Kinetic Accessibility of Buried DNA Sites in Nucleosomes

Using a theoretical model for spontaneous partial DNA unwrapping from histones, we study the transient exposure of protein-binding DNA sites within nucleosomes. We focus on the functional dependence of the rates for site exposure and reburial on the site position, which is measurable experimentally and pertinent to gene regulation. We find the dependence to be roughly described by a random walker model. Close inspection reveals a surprising physical effect of flexibility-assisted barrier crossing, which we characterize within a toy model, the "semiflexible Brownian rotor."Comment: final version as published in Phys. Rev. Let

Characterization of laser-driven single and double electron bunches with a permanent magnet quadrupole triplet and pepper-pot mask

Electron beams from laser-plasma wakefield accelerators have low transverse emittance, comparable to those from conventional radio frequency accelerators, which highlights their potential for applications, many of which will require the use of quadrupole magnets for optimal electron beam transport. We report on characterizing electron bunches where double bunches are observed under certain conditions. In particular, we present pepper-pot measurements of the transverse emittance of 120-200 MeV laser wakefield electron bunches after propagation through a triplet of permanent quadrupole magnets. It is shown that the normalized emittance at source can be as low as 1 π mm mrad (resolution limited), growing by about five times after propagation through the quadrupoles due to beam energy spread. The inherent energy-dependence of the magnets also enables detection of double electron bunches that could otherwise remain unresolved, providing insight into the self-injection of multiple bunches. The combination of quadrupoles and pepper-pot, in addition, acts as a diagnostic for the alignment of the magnetic triplet

Characteristics of brown carbon in Western United States wildfires

Brown carbon (BrC) associated with aerosol particles in western United States wildfires was measured between Jul. and Aug. 2019 onboard the NASA DC-8 research aircraft during the Fire Influence on Regional to Global Environments and Air Quality (FIREX-AQ) study. Two BrC measurement methods are investigated; highly spectrally-resolved light absorption in solvent (water and methanol) extracts of particles collected on filters and in-situ bulk aerosol particle light absorption measured at three wavelengths (405, 532, 664 nm) with a photo acoustic spectrometer (PAS). A light absorption closure analysis for wavelengths between 300 and 700 nm was performed. The combined light absorption of particle pure black carbon material, including enhancements due to internally mixed materials, plus soluble BrC and a Mie-predicted factor for conversion of soluble BrC to aerosol particle BrC, was compared to absorption spectra from a power law fit to the three PAS wavelengths. For the various parameters used, at a wavelength of roughly 400 nm they agreed, at lower wavelengths the individual component-predicted particle light absorption significantly exceeded the PAS and at higher wavelengths the PAS absorption was consistently higher, but more variable. Limitations with extrapolation of PAS data to wavelengths below 405 nm and missing BrC species of low solubility that more strongly absorb at higher wavelengths may account for the differences. Based on measurements closest to fires, the emission ratio of PAS measured BrC at 405 nm relative to carbon monoxide (CO) was on average 0.13 Mm−1 ppbv−1, emission ratios for soluble BrC are also provided. As the smoke moved away from the burning regions the evolution over time of BrC was observed to be highly complex; BrC enhancement, depletion, or constant levels with age were all observed in the first 8 hours after emission in different plumes. Within 8 hours following emissions, 4-nitrocatechol, a well characterized BrC chromophore commonly found in smoke particles, was largely depleted relative to the bulk BrC. In a descending plume where temperature increased by 15 K, 4-nitrocatechol dropped possibly due to temperature-driven evaporation, but bulk BrC remained largely unchanged. Evidence was found for reactions with ozone, or related species, as a pathway for secondary formation of BrC under both low and high oxides of nitrogen (NOx) conditions, while BrC was also observed to be bleached in regions of higher ozone and low NOx, consistent with complex behaviors of BrC observed in laboratory studies. Although the evolution of smoke in the first hours following emission is highly variable, a limited number of measurements of more aged smoke (15 to 30 hours) indicate a net loss of BrC. It is yet to be determined how the near-field BrC evolution in smoke affects the characteristics of smoke over longer time and spatial scales, where its environmental impacts are likely to be greater

Interrater Reliability of NI-RADS on Posttreatment PET/Contrast-enhanced CT Scans in Head and Neck Squamous Cell Carcinoma

Purpose: To evaluate the interrater reliability among radiologists examining posttreatment head and neck squamous cell carcinoma (HNSCC) fluorodeoxyglucose PET/contrast-enhanced CT (CECT) scans using Neck Imaging Reporting and Data System (NI-RADS). Materials and Methods: In this retrospective study, images in 80 patients with HNSCC who underwent posttreatment surveillance PET/CECT and immediate prior comparison CECT or PET/CECT (from June 2014 to July 2016) were uploaded to the American College of Radiology's cloud-based website, Cortex. Eight radiologists from seven institutions with variable NI-RADS experience independently evaluated each case and assigned an appropriate prose description and NI-RADS category for the primary site and the neck site. Five of these individuals were experienced readers (> 5 years of experience), and three were novices (< 5 years of experience). In total, 640 lexicon-based and NI-RADS categories were assigned to lesions among the 80 included patients by the eight radiologists. Light generalization of Cohen κ for interrater reliability was performed. Results: Of the 80 included patients (mean age, 63 years ± 10 [standard deviation]), there were 58 men (73%); 60 patients had stage IV HNSCC (75%), and the most common tumor location was oropharynx (n = 32; 40%). Light κ for lexicon was 0.30 (95% CI: 0.23, 0.36) at the primary site and 0.31 (95% CI: 0.24, 0.37) at the neck site. Light κ for NI-RADS category was 0.55 (95% CI: 0.46, 0.63) at the primary site and 0.60 (95% CI: 0.48, 0.69) at the neck site. Percent agreement between lexicon and correlative NI-RADS category was 84.4% (540 of 640) at the primary site and 92.6% (593 of 640) at the neck site. There was no significant difference in interobserver agreement among the experienced versus novice raters. Conclusion: Moderate agreement was achieved among eight radiologists using NI-RADS at posttreatment HNSCC surveillance imaging

Pharmacogenomics of statin-related myopathy:Meta-analysis of rare variants from whole-exome sequencing

AIMS:Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS:SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS:In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable

Mucedorus: the last ludic playbook, the first stage Arcadia

This article argues that two seemingly contradictory factors contributed to and sustained the success of the anonymous Elizabethan play Mucedorus (c. 1590; pub. 1598). First, that both the initial composition of Mucedorus and its Jacobean revival were driven in part by the popularity of its source, Philip Sidney's Arcadia. Second, the playbook's invitation to amateur playing allowed its romance narrative to be adopted and repurposed by diverse social groups. These two factors combined to create something of a paradox, suggesting that Mucedorus was both open to all yet iconographically connected to an elite author's popular text. This study will argue that Mucedorus pioneered the fashion for “continuations” or adaptations of the famously unfinished Arcadia, and one element of its success in print was its presentation as an affordable and performable version of Sidney's elite work. The Jacobean revival of Mucedorus by the King's Men is thus evidence of a strategy of engagement with the Arcadia designed to please the new Stuart monarchs. This association with the monarchy in part determined the cultural functions of the Arcadia and Mucedorus through the Interregnum to the close of the seventeenth century

Multi-campaign Ship and Aircraft Observations of Marine Cloud Condensation Nuclei and Droplet Concentrations

In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to expanding the available data in these difficult-to-reach regions of the Earth and improving our understanding of aerosol-cloud interactions. The data collection includes particle composition and continental tracers to identify potential contributing CCN sources. Several of these campaigns include High Spectral Resolution Lidar (HSRL) and polarimetric imaging measurements and retrievals that will be the basis for the next generation of space-based remote sensors and, thus, can be utilized as satellite surrogates

Network analysis of human glaucomatous optic nerve head astrocytes

<p>Abstract</p> <p>Background</p> <p>Astrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive.</p> <p>Methods</p> <p>To decipher the regulatory elements controlling astrocyte-mediated neurotoxicity in glaucoma, we conducted a systems-level functional analysis of gene expression, proteomic and genetic data associated with reactive optic nerve head astrocytes (ONHAs).</p> <p>Results</p> <p>Our reconstruction of the molecular interactions affected by glaucoma revealed multi-domain biological networks controlling activation of ONHAs at the level of intercellular stimuli, intracellular signaling and core effectors. The analysis revealed that synergistic action of the transcription factors AP-1, vitamin D receptor and Nuclear Factor-kappaB in cross-activation of multiple pathways, including inflammatory cytokines, complement, clusterin, ephrins, and multiple metabolic pathways. We found that the products of over two thirds of genes linked to glaucoma by genetic analysis can be functionally interconnected into one epistatic network via experimentally-validated interactions. Finally, we built and analyzed an integrative disease pathology network from a combined set of genes revealed in genetic studies, genes differentially expressed in glaucoma and closely connected genes/proteins in the interactome.</p> <p>Conclusion</p> <p>Our results suggest several key biological network modules that are involved in regulating neurotoxicity of reactive astrocytes in glaucoma, and comprise potential targets for cell-based therapy.</p