The Allegiance of Thomas Hobbes offers a new interpretation of Thomas Hobbes's response to the English Revolution. By focusing on his religious thought, it debunks the standard view of him as a ...royalist, and recovers his sympathies with the religious projects of the 1640s and 1650s. This reinterpretation culminates with an exploration of Hobbes's surprising sympathies with Oliver Cromwell and his supporters. By placing Thomas Hobbes within fresh contexts, Professor Collins offers a new angle of vision on the religious significance of the English Revolution itself.
Atmospheric
marine aerosol particles impact Earth's albedo and climate. These particles
can be primary or secondary and come from a variety of sources, including sea
salt, dissolved organic matter, ...volatile organic compounds, and
sulfur-containing compounds. Dimethylsulfide (DMS) marine emissions
contribute greatly to the global biogenic sulfur budget, and its oxidation
products can contribute to aerosol mass, specifically as sulfuric acid and
methanesulfonic acid (MSA). Further, sulfuric acid is a known nucleating
compound, and MSA may be able to participate in nucleation when bases are
available. As DMS emissions, and thus MSA and sulfuric acid from DMS
oxidation, may have changed since pre-industrial times and may change in a
warming climate, it is important to characterize and constrain the climate
impacts of both species. Currently, global models that simulate aerosol size
distributions include contributions of sulfate and sulfuric acid from DMS
oxidation, but to our knowledge, global models typically neglect the impact
of MSA on size distributions. In this study, we use the GEOS-Chem-TOMAS (GC-TOMAS) global aerosol
microphysics model to determine the impact on aerosol size distributions and
subsequent aerosol radiative effects from including MSA in the size-resolved
portion of the model. The effective equilibrium vapor pressure of MSA is
currently uncertain, and we use the Extended Aerosol Inorganics Model (E-AIM)
to build a parameterization for GC-TOMAS of MSA's effective volatility as a
function of temperature, relative humidity, and available gas-phase bases,
allowing MSA to condense as an ideally nonvolatile or semivolatile species or
too volatile to condense. We also present two limiting cases for MSA's
volatility, assuming that MSA is always ideally nonvolatile (irreversible
condensation) or that MSA is always ideally semivolatile (quasi-equilibrium
condensation but still irreversible condensation). We further present
simulations in which MSA participates in binary and ternary nucleation with
the same efficacy as sulfuric acid whenever MSA is treated as ideally
nonvolatile. When using the volatility parameterization described above (both
with and without nucleation), including MSA in the model changes the global
annual averages at 900 hPa of submicron aerosol mass by 1.2 %, N3
(number concentration of particles greater than 3 nm in diameter) by
−3.9 % (non-nucleating) or 112.5 % (nucleating), N80 by 0.8 %
(non-nucleating) or 2.1 % (nucleating), the cloud-albedo aerosol indirect
effect (AIE) by −8.6 mW m−2 (non-nucleating) or −26 mW m−2
(nucleating), and the direct radiative effect (DRE) by −15 mW m−2
(non-nucleating) or −14 mW m−2 (nucleating). The sulfate and
sulfuric acid from DMS oxidation produces 4–6 times more submicron mass than
MSA does, leading to an ∼10 times stronger cooling effect in the DRE.
But the changes in N80 are comparable between the contributions from MSA and
from DMS-derived sulfate/sulfuric acid, leading to comparable changes in the
cloud-albedo AIE. Model–measurement comparisons with the Heintzenberg et al. (2000) dataset
over the Southern Ocean indicate that the default model has a missing source
or sources of ultrafine particles: the cases in which MSA participates in
nucleation (thus increasing ultrafine number) most closely match the
Heintzenberg distributions, but we cannot conclude nucleation from MSA is the
correct reason for improvement. Model–measurement comparisons with
particle-phase MSA observed with a customized Aerodyne high-resolution
time-of-flight aerosol mass spectrometer (AMS) from the ATom campaign show
that cases with the MSA volatility parameterizations (both with and without
nucleation) tend to fit the measurements the best (as this is the first use
of MSA measurements from ATom, we provide a detailed description of these
measurements and their calibration). However, no one model sensitivity case
shows the best model–measurement agreement for both Heintzenberg and the
ATom campaigns. As there are uncertainties in both MSA's behavior (nucleation
and condensation) and the DMS emissions inventory, further studies on both
fronts are needed to better constrain MSA's past, current, and future impacts
upon the global aerosol size distribution and radiative forcing.
Materials that combine magnetic order with other desirable physical attributes could find transformative applications in spintronics, quantum sensing, low-density magnets and gas separations. Among ...potential multifunctional magnetic materials, metal-organic frameworks, in particular, bear structures that offer intrinsic porosity, vast chemical and structural programmability, and the tunability of electronic properties. Nevertheless, magnetic order within metal-organic frameworks has generally been limited to low temperatures, owing largely to challenges in creating a strong magnetic exchange. Here we employ the phenomenon of itinerant ferromagnetism to realize magnetic ordering at T
= 225 K in a mixed-valence chromium(II/III) triazolate compound, which represents the highest ferromagnetic ordering temperature yet observed in a metal-organic framework. The itinerant ferromagnetism proceeds through a double-exchange mechanism, which results in a barrierless charge transport below the Curie temperature and a large negative magnetoresistance of 23% at 5 K. These observations suggest applications for double-exchange-based coordination solids in the emergent fields of magnetoelectrics and spintronics.
Protein modification by SUMO helps orchestrate the elaborate events of meiosis to faithfully produce haploid gametes. To date, only a handful of meiotic SUMO targets have been identified. Here, we ...delineate a multidimensional SUMO-modified meiotic proteome in budding yeast, identifying 2747 conjugation sites in 775 targets, and defining their relative levels and dynamics. Modified sites cluster in disordered regions and only a minority match consensus motifs. Target identities and modification dynamics imply that SUMOylation regulates all levels of chromosome organization and each step of meiotic prophase I. Execution-point analysis confirms these inferences, revealing functions for SUMO in S-phase, the initiation of recombination, chromosome synapsis and crossing over. K15-linked SUMO chains become prominent as chromosomes synapse and recombine, consistent with roles in these processes. SUMO also modifies ubiquitin, forming hybrid oligomers with potential to modulate ubiquitin signaling. We conclude that SUMO plays diverse and unanticipated roles in regulating meiotic chromosome metabolism.
Cloud condensation nuclei (CCN) can affect cloud properties and therefore the Earth’s radiative balance. New particle formation (NPF) from condensable vapours in the free troposphere has been ...suggested to contribute to CCN, especially in remote, pristine atmospheric regions, but direct evidence is sparse, and the magnitude of this contribution is uncertain. Here we use in-situ aircraft measurements of vertical profiles of aerosol size distributions to present a global-scale survey of NPF occurrence. We observed intense NPF occurring at high altitude in tropical convective regions over both the Pacific and Atlantic Oceans. Together with the results of chemical-transport models, our findings indicate that NPF persists at all longitudes as a global-scale band in the tropical upper troposphere, covering about 40% of the Earth’s surface. Furthermore, we find that this NPF in the tropical upper troposphere is a globally important source of CCN in the lower troposphere, where they can affect cloud properties. Our findings suggest that the production of CCN, as these new particles descend towards the surface, is currently not adequately captured in global models, because they tend to underestimate both the magnitude of tropical upper tropospheric NPF and the subsequent growth to CCN sizes. This has potential implications for cloud albedo and the global radiative balance.
Black carbon (BC) aerosol plays an important role in the Earth’s climate system because it absorbs solar radiation and therefore potentially warms the climate; however, BC can also act as a seed for ...cloud particles, which may offset much of its warming potential. If BC acts as an ice nucleating particle (INP), BC could affect the lifetime, albedo, and radiative properties of clouds containing both supercooled liquid water droplets and ice particles (mixed-phase clouds). Over 40% of global BC emissions are from biomass burning; however, the ability of biomass burning BC to act as an INP in mixed-phase cloud conditions is almost entirely unconstrained. To provide these observational constraints, we measured the contribution of BC to INP concentrations (INP) in real-world prescribed burns and wildfires. We found that BC contributes, at most, 10% to INP during these burns. From this, we developed a parameterization for biomass burning BC and combined it with a BC parameterization previously used for fossil fuel emissions. Applying these parameterizations to global model output, we find that the contribution of BC to potential INP relevant to mixed-phase clouds is ∼5% on a global average.
Ship‐based aerosol measurements in the summertime Arctic indicate elevated concentrations of ultrafine particles with occasional growth to cloud condensation nuclei (CCN) sizes. Focusing on one ...episode with two continuously growing modes, growth occurs faster for a large, preexisting mode (dp ≈ 90 nm) than for a smaller nucleation mode (dp ≈ 20 nm). We use microphysical modeling to show that growth is largely via organic condensation. Unlike results for midlatitude forested regions, most of these condensing species behave as semivolatile organics, as lower volatility organics would lead to faster growth of the smaller mode. The magnitude of the CCN hygroscopicity parameter for the growing particles, ~0.1, is also consistent with organic species constituting a large fraction of the particle composition. Mixing ratios of common aerosol growth precursors, such as isoprene and sulfur dioxide, are not elevated during the episode, indicating that an unidentified aerosol growth precursor is present in this high‐latitude marine environment.
Key Points
A particle formation and growth event in the marine Arctic was observed leading to enhanced numbers of cloud condensation nuclei
Microphysical modeling and hygroscopicity measurements show that growth is governed by organic species of unknown origin
The condensing gas‐phase material is surprisingly semivolatile, whereas less volatile material condenses at continental, lower latitude sites
Abstract Background Clinical grading systems using clinical features alongside nomograms lack precision in guiding treatment decisions in prostate cancer (PCa). There is a critical need for ...identification of biomarkers that can more accurately stratify patients with primary PCa. Objective To identify a robust prognostic signature to better distinguish indolent from aggressive prostate cancer (PCa). Design, setting, and participants To develop the signature, whole-genome and whole-transcriptome sequencing was conducted on five PCa patient-derived xenograft (PDX) models collected from independent foci of a single primary tumor and exhibiting variable metastatic phenotypes. Multiple independent clinical cohorts including an intermediate-risk cohort were used to validate the biomarkers. Outcome measurements and statistical analysis The outcome measurement defining aggressive PCa was metastasis following radical prostatectomy. A generalized linear model with lasso regularization was used to build a 93-gene stroma-derived metastasis signature (SDMS). The SDMS association with metastasis was assessed using a Wilcoxon rank-sum test. Performance was evaluated using the area under the curve (AUC) for the receiver operating characteristic, and Kaplan-Meier curves. Univariable and multivariable regression models were used to compare the SDMS alongside clinicopathological variables and reported signatures. AUC was assessed to determine if SDMS is additive or synergistic to previously reported signatures. Results and limitations A close association between stromal gene expression and metastatic phenotype was observed. Accordingly, the SDMS was modeled and validated in multiple independent clinical cohorts. Patients with higher SDMS scores were found to have worse prognosis. Furthermore, SDMS was an independent prognostic factor, can stratify risk in intermediate-risk PCa, and can improve the performance of other previously reported signatures. Conclusions Profiling of stromal gene expression led to development of an SDMS that was validated as independently prognostic for the metastatic potential of prostate tumors. Patient summary Our stroma-derived metastasis signature can predict the metastatic potential of early stage disease and will strengthen decisions regarding selection of active surveillance versus surgery and/or radiation therapy for prostate cancer patients. Furthermore, profiling of stroma cells should be more consistent than profiling of diverse cellular populations of heterogeneous tumors.
Early detection of Primary Immunodeficiencies Disorders (PIDDs) is of paramount importance for effective treatment and disease management. Many PIDDs would be strong candidates for newborn screening ...(NBS) if robust screening methods could identify patients from dried blood spots (DBS) during the neonatal period. As majority of congenital PIDDs result in the reduction or absence of specific proteins, direct quantification of these target proteins represents an attractive potential screening tool. Unfortunately, detection is often limited by the extremely low protein concentrations in blood cells and limited blood volume present in DBS. We have recently developed a robust novel method for quantification of low abundance proteins in DBS for PIDDs using peptide immunoaffinity enrichment coupled to selected reaction monitoring (immuno-SRM). Here, we further generated a multiplexed Immuno-SRM panel for simultaneous screening of eight signature peptides representing five PIDD-specific and two cell-type specific proteins from DBS. In samples from 28 PIDD patients including two carriers, representing X-Linked Agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), X-Linked Chronic Granulomatous Disease (XL-CGD), DOCK8 Deficiency and ADA deficiency, peptides representing each disease are significantly reduced relative to normal controls and patient identification had excellent agreement with clinical and molecular diagnosis. Also included in the multiplex panel are cell specific markers for platelets (CD42) and Natural Killer Cells (CD56). In patients with WAS, CD42 levels were found to be significantly reduced consistent with characteristic thrombocytopenia. A patient with WAS analyzed before and after bone marrow transplant showed normalized WAS protein and platelet CD42 after treatment highlighting the ability of immuno-SRM to monitor the effects of PIDD treatment. The assay was readily reproduced in two separate laboratories with similar analytical performance and complete agreement in patient diagnosis demonstrating the effective standardized methods. A high-throughput Immuno-SRM method screens PIDD-specific peptides in a 2.5-min runtime meeting high volume NBS workflow requirements was also demonstrated in this report. This high-throughput method returned identical results to the standard Immuno-SRM PIDD panel. Immuno-SRM peptide analysis represents a robust potential clinical diagnostic for identifying and studying PIDD patients from easily collected and shipped DBS and supports a significant potential for early PIDD diagnosis through newborn screening.
Background:
Tibial tubercle–trochlear groove distance (TT-TG) is a commonly used measurement for surgical decision making in patients with patellofemoral malalignment and instability. This ...measurement has historically been performed utilizing axial computed tomography (CT). More recently, magnetic resonance imaging (MRI) has been proposed as an equivalent method, but this has not yet been fully validated.
Purpose:
To determine the reliability of TT-TG distance measurements on both MRI and CT and to determine whether the measurements are interchangeable with one another.
Study Design:
Cohort study (diagnosis); Level of evidence, 2.
Methods:
All patients with patellar instability who underwent both CT and MRI of the knee from 2003 to 2011 were included (n = 59 knees in 54 patients). Two fellowship-trained musculoskeletal radiologists measured the TT-TG distances for each patient by CT and MRI in a randomized, blinded fashion. Interobserver reliability was calculated between radiologists for both imaging modalities, and intermethod reliability was calculated between the 2 imaging modalities. The results are reported using intraclass correlation coefficients (ICCs) and Bland-Altman analysis.
Results:
The 59 knees had a mean TT-TG distance of 16.9 mm (range, 8.3-25.8 mm) by CT and 14.7 mm (range, 1.5-25.1 mm) by MRI. Interobserver reliability between the radiologists was considered excellent for both CT and MRI (ICC = 0.777 and 0.843, respectively). When comparing CT to MRI, the ICC was considered only fair for each of the raters (0.532 and 0.539). Eleven patients (19%) had a TT-TG distance of ≥20 mm on CT preoperatively and underwent distal realignment by tibial tubercle osteotomy. In this surgical subgroup, the mean TT-TG distance was 22.5 mm (range, 19.8-25.8 mm) by CT and only 18.7 mm (range, 14.4-22.8 mm) by MRI for a mean difference of 3.80 mm (P < .001).
Conclusion:
The TT-TG distance can be measured with excellent interrater reliability on both MRI and CT; however, the values derived from these 2 tests may not be interchangeable. This observation should be taken into consideration when MRI is used for surgical planning because MRI may underestimate the TT-TG distance when compared with CT.
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