Antigen depot is not required for alum adjuvanticity

Alum adjuvants have been in continuous clinical use for more than 80 yr. While the prevailing theory has been that depot formation and the associated slow release of antigen and/or inflammation are responsible for alum enhancement of antigen presentation and subsequent T- and B-cell responses, this has never been formally proven. To examine antigen persistence, we used the chimeric fluorescent protein EαGFP, which allows assessment of antigen presentation in situ, using the Y-Ae antibody. We demonstrate that alum and/or CpG adjuvants induced similar uptake of antigen, and in all cases, GFP signal did not persist beyond 24 h in draining lymph node antigen-presenting cells. Antigen presentation was first detectable on B cells within 6–12 h of antigen administration, followed by conventional dendritic cells (DCs) at 12–24 h, then finally plasmacytoid DCs at 48 h or later. Again, alum and/or CpG adjuvants did not have an effect on the magnitude or sequence of this response; furthermore, they induced similar antigen-specific T-cell activation in vivo. Notably, removal of the injection site and associated alum depot, as early as 2 h after administration, had no appreciable effect on antigen-specific T- and B-cell responses. This study clearly rules out a role for depot formation in alum adjuvant activity

Three-Electrode Study of Electrochemical Ionomer Degradation Relevant to Anion-Exchange-Membrane Water Electrolyzers

Among existing water electrolysis (WE) technologies, anion-exchange-membrane water electrolyzers (AEMWEs) show promise for low-cost operation enabled by the basic solid-polymer electrolyte used to conduct hydroxide ions. The basic environment within the electrolyzer, in principle, allows the use of non-platinum-group metal catalysts and less-expensive cell components compared to acidic-membrane systems. Nevertheless, AEMWEs are still underdeveloped, and the degradation and failure modes are not well understood. To improve performance and durability, supporting electrolytes such as KOH and K2CO3 are often added to the water feed. The effect of the anion interactions with the ionomer membrane (particularly other than OH-), however, remains poorly understood. We studied three commercial anion-exchange ionomers (Aemion, Sustainion, and PiperION) during oxygen evolution (OER) at oxidizing potentials in several supporting electrolytes and characterized their chemical stability with surface-sensitive techniques. We analyzed factors including the ionomer conductivity, redox potential, and pH tolerance to determine what governs ionomer stability during OER. Specifically, we discovered that the oxidation of Aemion at the electrode surface is favored in the presence of CO32-/HCO3- anions perhaps due to the poor conductivity of that ionomer in the carbonate/bicarbonate form. Sustainion tends to lose its charge-carrying groups as a result of electrochemical degradation favored in basic electrolytes. PiperION seems to be similarly negatively affected by a pH drop and low carbonate/bicarbonate conductivity under the applied oxidizing potential. The insight into the interactions of the supporting electrolyte anions with the ionomer/membrane helps shed light on some of the degradation pathways possible inside of the AEMWE and enables the informed design of materials for water electrolysis

The FENIKS Survey: Spectroscopic Confirmation of Massive Quiescent Galaxies at z ~ 3-5

The measured ages of massive, quiescent galaxies at $z\sim 3-4$ imply that massive galaxies quench as early as $z\sim 6$. While the number of spectroscopic confirmations of quiescent galaxies at $z < 3$ has increased over the years, there are only a handful at $z > 3.5$. We report spectroscopic redshifts of one secure ($z=3.757$) and two tentative ($z = 3.336$, $z=4.673$) massive ($\log(M_\ast/M_\odot) > 10.3$) quiescent galaxies with 11 hours of Keck/MOSFIRE $K$-band observations. Our candidates were selected from the FENIKS survey, which uses deep Gemini/Flamingos-2 $K_b$ $K_r$ imaging optimized for increased sensitivity to the characteristic red colors of galaxies at $z > 3$ with strong Balmer/4000 \AA\ breaks. The rest-frame $UVJ$ and $(ugi)_s$ colors of 3/4 quiescent candidates are consistent with $1-2$ Gyr old stellar populations. This places these galaxies as the oldest objects at these redshifts, and challenges the notion that quiescent galaxies at $z > 3$ are all recently-quenched, "post-starburst'' galaxies. Our spectroscopy shows that the other quiescent-galaxy candidate is a broad-line AGN ($z = 3.594$) with strong, redshifted $H\beta$+[O III] emission with a velocity offset $>1000$ km/s, indicative of a powerful outflow. The star-formation history of our highest redshift candidate suggests that its progenitor was already in place by $z \sim 7-11$, reaching $\sim$ 10$^{11} M_{\odot}$ by $z \simeq 10$. These observations reveal the limit of what is possible with deep near-infrared photometry and targeted spectroscopy from the ground and demonstrate that secure spectroscopic confirmation of quiescent galaxies at $z > 4$ is only feasible with JWST.Comment: 20 pages, 11 figures, submitted to Ap

Common methodological pitfalls in ICI pneumonitis risk prediction studies

BackgroundPneumonitis is one of the most common adverse events induced by the use of immune checkpoint inhibitors (ICI), accounting for a 20% of all ICI-associated deaths. Despite numerous efforts to identify risk factors and develop predictive models, there is no clinically deployed risk prediction model for patient risk stratification or for guiding subsequent monitoring. We believe this is due to systemic suboptimal approaches in study designs and methodologies in the literature. The nature and prevalence of different methodological approaches has not been thoroughly examined in prior systematic reviews.MethodsThe PubMed, medRxiv and bioRxiv databases were used to identify studies that aimed at risk factor discovery and/or risk prediction model development for ICI-induced pneumonitis (ICI pneumonitis). Studies were then analysed to identify common methodological pitfalls and their contribution to the risk of bias, assessed using the QUIPS and PROBAST tools.ResultsThere were 51 manuscripts eligible for the review, with Japan-based studies over-represented, being nearly half (24/51) of all papers considered. Only 2/51 studies had a low risk of bias overall. Common bias-inducing practices included unclear diagnostic method or potential misdiagnosis, lack of multiple testing correction, the use of univariate analysis for selecting features for multivariable analysis, discretization of continuous variables, and inappropriate handling of missing values. Results from the risk model development studies were also likely to have been overoptimistic due to lack of holdout sets.ConclusionsStudies with low risk of bias in their methodology are lacking in the existing literature. High-quality risk factor identification and risk model development studies are urgently required by the community to give the best chance of them progressing into a clinically deployable risk prediction model. Recommendations and alternative approaches for reducing the risk of bias were also discussed to guide future studies

A Cell-Free Microtiter Plate Screen for Improved [FeFe] Hydrogenases

, a potential renewable fuel. Attempts to exploit these catalysts in engineered systems have been hindered by the biotechnologically inconvenient properties of the natural enzymes, including their extreme oxygen sensitivity. Directed evolution has been used to improve the characteristics of a range of natural catalysts, but has been largely unsuccessful for [FeFe] hydrogenases because of a lack of convenient screening platforms. [FeFe] hydrogenase HydA1 with a specific activity ∼4 times that of the wild-type enzyme. cell extracts, which allows unhindered access to the protein maturation and assay environment

Robust Reproducible Resting State Networks in the Awake Rodent Brain

Resting state networks (RSNs) have been studied extensively with functional MRI in humans in health and disease to reflect brain function in the un-stimulated state as well as reveal how the brain is altered with disease. Rodent models of disease have been used comprehensively to understand the biology of the disease as well as in the development of new therapies. RSN reported studies in rodents, however, are few, and most studies are performed with anesthetized rodents that might alter networks and differ from their non-anesthetized state. Acquiring RSN data in the awake rodent avoids the issues of anesthesia effects on brain function. Using high field fMRI we determined RSNs in awake rats using an independent component analysis (ICA) approach, however, ICA analysis can produce a large number of components, some with biological relevance (networks). We further have applied a novel method to determine networks that are robust and reproducible among all the components found with ICA. This analysis indicates that 7 networks are robust and reproducible in the rat and their putative role is discussed

Spectroscopic verification of very luminous galaxy candidates in the early universe

During the first 500 million years of cosmic history, the first stars and galaxies formed and seeded the cosmos with heavy elements. These early galaxies illuminated the transition from the cosmic "dark ages" to the reionization of the intergalactic medium. This transitional period has been largely inaccessible to direct observation until the recent commissioning of JWST, which has extended our observational reach into that epoch. Excitingly, the first JWST science observations uncovered a surprisingly high abundance of early star-forming galaxies. However, the distances (redshifts) of these galaxies were, by necessity, estimated from multi-band photometry. Photometric redshifts, while generally robust, can suffer from uncertainties and/or degeneracies. Spectroscopic measurements of the precise redshifts are required to validate these sources and to reliably quantify their space densities, stellar masses, and star formation rates, which provide powerful constraints on galaxy formation models and cosmology. Here we present the results of JWST follow-up spectroscopy of a small sample of galaxies suspected to be amongst the most distant yet observed. We confirm redshifts z > 10 for two galaxies, including one of the first bright JWST-discovered candidates with z = 11.4, and show that another galaxy with suggested z ~ 16 instead has z = 4.9, with strong emission lines that mimic the expected colors of more distant objects. These results reinforce the evidence for the rapid production of luminous galaxies in the very young Universe, while also highlighting the necessity of spectroscopic verification for remarkable candidates.Comment: Submitted to Natur

The Dynamics of Functional Brain Networks:Integrated Network States during Cognitive Task Performance

Higher brain function relies upon the ability to flexibly integrate information across specialized communities of brain regions, however it is unclear how this mechanism manifests over time. In this study, we use time-resolved network analysis of functional magnetic resonance imaging data to demonstrate that the human brain traverses between two functional states that maximize either segregation into tight-knit communities or integration across otherwise disparate neural regions. The integrated state enables faster and more accurate performance on a cognitive task, and is associated with dilations in pupil diameter, suggesting that ascending neuromodulatory systems may govern the transition between these alternative modes of brain function. Our data confirm a direct link between cognitive performance and the dynamic reorganization of the network structure of the brain.Comment: 38 pages, 4 figure