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

A Strong Szego Theorem for Jacobi Matrices

We use a classical result of Gollinski and Ibragimov to prove an analog of the strong Szego theorem for Jacobi matrices on $l^2(\N)$. In particular, we consider the class of Jacobi matrices with conditionally summable parameter sequences and find necessary and sufficient conditions on the spectral measure such that $\sum_{k=n}^\infty b_k$ and $\sum_{k=n}^\infty (a_k^2 - 1)$ lie in $l^2_1$, the linearly-weighted $l^2$ space.Comment: 26 page

Translational use of homing peptides: Tumor and placental targeting

HypothesisTissue-specific homing peptides have been shown to improve chemotherapeutic efficacy due to their trophism for tumor cells. Other sequences that selectively home to the placenta are providing new and safer therapeutics to treat complications in pregnancy. Our hypothesis is that the placental homing peptide RSGVAKS (RSG) may have binding affinity to cancer cells, and that insight can be gained into the binding mechanisms of RSG and the tumor homing peptide CGKRK to model membranes that mimic the primary lipid compositions of the respective cells.ExperimentsFollowing cell culture studies on the binding efficacy of the peptides on a breast cancer cell line, a systematic translational characterization is delivered using ellipsometry, Brewster angle microscopy and neutron reflectometry of the extents, structures, and dynamics of the interactions of the peptides with the model membranes on a Langmuir trough.FindingsWe start by revealing that RSG does indeed have binding affinity to breast cancer cells. The peptide is then shown to exhibit stronger interactions and greater penetration than CGKRK into both model membranes, combined with greater disruption to the lipid component. RSG also forms aggregates bound to the model membranes, yet both peptides bind to a greater extent to the placental than cancer model membranes. The results demonstrate the potential for varying local reservoirs of peptide within cell membranes that may influence receptor binding. The innovative nature of our findings motivates the urgent need for more studies involving multifaceted experimental platforms to explore the use of specific peptide sequences to home to different cellular targets

Learning curve analysis of thoracic endovascular aortic repair in relation to credentialing guidelines

ObjectiveRecently, practice guideline documents have recommended the completion of different levels of interventional experience and 5 or 10 thoracic endovascular aortic cases prior to surgeon credentialing. This study’s purpose was to determine whether these requirements are valid by reviewing three surgeons’ learning curves with thoracic aortic endovascular repairs.MethodsBetween 1998 and 2006, 67 patients underwent emergent or elective endovascular repair of thoracic aortic pathologies by one of three vascular surgeons with extensive experience with catheter manipulation and abdominal aortic endografts. Following standard retrospective review, each surgeon’s learning curve was analyzed using the cumulative sum failure method with a target success rate of 95% derived from the literature. The main outcome variable was primary technical success.ResultsThese 67 patients presented with several pathologies including elective (n = 31) and ruptured (n = 11) thoracic aortic aneurysms, acute dissections or aortic ulcers (n = 10), and acute blunt thoracic aortic trauma (n = 15). The mean age was 65 (range: 20 to 90) and the early (30 day) mortality rate was 19.4% in urgent cases (n = 36) and 0% in elective cases (n = 31). Paraplegia occurred in two patients (3%). Primary technical success was achieved in 62 cases (92.5%) and did not differ between surgeons (92.6%, 91.3%, 94.1%, respectively; P = .9). Each surgeon’s cases were plotted sequentially and the resulting learning curves were similar. Although acceptable outcomes were obtained throughout the study period, improved results, compared with the target success rate, were not achieved until each surgeon treated 5 to 10 patients.ConclusionThis study supports the case volume requirements of the Society for Vascular Surgery credentialing guidelines, which also requires extensive catheter and guidewire experience. With this background in catheter manipulation and endovascular abdominal aortic repair, surgeons can achieve optimal outcomes with thoracic aortic lesions following 5 to 10 cases

Mechanisms of Müller glial cell morphogenesis

Müller Glia (MG), the radial glia cells of the retina, have spectacular morphologies subserving their enormous functional complexity. As early as 1892, the great neuroanatomist Santiago Ramon y Cajal studied the morphological development of MG, defining several steps in their morphogenesis [1, 2]. However, the molecular cues controlling these developmental steps remain poorly understood. As MG have roles to play in every cellular and plexiform layer, this review discusses our current understanding on how MG morphology may be linked to their function, including the developmental mechanisms involved in MG patterning and morphogenesis. Uncovering the mechanisms governing glial morphogenesis, using transcriptomics and imaging, may provide shed new light on the pathophysiology and treatment of human neurological disorders

Causes and consequences of spatial variation in sex ratios in a declining bird species

1. Male-biased sex ratios occur in many bird species, particularly in those with small or declining populations, but the causes of these skews and their consequences for local population demography are rarely known. Within-species variation in sex ratios can help to identify the demographic and behavioural processes associated with such biases. 2. Small populations may be more likely to have skewed sex ratios if sex differences in survival, recruitment or dispersal vary with local abundance. Analyses of species with highly variable local abundances can help to identify these mechanisms and the implications for spatial variation in demography. Many migratory bird species are currently undergoing rapid and severe declines in abundance in parts of their breeding ranges, and thus have sufficient spatial variation in abundance to explore the extent of sex ratio biases, their causes and implications. 3. Using national-scale bird ringing data for one such species (willow warbler, Phylloscopus trochilus), we show that sex ratios vary greatly across Britain, and that male-biased sites are more frequent in areas of low abundance, which are now widespread across much of south and east England. These sex ratio biases are sufficient to impact local productivity, as the relative number of juveniles caught at survey sites declines significantly with increasing sex ratio skew. 4. Sex differences in survival could influence this sex ratio variation, but we find little evidence for sex differences in survival increasing with sex ratio skew. In addition, sex ratios have become male-biased over the last two decades but there are no such trends in adult survival rates for males or females. This suggests that lower female recruitment into low abundance sites is contributing to these skews. 5. These findings suggest that male-biased sex ratios in small and declining populations can arise through local-scale sex-differences in survival and dispersal, with females recruiting disproportionately into larger populations. Given the high level of spatial variation in population declines and abundance of many migratory bird species across Europe at present, male-biased small populations may be increasingly common. As singing males are the primary records used in surveys of these species, and as unpaired males often sing throughout the breeding season, local sex ratio biases could also be masking the true extent of these population declines

Non-Equilibrium Statistical Physics of Currents in Queuing Networks

We consider a stable open queuing network as a steady non-equilibrium system of interacting particles. The network is completely specified by its underlying graphical structure, type of interaction at each node, and the Markovian transition rates between nodes. For such systems, we ask the question ``What is the most likely way for large currents to accumulate over time in a network ?'', where time is large compared to the system correlation time scale. We identify two interesting regimes. In the first regime, in which the accumulation of currents over time exceeds the expected value by a small to moderate amount (moderate large deviation), we find that the large-deviation distribution of currents is universal (independent of the interaction details), and there is no long-time and averaged over time accumulation of particles (condensation) at any nodes. In the second regime, in which the accumulation of currents over time exceeds the expected value by a large amount (severe large deviation), we find that the large-deviation current distribution is sensitive to interaction details, and there is a long-time accumulation of particles (condensation) at some nodes. The transition between the two regimes can be described as a dynamical second order phase transition. We illustrate these ideas using the simple, yet non-trivial, example of a single node with feedback.Comment: 26 pages, 5 figure

Real-time analysis of δ13C- and δD-CH4 in ambient air with laser spectroscopy:method development and first intercomparison results

In situ and simultaneous measurement of the three most abundant isotopologues of methane using mid-infrared laser absorption spectroscopy is demonstrated. A field-deployable, autonomous platform is realized by coupling a compact quantum cascade laser absorption spectrometer (QCLAS) to a preconcentration unit, called trace gas extractor (TREX). This unit enhances CH4 mole fractions by a factor of up to 500 above ambient levels and quantitatively separates interfering trace gases such as N2O and CO2. The analytical precision of the QCLAS isotope measurement on the preconcentrated (750 ppm, parts-per-million, µmole mole−1) methane is 0.1 and 0.5 ‰ for δ13C- and δD-CH4 at 10 min averaging time. Based on repeated measurements of compressed air during a 2-week intercomparison campaign, the repeatability of the TREX–QCLAS was determined to be 0.19 and 1.9 ‰ for δ13C and δD-CH4, respectively. In this intercomparison campaign the new in situ technique is compared to isotope-ratio mass spectrometry (IRMS) based on glass flask and bag sampling and real time CH4 isotope analysis by two commercially available laser spectrometers. Both laser-based analyzers were limited to methane mole fraction and δ13C-CH4 analysis, and only one of them, a cavity ring down spectrometer, was capable to deliver meaningful data for the isotopic composition. After correcting for scale offsets, the average difference between TREX–QCLAS data and bag/flask sampling–IRMS values are within the extended WMO compatibility goals of 0.2 and 5 ‰ for δ13C- and δD-CH4, respectively. This also displays the potential to improve the interlaboratory compatibility based on the analysis of a reference air sample with accurately determined isotopic composition

Absolute values of the London penetration depth in YBa2Cu3O6+y measured by zero field ESR spectroscopy on Gd doped single crystals

Zero-field electron spin resonance (ESR) of dilute Gd ions substituted for Y in the cuprate superconductor YBa$_2$Cu$_3$O$_{\rm 6+y}$ is used as a novel technique for measuring the absolute value of the low temperature magnetic penetration depth $\lambda(T\to 0)$. The Gd ESR spectrum of samples with $\approx 1$ substitution was obtained with a broadband microwave technique that measures power absorption bolometrically from 0.5 GHz to 21 GHz. This ESR spectrum is determined by the crystal field that lifts the level degeneracy of the spin 7/2 Gd$^{3+}$ ion and details of this spectrum provide information concerning oxygen ordering in the samples. The magnetic penetration depth is obtained by relating the number of Gd ions exposed to the microwave magnetic field to the frequency-integrated intensity of the observed ESR transitions. This technique has allowed us to determine precise values of $\lambda$ for screening currents flowing in the three crystallographic orientations ($\hat a$, $\hat b$ and $\hat c$) in samples of Gd$_{\rm x}$Y$_{\rm 1-x}$Ba$_2$Cu$_3$O$_{6+{\rm y}}$ of three different oxygen contents ${\rm y}=0.993$ ($T_c = 89$ K), ${\rm y}=0.77$ ($T_c=75$ K) and ${\rm y}=0.52$ ($T_c=56$ K). The in-plane values are found to depart substantially from the widely reported relation $T_c\propto 1/\lambda^2$.Comment: 14 pages, 12 figures; version to appear in PR