50 research outputs found
Impact of Single Links in Competitive Percolation -- How complex networks grow under competition
How a complex network is connected crucially impacts its dynamics and
function. Percolation, the transition to extensive connectedness upon gradual
addition of links, was long believed to be continuous but recent numerical
evidence on "explosive percolation" suggests that it might as well be
discontinuous if links compete for addition. Here we analyze the microscopic
mechanisms underlying discontinuous percolation processes and reveal a strong
impact of single link additions. We show that in generic competitive
percolation processes, including those displaying explosive percolation, single
links do not induce a discontinuous gap in the largest cluster size in the
thermodynamic limit. Nevertheless, our results highlight that for large finite
systems single links may still induce observable gaps because gap sizes scale
weakly algebraically with system size. Several essentially macroscopic clusters
coexist immediately before the transition, thus announcing discontinuous
percolation. These results explain how single links may drastically change
macroscopic connectivity in networks where links add competitively.Comment: non-final version, for final see Nature Physics homepag
Design and Characterization of a Human Monoclonal Antibody that Modulates Mutant Connexin 26 Hemichannels Implicated in Deafness and Skin Disorders
Background: Mutations leading to changes in properties, regulation, or expression of connexin-made channels have been implicated in 28 distinct human hereditary diseases. Eight of these result from variants of connexin 26 (Cx26), a protein critically involved in cell-cell signaling in the inner ear and skin. Lack of non-toxic drugs with defined mechanisms of action poses a serious obstacle to therapeutic interventions for diseases caused by mutant connexins. In particular, molecules that specifically modulate connexin hemichannel function without affecting gap junction channels are considered of primary importance for the study of connexin hemichannel role in physiological as well as pathological conditions. Monoclonal antibodies developed in the last three decades have become the most important class of therapeutic biologicals. Recombinant methods permit rapid selection and improvement of monoclonal antibodies from libraries with large diversity.Methods: By screening a combinatorial library of human single-chain fragment variable (scFv) antibodies expressed in phage, we identified a candidate that binds an extracellular epitope of Cx26. We characterized antibody action using a variety of biochemical and biophysical assays in HeLa cells, organotypic cultures of mouse cochlea and human keratinocyte-derived cells.Results: We determined that the antibody is a remarkably efficient, non-toxic, and completely reversible inhibitor of hemichannels formed by connexin 26 and does not affect direct cell-cell communication via gap junction channels. Importantly, we also demonstrate that the antibody efficiently inhibits hyperative mutant Cx26 hemichannels implicated in autosomal dominant non-syndromic hearing impairment accompanied by keratitis and hystrix-like ichthyosis-deafness (KID/HID) syndrome. We solved the crystal structure of the antibody, identified residues that are critical for binding and used molecular dynamics to uncover its mechanism of action.Conclusions: Although further studies will be necessary to validate the effect of the antibody in vivo, the methodology described here can be extended to select antibodies against hemichannels composed by other connexin isoforms and, consequently, to target other pathologies associated with hyperactive hemichannels. Our study highlights the potential of this approach and identifies connexins as therapeutic targets addressable by screening phage display libraries expressing human randomized antibodies
Physiological characteristics of dysphagia following thermal burn injury
The study aim was to document the acute physiological characteristics of swallowing impairment following thermal burn injury. A series of 19 participants admitted to a specialised burn centre with thermal burn injury were identified with suspected aspiration risk by a clinical swallow examination (CSE) conducted by a speech-language pathologist and referred to the study. Once medically stable, each then underwent more detailed assessment using both a CSE and fiberoptic evaluation of swallowing (FEES). FEES confirmed six individuals (32%) had no aspiration risk and were excluded from further analyses. Of the remaining 13, CSE confirmed that two had specific oral-phase deficits due to orofacial scarring and contractures, and all 13 had generalised oromotor weakness. FEES revealed numerous pharyngeal-phase deficits, with the major findings evident in greater than 50% being impaired secretion management, laryngotracheal edema, delayed swallow initiation, impaired sensation, inadequate movement of structures within the hypopharynx and larynx, and diffuse pharyngeal residue. Penetration and/or aspiration occurred in 83% (n = 10/12) of thin fluids trials, with a lack of response to the penetration/aspiration noted in 50% (n = 6/12 penetration aspiration events) of the cases. Most events occurred post swallow. Findings support the fact that individuals with dysphagia post thermal burn present with multiple risk factors for aspiration that appear predominantly related to generalised weakness and inefficiency and further impacted by edema and sensory impairments. Generalised oromotor weakness and orofacial contractures (when present) impact oral-stage swallow function. This study has identified a range of factors that may contribute to both oral- and pharyngeal-stage dysfunction in this clinical population and has highlighted the importance of using a combination of clinical and instrumental assessments to fully understand the influence of burn injury on oral intake and swallowing
Sloan Digital Sky Survey IV: Mapping the Milky Way, Nearby Galaxies, and the Distant Universe
We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median ). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July
Sloan Digital Sky Survey IV: mapping the Milky Way, nearby galaxies, and the distant universe
We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median ). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July
Sloan Digital Sky Survey IV : mapping the Milky Way, nearby galaxies, and the distant universe
We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median z ~ 0.03). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between z ~ 0.6 and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July
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Sloan Digital Sky Survey IV: Mapping the Milky Way, Nearby Galaxies, and the Distant Universe
We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing
three major spectroscopic programs. The Apache Point Observatory Galactic
Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky
Way stars at high resolution and high signal-to-noise ratio in the
near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA)
survey is obtaining spatially-resolved spectroscopy for thousands of nearby
galaxies (median redshift of z = 0.03). The extended Baryon Oscillation
Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas
distributions between redshifts z = 0.6 and 3.5 to constrain cosmology using
baryon acoustic oscillations, redshift space distortions, and the shape of the
power spectrum. Within eBOSS, we are conducting two major subprograms: the
SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray
AGN and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey
(TDSS), obtaining spectra of variable sources. All programs use the 2.5-meter
Sloan Foundation Telescope at Apache Point Observatory; observations there
began in Summer 2014. APOGEE-2 also operates a second near-infrared
spectrograph at the 2.5-meter du Pont Telescope at Las Campanas Observatory,
with observations beginning in early 2017. Observations at both facilities are
scheduled to continue through 2020. In keeping with previous SDSS policy,
SDSS-IV provides regularly scheduled public data releases; the first one, Data
Release 13, was made available in July 2016
Sloan Digital Sky Survey IV: mapping the Milky Way, nearby galaxies, and the distant universe
We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median ). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July
Disruption of G-Protein Îł<sub>5</sub> Subtype Causes Embryonic Lethality in Mice
<div><p>Heterotrimeric G-proteins modulate many processes essential for embryonic development including cellular proliferation, migration, differentiation, and survival. Although most research has focused on identifying the roles of the various αsubtypes, there is growing recognition that similarly divergent ÎČÎł dimers also regulate these processes. In this paper, we show that targeted disruption of the mouse <i>Gng5</i> gene encoding the Îł<sub>5</sub> subtype produces embryonic lethality associated with severe head and heart defects. Collectively, these results add to a growing body of data that identify critical roles for the Îł subunits in directing the assembly of functionally distinct G-αÎČÎł trimers that are responsible for regulating diverse biological processes. Specifically, the finding that loss of the G-Îł<sub>5</sub> subtype is associated with a reduced number of cardiac precursor cells not only provides a causal basis for the mouse phenotype but also raises the possibility that G-ÎČÎł<sub>5</sub> dependent signaling contributes to the pathogenesis of human congenital heart problems.</p></div
Successful targeting of the <i>Gng5</i> locus.
<p><b>A.</b> Region of mouse chromosome 3â¶146,110,000â147,170,000 containing the <i>Gng5</i> locus from the UCSC genome browser. <b>B.</b> The top bar of this schematic illustrates the arrangement of exons of <i>Gng5</i> (orange boxes), <i>Ctbs</i> (blue boxes), and <i>Spata1</i> (yellow boxes). The bars underneath illustrate the <i>Gng5</i> mRNA transcript, the two <i>Ctbs</i> splice variants, the two <i>Ctbs-Gng5</i> splice variants, and the three <i>Spata1</i> splice variants (not drawn to scale). Letters indicate RT-PCR primers which can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090970#pone.0090970.s003" target="_blank">Table S1</a>. <b>C.</b> RT-PCR of the <i>Ctbs-Gng5</i> fusion transcript (primers <b>f</b> and <b>g</b>) from the same embryos shown in Fig. 1E, confirming that expression of this fusion transcript is preserved in knockout embryos. Identification of the amplified products marked <i>Ctbs-Gng5</i> was confirmed by DNA sequence analysis (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090970#pone.0090970.s001" target="_blank">Figure S1</a>). The first lane on both gels is a molecular weight marker, ÏX digested with HaeIII. <b>D.</b> RT-PCR of <i>Spata1</i> from the same embryos (primers <b>f</b> and <b>h</b>), demonstrating that expression of <i>Spata1</i> is preserved in knockout embryos.</p