Pilot Clinical Trial of Indocyanine Green Fluorescence-Augmented Colonoscopy in High Risk Patients

White light colonoscopy is the current gold standard for early detection and treatment of colorectal cancer, but emerging data suggest that this approach is inherently limited. Even the most experienced colonoscopists, under optimal conditions, miss at least 15–25% of adenomas. There is an unmet clinical need for an adjunctive modality to white light colonoscopy with improved lesion detection and characterization. Optical molecular imaging with exogenously administered organic fluorochromes is a burgeoning imaging modality poised to advance the capabilities of colonoscopy. In this proof-of-principle clinical trial, we investigated the ability of a custom-designed fluorescent colonoscope and indocyanine green, a clinically approved fluorescent blood pool imaging agent, to visualize polyps in high risk patients with polyposis syndromes or known distal colonic masses. We demonstrate (1) the successful performance of real-time, wide-field fluorescence endoscopy using off-the-shelf equipment, (2) the ability of this system to identify polyps as small as 1 mm, and (3) the potential for fluorescence imaging signal intensity to differentiate between neoplastic and benign polyps

Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel.

α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 Å resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs

A Turnover in the Galaxy Main Sequence of Star Formation at M∗∼1010M⊙M_{*} \sim 10^{10} M_{\odot} for Redshifts z<1.3z < 1.3

The relationship between galaxy star formation rates (SFR) and stellar masses ($M_\ast$) is re-examined using a mass-selected sample of $\sim$62,000 star-forming galaxies at $z \le 1.3$ in the COSMOS 2-deg$^2$ field. Using new far-infrared photometry from $Herschel$-PACS and SPIRE and $Spitzer$-MIPS 24 $\mu$m, along with derived infrared luminosities from the NRK method based on galaxies' locations in the restframe color-color diagram $(NUV - r)$ vs. $(r - K)$, we are able to more accurately determine total SFRs for our complete sample. At all redshifts, the relationship between median $SFR$ and $M_\ast$ follows a power-law at low stellar masses, and flattens to nearly constant SFR at high stellar masses. We describe a new parameterization that provides the best fit to the main sequence and characterizes the low mass power-law slope, turnover mass, and overall scaling. The turnover in the main sequence occurs at a characteristic mass of about $M_{0} \sim 10^{10} M_{\odot}$ at all redshifts. The low mass power-law slope ranges from 0.9-1.3 and the overall scaling rises in SFR as a function of $(1+z)^{4.12 \pm 0.10}$. A broken power-law fit below and above the turnover mass gives relationships of $SFR \propto M_{*}^{0.88 \pm 0.06}$ below the turnover mass and $SFR \propto M_{*}^{0.27 \pm 0.04}$ above the turnover mass. Galaxies more massive than $M_\ast \gtrsim 10^{10}\ M_{\rm \odot}$ have on average, a much lower specific star formation rate (sSFR) than would be expected by simply extrapolating the traditional linear fit to the main sequence found for less massive galaxies.Comment: 16 pages, 7 figures. Accepted for publication in Ap

Galaxy Zoo: The Environmental Dependence of Bars and Bulges in Disc Galaxies

We present an analysis of the environmental dependence of bars and bulges in disc galaxies, using a volume-limited catalogue of 15810 galaxies at z<0.06 from the Sloan Digital Sky Survey with visual morphologies from the Galaxy Zoo 2 project. We find that the likelihood of having a bar, or bulge, in disc galaxies increases when the galaxies have redder (optical) colours and larger stellar masses, and observe a transition in the bar and bulge likelihoods, such that massive disc galaxies are more likely to host bars and bulges. We use galaxy clustering methods to demonstrate statistically significant environmental correlations of barred, and bulge-dominated, galaxies, from projected separations of 150 kpc/h to 3 Mpc/h. These environmental correlations appear to be independent of each other: i.e., bulge-dominated disc galaxies exhibit a significant bar-environment correlation, and barred disc galaxies show a bulge-environment correlation. We demonstrate that approximately half (50 +/- 10%) of the bar-environment correlation can be explained by the fact that more massive dark matter haloes host redder disc galaxies, which are then more likely to have bars. Likewise, we show that the environmental dependence of stellar mass can only explain a small fraction (25 +/- 10%) of the bar-environment correlation. Therefore, a significant fraction of our observed environmental dependence of barred galaxies is not due to colour or stellar mass dependences, and hence could be due to another galaxy property. Finally, by analyzing the projected clustering of barred and unbarred disc galaxies with halo occupation models, we argue that barred galaxies are in slightly higher-mass haloes than unbarred ones, and some of them (approximately 25%) are satellite galaxies in groups. We also discuss implications about the effects of minor mergers and interactions on bar formation.Comment: 20 pages, 18 figures; references updated; published in MNRA

Galaxy Zoo: CANDELS barred discs and bar fractions

The formation of bars in disc galaxies is a tracer of the dynamical maturity of the population. Previous studies have found that the incidence of bars in discs decreases from the local Universe to z ~ 1, and by z > 1 simulations predict that bar features in dynamically mature discs should be extremely rare. Here, we report the discovery of strong barred structures in massive disc galaxies at z ~ 1.5 in deep rest-frame optical images from the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey. From within a sample of 876 disc galaxies identified by visual classification in Galaxy Zoo, we identify 123 barred galaxies. Selecting a subsample within the same region of the evolving galaxy luminosity function (brighter than L*), we find that the bar fraction across the redshift range 0.5 ≤ z ≤ 2 (fbar = 10.7+6.3 -3.5 per cent after correcting for incompleteness) does not significantly evolve.We discuss the implications of this discovery in the context of existing simulations and our current understanding of the way disc galaxies have evolved over the last 11 billion yearsPeer reviewedFinal Accepted Versio

The 2dF-SDSS LRG and QSO survey: evolution of the clustering of luminous red galaxies since z = 0.6

We present an analysis of the small-to-intermediate scale clustering of samples of Luminous Red Galaxies (LRGs) from the Sloan Digital Sky Survey and the 2dF-SDSS LRG and QSO (2SLAQ) survey carefully matched to have the same rest-frame colours and luminosity. We study the spatial two-point auto-correlation function in both redshift-space and real-space of a combined sample of over 10,000 LRGs, which represent the most massive galaxies in the universe with stellar masses > 10^11 h^-1 M_sun and space densities 10^-4 h^-3 Mpc^-3. We find no significant evolution in the amplitude r_0 of the correlation function with redshift, but do see a slight decrease in the slope with increasing redshift over 0.19 < z < 0.55 and scales of 0.32 < r < 32 h^-1 Mpc. We compare our measurements with the predicted evolution of dark matter clustering and use the halo model to interpret our results. We find that our clustering measurements are inconsistent (>99.9% significance) with a passive model whereby the LRGs do not merge with one another; a model with a merger rate of 7.5 +/- 2.3% from z = 0.55 to z = 0.19 (i.e. an average rate of 2.4% Gyr^-1) provides a better fit to our observations. Our clustering and number density measurements are consistent with the hypothesis that the merged LRGs were originally central galaxies in different haloes which, following the merger of these haloes, merged to create a single Brightest Cluster Galaxy. In addition, we show that the small-scale clustering signal constrains the scatter in halo merger histories. When combined with measurements of the luminosity function, our results suggest that this scatter is sub-Poisson. While this is a generic prediction of hierarchical models, it has not been tested before.Comment: 20 pages, replaced with version accepted for publication in MNRA

Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities

Cilostazol is a phosphodiesterase III inhibitor with a long track record of safety that is FDA and EMA approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with non-cardioembolic stroke. The onset of benefit appears after 60–90 days of treatment, which is consistent with cilostazol’s pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com). Due to limitations of prior trials, such as open label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have suffered a non-cardioembolic ischemic stroke

Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity.

Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit fusions and loss. Two of the enhancers are evolutionary ancient and highly conserved from basal fishes to mammals. Analysing these enhancers from different species reveal the substantial spatial plasticity in Grem1 regulation in tetrapods and basal fishes, which provides insights into the fin-to-limb transition and evolutionary diversification of pentadactyl limbs