Co-ordinating retinal histogenesis: early cell cycle exit enhances early cell fate determination in the Xenopus retina

The laminar arrays of distinct cell types in the vertebrate retina are built by a histogenic process in which cell fate is correlated with birth order. To explore this co-ordination mechanistically, we altered the relative timing of cell cycle exit in the developing Xenopus retina and asked whether this affected the activity of neural determinants. We found that Xath5, a bHLH proneural gene that promotes retinal ganglion cell (RGC) fate, ( Kanekar, S., Perron, M., Dorsky, R., Harris, W. A., Jan, L. Y., Jan, Y. N. and Vetter, M. L. (1997) Neuron 19, 981-994), does not cause these cells to be born prematurely. To drive cells out of the cell cycle early, therefore, we misexpressed the cyclin kinase inhibitor, p27Xic1. We found that early cell cycle exit potentiates the ability of Xath5 to promote RGC fate. Conversely, the cell cycle activator, cyclin E1, which inhibits cell cycle exit, biases Xath5-expressing cells toward later neuronal fates. We found that Notch activation in this system caused cells to exit the cell cycle prematuely, and when it is misexpressed with Xath5, it also potentiates the induction of RGCs. The potentiation is counteracted by co-expression of cyclin E1. These results suggest a model of histogenesis in which the activity of factors that promote early cell cycle exit enhances the activity of factors that promote early cellular fates

On the Convergence of Sampling-Based Decomposition Algorithms for Multistage Stochastic Programs

The paper presents a convergence proof for a broad class of sampling algorithms for multistage stochastic linear programs in which the uncertain parameters occur only in the constraint right-hand sides. This class includes SDDP, AND, ReSa, and CUPPS. We show that, under some independence assumptions on the sampling procedure, the algorithms converge with probability

The effect of sterilization on biological, organic geochemical and morphological information in natural samples

The loss of biological, organic geochemical, and morphological science information that may occur should a Mars surface sample be sterilized prior to return to earth is examined. Results of experimental studies are summarized

Supply function equilibria in transportation networks

Transport constraints limit competition and arbitrageurs' possibilities of exploiting price differences between commodities in neighbouring markets. We analyze a transportation network where oligopoly producers compete with supply functions under uncertain demand, as in wholesale electricity markets. For symmetric networks with a radial structure, we show that existence of symmetric supply function equilibria (SFE) is ensured if demand shocks are sufficiently evenly distributed. We can explicitly solve for them for uniform multi-dimensional nodal demand shocks

Management of Incomplete Abortion as an Outpatient Procedure

A CAJM article on abortion.Between 800 and 1,200 cases of abortion are seen annually at Harare Hospital, Salisbury. Prior to 1st February, 1969, all cases of incomplete abortion were routinely admitted to the gynecological ward for observation and further treatment. In 1967, for example, 533 cases of abortion were seen during the six-month period 1st February to 31st of July. Of these, 396 were classified as non-septic and 137 as septic. All 533 patients were hospitalized, the average duration of stay in hospital being four days

Intranasal sodium citrate solution improves olfaction in post-viral hyposmia

Background: Calcium plays an integral role in olfactory signal transduction, including feedback inhibition. Sodium citrate acts as a calcium sequestrant and when applied intranasally, reduces free calcium available for feedback inhibition, which should theoretically improve olfaction. We aimed to investigate the utility of intranasal sodium citrate in improving the olfactory function of hyposmic patients, by performing this prospective placebo controlled, single-blinded trial. Methodology: Monorhinal olfactory testing for odour identification and threshold was performed in hyposmic patients using “Sniffin’ Sticks”, before and after treatment. Treatment consisted of sodium citrate solution application to the olfactory cleft. Sodium chloride solution was applied to the contralateral olfactory cleft, which therefore acted as placebo control. Patients were blinded to the side of sodium citrate application, and side of treatment was randomized between patients. Results: 57 patients participated in the trial, aged 22-79. Causes of hyposmia included: post-viral (7); posttraumatic (10); sinonasal (30) and idiopathic (10). Compared with placebo, there was significant improvement in the identification scores of participants with post-viral hyposmia, following sodium citrate treatment. No significant change in olfactory function occurred for either identification or threshold in any other aetiological subgroup. Conclusions: Intranasal sodium citrate may be of benefit to patients with post-viral hyposmia

On the convergence of stochastic dual dynamic programming and related methods

We discuss the almost-sure convergence of a broad class of sampling algorithms for multi-stage stochastic linear programs. We provide a convergence proof based on the finiteness of the set of distinct cutcoefficients. This differs from existing published proofs in that it does not require a restrictive assumption

MyoD phosphorylation on multiple C terminal sites regulates myogenic conversion activity

MyoD is a master regulator of myogenesis with a potent ability to redirect the cell fate of even terminally differentiated cells. Hence, enhancing the activity of MyoD is an important step to maximising its potential utility for $\textit{in vitro}$ disease modelling and cell replacement therapies. We have previously shown that the reprogramming activity of several neurogenic bHLH proteins can be substantially enhanced by inhibiting their multi-site phosphorylation by proline-directed kinases. Here we have used Xenopus embryos as an $\textit{in vivo}$ developmental and reprogramming system to investigate the multi-site phospho-regulation of MyoD during muscle differentiation. We show that, in addition to modification of a previously well-characterised site, Serine 200, MyoD is phosphorylated on multiple additional serine/threonine sites during primary myogenesis. Through mutational analysis, we derive an optimally active phospho-mutant form of MyoD that has a dramatically enhanced ability to drive myogenic reprogramming $\textit{in vivo}$. Mechanistically, this is achieved through increased protein stability and enhanced chromatin association. Therefore, multi-site phospho-regulation of class II bHLH proteins is conserved across cell lineages and germ layers, and manipulation of phosphorylation of these key regulators may have further potential for enhancing mammalian cell reprogramming.This work was supported by UK Medical Research Council (MRC) Research Grants MR/L021129/1 and MR/K01329/1, and core support from Wellcome Trust and MRC Cambridge Stem Cell Institute. LH was supported by an MRC Doctoral Training Award