Hydrogel encapsulation of genome-engineered stem cells for long-term self-regulating anti-cytokine therapy

Biologic therapies have revolutionized treatment options for rheumatoid arthritis (RA) but their continuous administration at high doses may lead to adverse events. Thus, the development of improved drug delivery systems that can sense and respond commensurately to disease flares represents an unmet medical need. Toward this end, we generated induced pluripotent stem cells (iPSCs) that express interleukin-1 receptor antagonist (IL-1Ra, an inhibitor of IL-1) in a feedback-controlled manner driven by the macrophage chemoattractant protein-1 (Ccl2) promoter. Cells were seeded in agarose hydrogel constructs made from 3D printed molds that can be injected subcutaneously via a blunt needle, thus simplifying implantation of the constructs, and the translational potential. We demonstrated that the subcutaneously injected agarose hydrogels containing genome-edited Ccl2-IL1Ra iPSCs showed significant therapeutic efficacy in the K/BxN model of inflammatory arthritis, with nearly complete abolishment of disease severity in the front paws. These implants also exhibited improved implant longevity as compared to the previous studies using 3D woven scaffolds, which require surgical implantation. This minimally invasive cell-based drug delivery strategy may be adapted for the treatment of other autoimmune or chronic diseases, potentially accelerating translation to the clinic

Survival Strategies: Doctoral Students’ Perceptions of Challenges and Coping Methods

The purpose of this collective case study was to use a critical dialectical pluralistic (CDP) philosophical lens to investigate select doctoral students’ perceptions about the challenges that they encountered while in a doctorate program and the coping strategies that they found effective in mitigating these challenges. A major goal of CDP is to empower research participants maximally by giving them the role of participant-researchers. Participants were 10 doctoral students enrolled at a Tier-II university in the United States, who were selected via convenience sampling. Each student participated in a face-to-face interview with a member of the research team—consistent with a CDP approach. A qualitative-dominant crossover mixed analysis was used wherein both quantitative and qualitative analyses were used to analyze the qualitative data, with the qualitative analysis phase being dominant. The qualitative analyses (e.g., constant comparison analysis, classical content analysis) revealed the following five themes: compartmentalization of life, outside support systems, justification for participation in program, emotional status, and structure of program. These themes indicated that although challenges are plentiful, particularly in terms of balancing one’s academic life with other obligations, participants found support and encouragement from family, friends, and other doctoral students to be the most beneficial coping strategy. These findings have important implications for the structuring of doctoral programs

Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes

Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis

Multivariable association discovery in population-scale meta-omics studies.

It is challenging to associate features such as human health outcomes, diet, environmental conditions, or other metadata to microbial community measurements, due in part to their quantitative properties. Microbiome multi-omics are typically noisy, sparse (zero-inflated), high-dimensional, extremely non-normal, and often in the form of count or compositional measurements. Here we introduce an optimized combination of novel and established methodology to assess multivariable association of microbial community features with complex metadata in population-scale observational studies. Our approach, MaAsLin 2 (Microbiome Multivariable Associations with Linear Models), uses generalized linear and mixed models to accommodate a wide variety of modern epidemiological studies, including cross-sectional and longitudinal designs, as well as a variety of data types (e.g., counts and relative abundances) with or without covariates and repeated measurements. To construct this method, we conducted a large-scale evaluation of a broad range of scenarios under which straightforward identification of meta-omics associations can be challenging. These simulation studies reveal that MaAsLin 2\u27s linear model preserves statistical power in the presence of repeated measures and multiple covariates, while accounting for the nuances of meta-omics features and controlling false discovery. We also applied MaAsLin 2 to a microbial multi-omics dataset from the Integrative Human Microbiome (HMP2) project which, in addition to reproducing established results, revealed a unique, integrated landscape of inflammatory bowel diseases (IBD) across multiple time points and omics profiles

SN 2011ht: Confirming a Class of Interacting Supernovae with Plateau Light Curves (Type IIn-P)

We present photometry and spectroscopy of the Type IIn supernova (SN) 2011ht, identified previously as a SN impostor. The light curve exhibits an abrupt transition from a well-defined ~120 day plateau to a steep bolometric decline. Leading up to peak brightness, a hot emission-line spectrum exhibits signs of interaction with circumstellar material (CSM), in the form of relatively narrow P-Cygni features of H I and He I superimposed on broad Lorentzian wings. For the remainder of the plateau phase the spectrum exhibits strengthening P-Cygni profiles of Fe II, Ca II, and H-alpha. By day 147, after the plateau has ended, the SN entered the nebular phase, heralded by the appearance of forbidden transitions of [O I], [O II], and [Ca II] over a weak continuum. At this stage, the light curve exhibits a low luminosity that is comparable to that sub-luminous Type II-P supernovae, and a relatively fast visual-wavelength decline that is significantly steeper than the Co-56 decay rate. However, the total bolometric decline, including the IR luminosity, is consistent with Co-56 decay, and implies a low Ni-56 mass of ~0.01 M(Sun). We therefore characterize SN 2011ht as a bona-fide core-collapse SN very similar to the peculiar SNe IIn 1994W and 2009kn. These three SNe define a subclass, which are Type IIn based on their spectrum, but that also exhibit well-defined plateaus and produce low Ni-56 yields. We therefore suggest Type IIn-P as a name for this subclass. Possible progenitors of SNe IIn-P, consistent with the available data, include 8-10 M(Sun) stars, which undergo core collapse as a result of electron capture after a brief phase of enhanced mass loss, or more massive M>25 M(Sun) progenitors, which experience substantial fallback of the metal-rich radioactive ejecta. In either case, the energy radiated by these three SNe during their plateau must be dominated by CSM interaction (abridged).Comment: accepted, post-proof version (includes new data

The apparent British sea slope is caused by systematic errors in the levelling-based vertical datum

The spirit-levelling–based British vertical datum (Ordnance Datum Newlyn) implies a south–north apparent slope in mean sea level of up to 53 mm deg–1 latitude, due to the datum falling on heading northwards. Although this apparent slope has been investigated since the 1960s, explanations of its origin have remained inconclusive. It has also been suggested that, rather than a slope, the British vertical datum includes a step of about 240 mm affecting all sites north of about 53°N. In either case, the British vertical datum may be of limited use for any study requiring accurate heights or changes in heights, such as testing geoid models, groundwater and hydrocarbon extraction, the calibration and validation of satellite-based digital terrain models, and the unification of vertical datums internationally. Within the last decade, however, based on an apparent reduction in the slope to only −12 mm deg–1 latitude with respect to recent geoid models, it has been claimed that the British vertical datum does provide a physically meaningful surface for use in scientific applications.In this paper, we reinvestigate the presence of apparent south–north sea slopes around Britain and reported slopes in the vertical datum, using the EGM2008 global gravitational model, together with mean sea level and GPS data from British tide gauges, GPS ellipsoidal heights of 178 fundamental benchmarks across mainland Britain, and vertical deflection observations at 192 stations. We demonstrate a south–north slope in the British vertical datum of −(20–25) mm deg–1 latitude with respect to both mean sea level (corrected for the ocean's mean dynamic topography and the inverse barometer response to atmospheric pressure loading) and the EGM2008 quasigeoid model, while EGM2008 is shown to exhibit a negligible slope of (2 ± 4) mm deg–1 with respect to mean sea level. It is clear, therefore, that the slope can only arise from systematic errors in the levelling, although we are unable to isolate their exact origin. Using an offset detection method based on a penalized likelihood maximization using the Schwarz Information Criterion, we do not detect a step in the vertical datum affecting all sites north of 53°N, but do identify regional distortions that we attribute to the inhomogeneity in both the levelling data used and the least squares adjustment procedures used to realize the datum. We conclude that the British vertical datum remains unsuitable for scientific purposes

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU

The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men

INTRODUCTION: We recently described the sulfur microbial diet, a pattern of intake associated with increased gut sulfur-metabolizing bacteria and incidence of distal colorectal cancer (CRC). We assessed whether this risk differed by CRC molecular subtypes or presence of intratumoral microbes involved in CRC pathogenesis (Fusobacterium nucleatum and Bifidobacterium spp.). METHODS: We performed Cox proportional hazards modeling to examine the association between the sulfur microbial diet and incidence of overall and distal CRC by molecular and microbial subtype in the Health Professionals Follow-Up Study (1986-2012). RESULTS: We documented 1,264 incident CRC cases among 48,246 men, approximately 40% of whom had available tissue data. After accounting for multiple hypothesis testing, the relationship between the sulfur microbial diet and CRC incidence did not differ by subtype. However, there was a suggestion of an association by prostaglandin synthase 2 (PTGS2) status with a multivariable adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.31 (95% confidence interval: 0.99-1.74, Ptrend = 0.07, Pheterogeneity = 0.04) for PTGS2-high CRC. The association of the sulfur microbial diet with distal CRC seemed to differ by the presence of intratumoral Bifidobacterium spp. with an adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.65 (95% confidence interval: 1.14-2.39, Ptrend = 0.01, Pheterogeneity = 0.03) for Bifidobacterium-negative distal CRC. We observed no apparent heterogeneity by other tested molecular markers. DISCUSSION: Greater long-term adherence to the sulfur microbial diet could be associated with PTGS2-high and Bifidobacterium-negative distal CRC in men. Additional studies are needed to further characterize the role of gut microbial sulfur metabolism and CRC

A Tabletop X-Ray Tomography Instrument for Nanometer-Scale Imaging: Integration of a Scanning Electron Microscope with a Transition-Edge Sensor Spectrometer

X-ray nanotomography is a powerful tool for the characterization of nanoscale materials and structures, but is difficult to implement due to competing requirements on X-ray flux and spot size. Due to this constraint, state-of-the-art nanotomography is predominantly performed at large synchrotron facilities. Compact X-ray nanotomography tools operated in standard analysis laboratories exist, but are limited by X-ray optics and destructive sample preparation techniques. We present a laboratory-scale nanotomography instrument that achieves nanoscale spatial resolution while changing the limitations of conventional tomography tools. The instrument combines the electron beam of a scanning electron microscope (SEM) with the precise, broadband X-ray detection of a superconducting transition-edge sensor (TES) microcalorimeter. The electron beam generates a highly focused X-ray spot in a metal target, while the TES spectrometer isolates target photons with high signal-to-noise. This combination of a focused X-ray spot, energy-resolved X-ray detection, and unique system geometry enable nanoscale, element-specific X-ray imaging in a compact footprint. The proof-of-concept for this approach to X-ray nanotomography is demonstrated by imaging 160 nm features in three dimensions in a Cu-SiO2 integrated circuit, and a path towards finer resolution and enhanced imaging capabilities is discussed.Comment: The following article has been submitted to Physical Review Applie