The Dynamics of Signaling as a Pharmacological Target

SummaryHighly networked signaling hubs are often associated with disease, but targeting them pharmacologically has largely been unsuccessful in the clinic because of their functional pleiotropy. Motivated by the hypothesis that a dynamic signaling code confers functional specificity, we investigated whether dynamic features may be targeted pharmacologically to achieve therapeutic specificity. With a virtual screen, we identified combinations of signaling hub topologies and dynamic signal profiles that are amenable to selective inhibition. Mathematical analysis revealed principles that may guide stimulus-specific inhibition of signaling hubs, even in the absence of detailed mathematical models. Using the NFκB signaling module as a test bed, we identified perturbations that selectively affect the response to cytokines or pathogen components. Together, our results demonstrate that the dynamics of signaling may serve as a pharmacological target, and we reveal principles that delineate the opportunities and constraints of developing stimulus-specific therapeutic agents aimed at pleiotropic signaling hubs

Population expansion in the North African Late Pleistocene signalled by mitochondrial DNA haplogroup U6

Background <br/> The archaeology of North Africa remains enigmatic, with questions of population continuity versus discontinuity taking centre-stage. Debates have focused on population transitions between the bearers of the Middle Palaeolithic Aterian industry and the later Upper Palaeolithic populations of the Maghreb, as well as between the late Pleistocene and Holocene. <br/> Results Improved resolution of the mitochondrial DNA (mtDNA) haplogroup U6 phylogeny, by the screening of 39 new complete sequences, has enabled us to infer a signal of moderate population expansion using Bayesian coalescent methods. To ascertain the time for this expansion, we applied both a mutation rate accounting for purifying selection and one with an internal calibration based on four approximate archaeological dates: the settlement of the Canary Islands, the settlement of Sardinia and its internal population re-expansion, and the split between haplogroups U5 and U6 around the time of the first modern human settlement of the Near East. <br/> Conclusions <br/> A Bayesian skyline plot placed the main expansion in the time frame of the Late Pleistocene, around 20 ka, and spatial smoothing techniques suggested that the most probable geographic region for this demographic event was to the west of North Africa. A comparison with U6's European sister clade, U5, revealed a stronger population expansion at around this time in Europe. Also in contrast with U5, a weak signal of a recent population expansion in the last 5,000 years was observed in North Africa, pointing to a moderate impact of the late Neolithic on the local population size of the southern Mediterranean coast

Migrant Hispanic Families of Young Children: An Analysis of Parent Needs and Family Support

The population served by early interventionists has changed to include more migrant families. Although there has been much research concerning Caucasian families, less is known about culturally and linguistically diverse families. Forming partnerships with families can be aided by understanding how to identify families\u27 needs and support networks. The purpose of this study was to assess the group differences between Hispanic migrant families of young children with and without disabilities (ages birth - 5) regarding their perceptions of needs and use of support systems. The findings indicate that there is little difference between migrant families of young children with and without disabilities. Implications of the findings and suggestions for further research are discussed

A Study of the Coronal Plasma in RS CVn binary systems

XMM-Newton has been performing comprehensive studies of X-ray bright RS CVn binaries in its Calibration and Guaranteed Time programs. We present results from ongoing investigations in the context of a systematic study of coronal emission from RS CVns. We concentrate in this paper on coronal abundances and investigate the abundance pattern in RS CVn binaries as a function of activity and average temperature. A transition from an Inverse First Ionization Potential (FIP) effect towards an absence of a clear trend is found in intermediately active RS CVn systems. This scheme corresponds well into the long-term evolution from an IFIP to a FIP effect found in solar analogs. We further study variations in the elemental abundances during a large flare.Comment: to appear in The Twelfth Cool Stars, Stellar Systems and the Sun, eds. A. Brown, T.R. Ayres, G.M. Harper, (Boulder: Univ. of Colorado), in pres

The X-ray spectrum of the Seyfert I galaxy Markarian 766: Dusty warm absorber or relativistic emission lines?

Competing models for broad spectral features in the soft X-ray spectrum of the Seyfert I galaxy Mrk 766 are tested against data from a 130 ks XMM-Newton observation. A model including relativistically broadened Lyalpha emission lines of O VIII N VII and C VI is a better fit to 0.3-2 keV XMM RGS data than a dusty warm absorber. Moreover, the measured depth of neutral iron absorption lines in the spectrum is inconsistent with the magnitude of the iron edge required to produce the continuum break at 17-18 Angstrom in the dusty warm absorber model. The relativistic emission line model can reproduce the broadband (0.1-12 keV) XMM EPIC data with the addition of a fourth line to represent emission from ionized iron at 6.7 keV and an excess due to reflection at energies above the iron line. The pro le of the 6.7 keV iron line is consistent with that measured for the low-energy lines. There is evidence in the RGS data, at the 3sigma level, of spectral features that vary with source flux. The covering fraction of warm absorber gas is estimated to be 12%. Iron in the warm absorber is found to be overabundant with respect to CNO, compared to solar values

Gastrointestinal Motility in Health and Disease

Michael Zabinski (with Biancani, P., M. P. Zabinski, M. D. Kerstein, and J. Behar) is a contributing author, Comparison of mechanical characteristics of the lower oesophageal sphincter and pyloric sphincter, p.547-551. Book description: Proceedings of the 6th International Symposium on Gastrointestinal Motility, held at the Royal College of Surgeons of Edinburgh, 12–16th September, 1977.https://digitalcommons.fairfield.edu/engineering-books/1036/thumbnail.jp

West Asian sources of the Eurasian component in Ethiopians: a reassessment

The presence of genomic signatures of Eurasian origin in contemporary Ethiopians has been reported by several authors and estimated to have arrived in the area from 3000 years ago. Several studies reported plausible source populations for such a signature, using haplotype based methods on modern data or single-site methods on modern or ancient data. These studies did not reach a consensus and suggested an Anatolian or Sardinia-like proxy, broadly Levantine or Neolithic Levantine as possible sources. We demonstrate, however, that the deeply divergent, autochthonous African component which accounts for ~50% of most contemporary Ethiopian genomes, affects the overall allele frequency spectrum to an extent that makes it hard to control for it and, at once, to discern between subtly different, yet important, Eurasian sources (such as Anatolian or Levant Neolithic ones). Here we re-assess pattern of allele sharing between the Eurasian component of Ethiopians (here called “NAF” for Non African) and ancient and modern proxies. Our results unveil a genomic legacy that may connect the Eurasian genetic component of contemporary Ethiopians with Sea People and with population movements that affected the Mediterranean area and the Levant after the fall of the Minoan civilization

Transscleral Optical Phase Imaging of the Human Retina.

In-vivo observation of the human retina at the cellular level is crucial to detect the first signs of retinal diseases and properly treat them. Despite the phenomenal advances in adaptive optics (AO) systems, clinical imaging of many retinal cells is still elusive due to the low signal-to-noise ratio induced by transpupillary illumination. We present a transscleral optical phase imaging (TOPI) method, which relies on high-angle oblique illumination of the retina, combined with AO, to enhance cell contrast. Examination of eleven healthy volunteer eyes, without pupil dilation, shows the ability of this method to produce in-vivo images of retinal cells, from the retinal pigment epithelium to the nerve fibre layer. This method also allows the generation of high-resolution label-free ex-vivo phase images of flat-mounted retinas. The 4.4°x 4.4° field-of-view in-vivo images are recorded in less than 10 seconds, opening new avenues in the exploration of healthy and diseased retinas

Energy-angle dispersion of accelerated heavy ions at 67P/Churyumov–Gerasimenko: implication in the mass-loading mechanism

The Rosetta spacecraft studied the comet 67P/Churyumov–Gerasimenko for nearly two years. The Ion Composition Analyzer instrument on board Rosetta observed the positive ion distributions in the environment of the comet during the mission. A portion of the comet's neutral coma is expected to get ionized, depending on the comet's activity and position relative to the Sun, and the newly created ions are picked up and accelerated by the solar wind electric field, while the solar wind flow is deflected in the opposite direction. This interaction, known as the mass-loading mechanism, was previously studied by comparing the bulk flow direction of both the solar wind protons and the accelerated cometary ions with respect to the direction of the magnetic and the convective solar wind electric field. In this study, we show that energy–angle dispersion is occasionally observed. We report two types of dispersion: one where the observed motion is consistent with ions gyrating in the local magnetic field and another where the energy–angle dispersion is opposite to that expected from gyration in the local magnetic field. Given that the cometary ion gyro-radius in the undisturbed solar wind magnetic and electric field is expected to be too large to be detected in this way, our observations indicate that the local electric field might be significantly smaller than that of the undisturbed solar wind. We also discuss how the energy–angle dispersion, which is not consistent with gyration, may occur due to spatially inhomogeneous densities and electric fields