Ixekizumab Efficacy and Safety with and without Concomitant Conventional Disease-modifying Antirheumatic Drugs (cDMARDs) in Biologic DMARD (bDMARD)-naive Patients with Active Psoriatic Arthritis (PsA): Results from SPIRIT-P1

Objective: To evaluate the efficacy and safety of ixekizumab alone or with concomitant conventional disease-modifying antirheumatic drugs (cDMARDs) versus placebo in patients with active psoriatic arthritis (PsA) as part of a SPIRIT-P1 subgroup analysis (NCT01695239). Methods: Patients were stratified by cDMARD use (concomitant cDMARDs use (including methotrexate) or none (past or naive use)) and randomly assigned to treatment groups (ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) or placebo). Efficacy was evaluated versus placebo at week 24 by the American College of Rheumatology criteria (ACR20/50/70), modified total Sharp score and Health Assessment Questionnaire-Disability Index (HAQ-DI). Safety was assessed according to cDMARD status. Results: Regardless of concomitant cDMARD usage, ACR20, ACR50 and ACR70 response rates were significantly higher versus placebo with IXEQ4W and IXEQ2W. The proportion of patients achieving HAQ-DI minimal clinically important difference was significantly higher versus placebo with IXEQ4W with concomitant cDMARD use and IXEQ2W, regardless of concomitant cDMARD use. Treatment-emergent adverse events (AE) were more frequent versus placebo for either ixekizumab-dosing regimen, regardless of concomitant cDMARD use. Serious AEs were not higher versus placebo, regardless of concomitant cDMARD use. Conclusion: Ixekizumab treatment improved measures of disease activity and physical function in patients with active PsA relative to placebo, when used with or without concomitant cDMARD therapy

Integral Field Spectroscopy of High-Redshift Star Forming Galaxies with Laser Guided Adaptive Optics: Evidence for Dispersion-Dominated Kinematics

We present early results from an ongoing study of the kinematic structure of star-forming galaxies at redshift z ~ 2 - 3 using integral-field spectroscopy of rest-frame optical nebular emission lines in combination with Keck laser guide star adaptive optics (LGSAO). We show kinematic maps of 3 target galaxies Q1623-BX453, Q0449-BX93, and DSF2237a-C2 located at redshifts z = 2.1820, 2.0067, and 3.3172 respectively, each of which is well-resolved with a PSF measuring approximately 0.11 - 0.15 arcsec (~ 900 - 1200 pc at z ~ 2-3) after cosmetic smoothing. Neither galaxy at z ~ 2 exhibits substantial kinematic structure on scales >~ 30 km/s; both are instead consistent with largely dispersion-dominated velocity fields with sigma ~ 80 km/s along any given line of sight into the galaxy. In contrast, DSF2237a-C2 presents a well-resolved gradient in velocity over a distance of ~ 4 kpc with peak-to-peak amplitude of 140 km/s. It is unlikely that DSF2237a-C2 represents a dynamically cold rotating disk of ionized gas as the local velocity dispersion of the galaxy (sigma = 79 km/s) is comparable to the observed shear. Using extant multi-wavelength spectroscopy and photometry we relate these kinematic data to physical properties such as stellar mass, gas fraction, star formation rate, and outflow kinematics and consider the applicability of current galaxy formation models.[Abridged]Comment: 19 pages, 10 figures (5 color); accepted for publication in ApJ. Version with full-resolution figures is available at http://www.astro.caltech.edu/~drlaw/Papers/OSIRIS_data1.pd

Design, engineering and utility of biotic games

Games are a significant and defining part of human culture, and their utility beyond pure entertainment has been demonstrated with so-called ‘serious games’. Biotechnology – despite its recent advancements – has had no impact on gaming yet. Here we propose the concept of ‘biotic games’, i.e., games that operate on biological processes. Utilizing a variety of biological processes we designed and tested a collection of games: ‘Enlightenment’, ‘Ciliaball’, ‘PAC-mecium’, ‘Microbash’, ‘Biotic Pinball’, ‘POND PONG’, ‘PolymerRace’, and ‘The Prisoner's Smellemma’. We found that biotic games exhibit unique features compared to existing game modalities, such as utilizing biological noise, providing a real-life experience rather than virtual reality, and integrating the chemical senses into play. Analogous to video games, biotic games could have significant conceptual and cost-reducing effects on biotechnology and eventually healthcare; enable volunteers to participate in crowd-sourcing to support medical research; and educate society at large to support personal medical decisions and the public discourse on bio-related issues

Manipulating the ABCs of self-assembly via low-χ block polymer design

Block polymer self-assembly typically translates molecular chain connectivity into mesoscale structure by exploiting incompatible blocks with large interaction parameters (χ_ij). In this article, we demonstrate that the converse approach, encoding low-χ interactions in ABC bottlebrush triblock terpolymers (χ_(AC) ≲ 0), promotes organization into a unique mixed-domain lamellar morphology, which we designate LAM_P. Transmission electron microscopy indicates that LAM_P exhibits ACBC domain connectivity, in contrast to conventional three-domain lamellae (LAM_3) with ABCB periods. Complementary small-angle X-ray scattering experiments reveal a strongly decreasing domain spacing with increasing total molar mass. Self-consistent field theory reinforces these observations and predicts that LAM_P is thermodynamically stable below a critical χ_(AC), above which LAM_3 emerges. Both experiments and theory expose close analogies to ABA′ triblock copolymer phase behavior, collectively suggesting that low-χ interactions between chemically similar or distinct blocks intimately influence self-assembly. These conclusions provide fresh opportunities for block polymer design with potential consequences spanning all self-assembling soft materials

Effects of resveratrol supplementation on methotrexate chemotherapy‐induced bone loss

Intensive cancer chemotherapy is known to cause bone defects, which currently lack treatments. This study investigated the effects of polyphenol resveratrol (RES) in preventing bone defects in rats caused by methotrexate (MTX), a commonly used antimetabolite in childhood oncology. Young rats received five daily MTX injections at 0.75 mg/kg/day. RES was orally gavaged daily for seven days prior to, and during, five‐day MTX administration. MTX reduced growth plate thickness, primary spongiosa height, trabecular bone volume, increased marrow adipocyte density, and increased mRNA expression of the osteogenic, adipogenic, and osteoclastogenic factors in the tibial bone. RES at 10 mg/kg was found not to affect bone health in normal rats, but to aggravate the bone damage in MTX‐treated rats. However, RES supplementation at 1 mg/kg preserved the growth plate, primary spongiosa, bone volume, and lowered the adipocyte density. It maintained expression of genes involved in osteogenesis and decreased expression of adipogenic and osteoclastogenic factors. RES suppressed osteoclast formation ex vivo of bone marrow cells from the treated rats. These data suggest that MTX can enhance osteoclast and adipocyte formation and cause bone loss, and that RES supplementation at 1 mg/kg may potentially prevent these bone defects

The SINS Survey: Broad Emission Lines in High-Redshift Star-Forming Galaxies

High signal-to-noise, representative spectra of star-forming galaxies at z~2, obtained via stacking, reveal a high-velocity component underneath the narrow H-alpha and [NII] emission lines. When modeled as a single Gaussian, this broad component has FWHM > 1500 km/s; when modeled as broad wings on the H-alpha and [NII] features, it has FWHM > 500 km/s. This feature is preferentially found in the more massive and more rapidly star-forming systems, which also tend to be older and larger galaxies. We interpret this emission as evidence of either powerful starburst-driven galactic winds or active supermassive black holes. If galactic winds are responsible for the broad emission, the observed luminosity and velocity of this gas imply mass outflow rates comparable to the star formation rate. On the other hand, if the broad line regions of active black holes account for the broad feature, the corresponding black holes masses are estimated to be an order of magnitude lower than those predicted by local scaling relations, suggesting a delayed assembly of supermassive black holes with respect to their host bulges.Comment: 11 pages, 5 figures. Accepted version, incorporating referee comments, including changes to title, abstract, figures, and discussion sectio

Investigation of attentional bias in obsessive compulsive disorder with and without depression in visual search

Copyright: © 2013 Morein-Zamir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedWhether Obsessive Compulsive Disorder (OCD) is associated with an increased attentional bias to emotive stimuli remains controversial. Additionally, it is unclear whether comorbid depression modulates abnormal emotional processing in OCD. This study examined attentional bias to OC-relevant scenes using a visual search task. Controls, non-depressed and depressed OCD patients searched for their personally selected positive images amongst their negative distractors, and vice versa. Whilst the OCD groups were slower than healthy individuals in rating the images, there were no group differences in the magnitude of negative bias to concern-related scenes. A second experiment employing a common set of images replicated the results on an additional sample of OCD patients. Although there was a larger bias to negative OC-related images without pre-exposure overall, no group differences in attentional bias were observed. However, OCD patients subsequently rated the images more slowly and more negatively, again suggesting post-attentional processing abnormalities. The results argue against a robust attentional bias in OCD patients, regardless of their depression status and speak to generalized difficulties disengaging from negative valence stimuli. Rather, post-attentional processing abnormalities may account for differences in emotional processing in OCD.Peer reviewedFinal Published versio

Bacillus thuringiensis Cry5B protein as a new pan-hookworm cure

Hookworms are intestinal nematode parasites that infect nearly half a billion people and are globally one of the most important contributors to iron-deficiency anemia. These parasites have significant impacts in developing children, pregnant women and working adults. Of all the soil-transmitted helminths or nematodes (STNs), hookworms are by far the most important, with disease burdens conservatively estimated at four million DALYs (Disability-Adjusted Life Years) and with productivity losses of up to US$139 billion annually. To date, mainly one drug, albendazole is used for hookworm therapy in mass drug administration, which has on average approximately 80% cure rate that is lower ( \u3c 40%) in some places. Given the massive numbers of people needing treatment, the threat of parasite resistance, and the inadequacy of current treatments, new and better cures against hookworms are urgently needed. Cry5B, a pore-forming protein produced by the soil bacterium Bacillus thuringiensis (Bt) has demonstrated good efficacy against Ancylostoma ceylanicum hookworm infections in hamsters. Here we broaden studies of Cry5B to include tests against infections of Ancylostoma caninum hookworms in dogs and against infections of the dominant human hookworm, Necator americanus, in hamsters. We show that Cry5B is highly effective against all hookworm parasites tested in all models. Neutralization of stomach acid improves Cry5B efficacy, which will aid in practical application of Cry5B significantly. Importantly, we also demonstrate that the anti-nematode therapeutic efficacy of Cry5B is independent of the host immune system and is not itself negated by repeated dosing. This study indicates that Bt Cry5B is a pan-hookworm anthelmintic with excellent properties for use in humans and other animals

Mukaiyama addition of (trimethylsilyl) acetonitrile to dimethyl acetals mediated by trimethylsilyl trifluoromethanesulfonate

(Trimethylsilyl) acetonitrile reacts smoothly with dimethyl acetals in the presence of stoichiometric trimethylsilyl trifluoromethanesulfonate (TMSOTf) to yield β-methoxynitriles. The ideal substrates for this reaction are acetals derived from aromatic aldehydes. Elimination to the corresponding α,β-unsaturated nitriles is observed as the major product in the case of electron-rich acetals. A mechanistic hypothesis that includes isomerization of the silylnitrile to a nucleophilic N-silyl ketene imine is presented