffusion, and mRNA loop formation in translational regulation

We explore and quantify the physical and biochemical mechanisms that may be relevant in the regulation of translation. After elongation and detachment from the 3' termination site of mRNA, parts of the ribosome machinery can diffuse back to the initiation site, especially if it is held nearby, enhancing overall translation rates. The elongation steps of the mRNA-bound ribosomes are modeled using exact and asymptotic results of the totally asymmetric exclusion process (TASEP).Since the ribosome injection rates of the TASEP depend on the local concentrations at the initiation site, a source of ribosomes emanating from the termination end can feed back to the initiation site, leading to a self-consistent set of equations for the steady-state ribosome throughput. Additional mRNA binding factors can also promote loop formation, or cyclization, bringing the initiation and termination sites into close proximity. The probability distribution of the distance between the initiation and termination sites is described using simple noninteracting polymer models. We find that the initiation, or initial ribosome adsorption binding required for maximal throughput can vary dramatically depending on certain values of the bulk ribosome concentration and diffusion constant. If cooperative interactions among the loop-promoting proteins and the initiation/termination sites are considered, the throughput can be further regulated in a nonmonotonic manner. Potential experiments to test the hypothesized physical mechanisms are discussed.Comment: 21 pp, 11 .eps figs, realigned figures and magin

Discovery of Yttrium, Zirconium, Niobium, Technetium, and Ruthenium Isotopes

Currently, thirty-four yttrium, thirty-five zirconium, thirty-four niobium, thirty-five technetium, and thirty-eight ruthenium isotopes have been observed and the discovery of these isotopes is discussed here. For each isotope a brief synopsis of the first refereed publication, including the production and identification method, is presented.Comment: To be published in Atomic Data and Nuclear Data Table

Very Long Baseline Neutrino Oscillation Experiment for Precise Measurements of Mixing Parameters and CP Violating Effects

We analyze the prospects of a feasible, Brookhaven National Laboratory based, very long baseline (BVLB) neutrino oscillation experiment consisting of a conventional horn produced low energy wide band beam and a detector of 500 kT fiducial mass with modest requirements on event recognition and resolution. Such an experiment is intended primarily to determine CP violating effects in the neutrino sector for 3-generation mixing. We analyze the sensitivity of such an experiment. We conclude that this experiment will allow determination of the CP phase $\delta_{CP}$ and the currently unknown mixing parameter $\theta_{13}$, if $\sin ^2 2 \theta_{13} \geq 0.01$, a value $\sim 15$ times lower than the present experimental upper limit. In addition to $\theta_{13}$ and $\delta_{CP}$, the experiment has great potential for precise measurements of most other parameters in the neutrino mixing matrix including $\Delta m^2_{32}$, $\sin^2 2\theta_{23}$, $\Delta m^2_{21}\times \sin 2 \theta_{12}$, and the mass ordering of neutrinos through the observation of the matter effect in the $\nu_\mu \to \nu_e$ appearance channel.Comment: 12 pages, 10 figure

Stem Cell-Based Tissue-Engineered Laryngeal Replacement.

Patients with laryngeal disorders may have severe morbidity relating to swallowing, vocalization, and respiratory function, for which conventional therapies are suboptimal. A tissue-engineered approach would aim to restore the vocal folds and maintain respiratory function while limiting the extent of scarring in the regenerated tissue. Under Good Laboratory Practice conditions, we decellularized porcine larynges, using detergents and enzymes under negative pressure to produce an acellular scaffold comprising cartilage, muscle, and mucosa. To assess safety and functionality before clinical trials, a decellularized hemilarynx seeded with human bone marrow-derived mesenchymal stem cells and a tissue-engineered oral mucosal sheet was implanted orthotopically into six pigs. The seeded grafts were left in situ for 6 months and assessed using computed tomography imaging, bronchoscopy, and mucosal brushings, together with vocal recording and histological analysis on explantation. The graft caused no adverse respiratory function, nor did it impact swallowing or vocalization. Rudimentary vocal folds covered by contiguous epithelium were easily identifiable. In conclusion, the proposed tissue-engineered approach represents a viable alternative treatment for laryngeal defects. Stem Cells Translational Medicine 2017;6:677-687

Stepwise bending of DNA by a single TATA-box Binding Protein

The TATA-box Binding Protein (TBP) is required by all three eukaryotic RNA polymerases for the initiation of transcription from most promoters. TBP recognizes, binds to, and bends promoter sequences called ``TATA-boxes'' in the DNA. We present results from the study of individual Saccharomyces cerevisia TBPs interacting with single DNA molecules containing a TATA-box. Using video microscopy, we observed the Brownian motion of beads tethered by short surface-bound DNA. When TBP binds to and bends the DNA, the conformation of the DNA changes and the amplitude of Brownian motion of the tethered bead is reduced compared to that of unbent DNA. We detected individual binding and dissociation events and derived kinetic parameters for the process. Dissociation was induced by increasing the salt concentration or by directly pulling on the tethered bead using optical tweezers. In addition to the well-defined free and bound classes of Brownian motion, we observed another two classes of motion. These extra classes were identified with intermediate states on a three-step, linear binding pathway. Biological implications of the intermediate states are discussed.Comment: Accepted for publication in: Biophysical Journa

Dependencies in evidential reports: the case for informational advantages

Whether assessing the accuracy of expert forecasting, the pros and cons of group communication, or the value of evidence in diagnostic or predictive reasoning, dependencies between experts, group members, or evidence have traditionally been seen as a form of redundancy. We demonstrate that this conception of dependence conflates the structure of a dependency network, and the observations across this network. By disentangling these two elements we show, via mathematical proof and specific examples, that there are cases where dependencies yield an informational advantage over independence. More precisely, when a structural dependency exists, but observations are either partial or contradicting, these observations provide more support to a hypothesis than when this structural dependency does not exist, ceterus paribus. Furthermore, we show that lay reasoners endorse sufficient assumptions underpinning these advantageous structures yet fail to appreciate their implications for probability judgements and belief revision

Impaired performance of alpha7 nicotinic receptor knockout mice in the five-choice serial reaction time task

RATIONALE: Nicotinic receptors have been implicated in attentional performance. Nicotine can improve attention in animals and humans, but knowledge about relevant receptor subtypes is very limited. OBJECTIVES: The aim was to examine the role of α7 receptors in attentional performance of mice and in effects of nicotine. MATERIALS AND METHODS: Mice with targeted deletion of the gene coding for the α7 subunit of nicotinic receptors and wild-type controls were trained on a five-choice serial reaction time task with food reinforcers presented under varying parametric conditions. Nicotine was administered in a range of doses (0.001–1.0 mg/kg sc), including those reported to enhance attentional performance. RESULTS: Initially the α7(−/−) (knockout) mice responded less accurately and made more anticipatory responses. After task parameters were altered so that the time allowed for responding was reduced and anticipatory (impulsive) responses were punished by a time-out, the pattern of performance deficits changed; there were increased omission errors in α7(−/−) mice but normal levels of accuracy and anticipatory responding. Nicotine did not improve any measure of performance, either with the original training parameters or after retraining; the largest dose used (1.0 mg/kg) produced a general impairment of responding in α7(−/−) and wild-type mice. CONCLUSIONS: α7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for α7 receptors in attentional processing. However, identification of a protocol for assessing attention-enhancing effects of nicotine in mice may require further modifications of test procedures or the use of different strains of animal